Next Article in Journal
Usefulness of Clinical and Laboratory Criteria for Diagnosing Autoimmune Liver Disease among Patients with Systemic Lupus Erythematosus: An Observational Study
Previous Article in Journal
Hypertensive Hypoalgesia in a Complex Chronic Disease Population
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 10
Issue 17
10.3390/jcm10173819
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation

by
Young-Kook Kim
1 and
Juhyun Song
2,*
1
Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Korea
2
Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Jeollanam-do, Korea
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2021, 10(17), 3819; https://doi.org/10.3390/jcm10173819
Submission received: 26 July 2021 / Revised: 22 August 2021 / Accepted: 24 August 2021 / Published: 25 August 2021
(This article belongs to the Section Brain Injury)
Browse Figures
Versions Notes

Abstract

Hepatic encephalopathy is a common complication in patients with liver cirrhosis and portosystemic shunting. Patients with hepatic encephalopathy present a variety of clinical features, including neuropsychiatric manifestations, cognitive dysfunction, impaired gut barrier function, hyperammonemia, and chronic neuroinflammation. These pathogeneses have been linked to various factors, including ammonia-induced oxidative stress, neuronal cell death, alterations in the gut microbiome, astrocyte swelling, and blood-brain barrier disruptions. Many researchers have focused on identifying novel therapeutics and prebiotics in the hope of improving the treatment of these conditions. Resveratrol is a natural polyphenic compound and is known to exert several pharmacological effects, including antioxidant, anti-inflammatory, and neuroprotective activities. Recent studies suggest that resveratrol contributes to improving the neuropathogenic effects of liver failure. Here, we review the current evidence describing resveratrol’s effects in neuropathogenesis and its impact on the gut-liver axis relating to hepatic encephalopathy. We highlight the hypothesis that resveratrol exerts diverse effects in hepatic encephalopathy and suggest that these effects are likely mediated by changes to the gut microbiota, brain edema, and neuroinflammation.

Graphical Abstract

1. Introduction

Hepatic encephalopathy (HE) is a type of liver failure affecting up to 40% of all liver cirrhosis patients [1], and epidemiological studies have shown that the prevalence of HE is gradually increasing all over the world [2,3]. A recent study identified HE as an impairment of the brain function caused by liver failure and portosystemic blood shunting, characterized by emotional impairment, cognitive dysfunction, psychiatric problems, and neuromuscular dysfunction [4,5]. Moreover, the patients with HE present impaired visual temporal perception [6] and impaired tactile temporal discrimination [7].
HE pathogenesis is linked to poor glucose utilization, impaired cerebral energy metabolism, mitochondrial dysfunction, oxidative stress, and high levels of ammonia [8,9]. Clinically, HE is mainly divided into overt HE and minimal HE [10]. Overt HE patients can be diagnosed through several symptoms and are present in almost 30% of patients with liver cirrhosis, whereas minimal HE patients can be diagnosed based on impairment in specialized tests and are considered as patients of a preclinical stage of overt HE [10,11]. Over 60% of patients with minimal HE suffer from cognitive dysfunction, which leads to poor life quality [10].
Although many researchers have tried to identify natural products with some therapeutic effect on HE to reduce the therapeutic side effects, there are still no approved natural compounds for the treatment of this condition.
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a natural antioxidant polyphenol and is synthesized by various plants, including peanuts, berries, and grapes [12,13]. Resveratrol has been reported to exert anti-inflammatory, antiviral, and antioxidant effects in cells and has been shown to reduce oxidative stress-related cell damage [14,15,16]. Resveratrol acts as a reactive oxygen species (ROS) scavenger during oxidative stress and boosts the antioxidant enzyme activity [17]. Resveratrol regulates multiple cellular activities via its interactions with silent mating type information regulation 2 homolog 1 (SIRT1) [18]. SIRTs have been shown to be affected by resveratrol and are known to have a relationship with cellular energy metabolism, mitochondrial function, and cellular longevity [19], and a neuroprotective response [20]. One study observed that the treatment of embryonic stem cells with resveratrol resulted in an improved DNA repair when faced with DNA-damaging conditions [21], suggesting the potential of resveratrol to protect the tissue against ionizing radiation-induced damage [22]. In the brain, the expression of SIRT1 is widely observed in diverse neuronal nuclei and is commonly found in glia, neural stem cells, mature neuron [23], hypothalamus related with mood [24], and a suprachiasmatic nucleus related with sleep pattern [25]. A recent study mentioned that resveratrol-mediated SIRT1 activation reduces apical dendrite damage in hippocampal pyramidal neurons and enhances neurobehavioral impairment in HE rats [26].
In the central nervous system (CNS), resveratrol has been shown to exert neuroprotective effects in neurodegenerative disease models such as dementia [27] and depression [15,28]. Resveratrol, which is a lipophilic compound, crosses the blood-brain barrier (BBB) and enters the brain after intraperitoneal injection [29,30], ultimately influencing various neurological mechanisms within these tissues [31]. The resveratrol-mediated activation of the SIRT1 gene induces increased ROS scavenging and ultimately improves cognitive function [32,33]. Although a meta-analysis study suggested that resveratrol has no significant effect on cognitive function [34], another meta-analysis study indicated that oral resveratrol treatment improves some cognitive performances in subjects [35]. Based on these reports, the effect of resveratrol on cognitive improvement has so far been controversial [36].
Here, we review significant pieces of evidence relating to the therapeutic effects of resveratrol in HE. We summarize the therapeutic potential of resveratrol in HE from several points of view, including its impact on the microbiota, brain edema, and inflammation.

2. Resveratrol and HE

HE is a metabolic brain disorder associated with progressive liver failure and is characterized by neurological problems including brain edema which result in a variety of cognitive dysfunctions, such as attention deficit, motor dysfunction, memory impairment, emotional problems [37,38,39]. HE pathology is commonly reported in patients with liver cirrhosis and transjugular intrahepatic portosystemic shunts [40,41]. HE demonstrates several central features, including elevated levels of ammonia in the circulation and brain tissues, often referred to as hyperammonemia [42]. This hyperammonemia is a direct result of the disruption of the ammonia metabolism in the diseased liver [43,44]. HE has also been linked to imbalances in excitatory and inhibitory neurotransmitters such as GABA and glutamate and to the inactivation of neurotransmitter receptors [45,46]. In addition, HE leads to severe neuroinflammation, glial activation, and glial polarization in the brain, triggering increased oxidative stress [47]. HE aggravates neuronal dysfunction, inhibits the interactions between the neurons and glia [48,49], and may disrupt the BBB and induce cerebral edema [50,51,52] (Figure 1B,C).
Resveratrol is one of the polyphenols produced by berries and grapes [13] and has been known to exert several different cellular effects [15,16]. The addition of resveratrol has been reported to reduce the proliferation of liver myofibroblasts [53] and inhibit the over-accumulation of triacylglycerols through the activation of the AMP-activated protein kinase (AMPK) pathway in the liver cancer cell line [54]. It has also been reported that resveratrol treatment suppresses the growth of hepatic stellate cells [55] and induces the apoptosis of hepatic cancer cells [56]. Other studies have shown that resveratrol blocked the hydroquinone-induced cellular apoptosis of primary hepatocytes [57] and inhibited cellular oxidative stress responses in hepatocytes via its activation of catalase and glutathione peroxidase in these cells [58].
Resveratrol reverses the ethanol-induced impairment of energy homeostasis in the liver by increasing the ATP production in cellular mitochondria [59]. One study suggests that a resveratrol injection contributes to a normal liver function in liver-transplanted rats [60]. Another study reported that resveratrol improves hepatic glucose metabolism and insulin activity in the liver through the activation of several signaling pathways, including insulin receptor substrate 1 signaling, AKT phosphorylation signaling, and the peroxisome proliferating activation receptor-γ coactivator 1α pathway [61]. In addition, resveratrol supplementation reduced lipid peroxidation and increased the antioxidant enzyme activity in the liver [62], and a previous study mentioned that resveratrol treatment prevents cholestatic liver injury and induces hepatic regeneration after bile duct ligation [63]. One experimental study indicated that resveratrol reduces the amount of superoxide anions and the expression of inflammatory mediators while increasing antioxidant enzymes in response to lipopolysaccharide-induced hepatotoxicity [64].
Taken together, these reports suggest that resveratrol improves various liver dysfunctions. Although there are many types of liver failure, the discovery of efficient HE treatments has been particularly difficult because the onset and progression of HE are broad, systemic, and gradual, and largely facilitated by the brain–liver axis. This means that it is critical to identify an effective treatment for HE, and the current data suggest that resveratrol may be a promising candidate for these therapeutic interventions. Below, we discuss this point with a focus on the effects of resveratrol on the gut microbiota, brain edema, and neuroinflammation associated with HE.

3. Resveratrol and the Microbiome in HE

There are over 100 quintillion microorganisms in the gut, including bacteria and viruses, and its epithelium is considered the primary immune barrier against bacterial toxins [65,66]. The gut microbiome is a complicated system with a mass of approximately 1 kg per person [67]. In general, the human gut microbiota is divided into four main categories, including Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria [68]. The gut microbiota act as protectants against pathogens and maintain a healthy immune homeostasis while also helping to facilitate digestion [69,70,71].
The gut and liver are connected via the portal vein, biliary tract, and systemic blood circulation [72]. Abnormal gut microbiota influence liver function via their connected network [73]. Patients with liver cirrhosis have presented a reduction in the expression of genes associated with the metabolism of various nutrients, such as amino acids and nucleotides [74]. Endotoxins and toxic molecules from the gut are transferred to the portal vein and may ultimately trigger the activation of inflammatory signaling in the liver [67]. Plasma endotoxin levels are increased in association with the progression of liver cirrhosis [75].
Breakdowns in the gut barrier function contribute to liver failure by worsening the intestinal mucosal damage [76,77]. Dysbiosis, described by changes in the microbial community, is often caused by changes in the number and composition of the microbial communities in the gut [78]. Dysbiosis results in gut barrier impairment through the inactivation of the epithelial mucosal repair system and is common to a variety of inflammatory diseases [78,79]. The alteration of the gut microbiome is known to be a critical component in the pathogenesis and progression of liver cirrhosis, hepato-renal diseases, and HE [80,81] (Figure 2).
Several studies have demonstrated that the gut microbiome in liver cirrhosis patients presents with a decreased abundance of autochthonous bacteria such as Subdoligranulum and an increased abundance of pathogenic bacteria such as Enterococcus, Dialister, and Prevotella compared to the normal gut [82,83]. In addition, a recent study mentioned that the increase in ammonia accumulation associated with HE is strongly linked to the imbalances in the gut microbiota of these patients [84]. Interestingly, one study suggested that specific microbiota-based biomarkers could be used as a diagnostic factor for liver cirrhosis [85].
Probiotics, prebiotics, and natural compounds could promote the growth of beneficial microbes and the reduction of harmful microbes [86] in the gut of patients with liver failure [87,88,89,90]. One recent study tried to use a mixture of probiotics to treat HE pathogenesis by improving the health of the gut microbiota [91]. Several HE studies have shown that there are a number of probiotics and prebiotics, including lactulose, which can modulate the gut microbiota by reducing the intraluminal pH and decreasing the ammonia concentration, leading to improvements in the gut epithelium [92,93,94].
Resveratrol can modulate the gut microbiota by decreasing the levels of Bacteroides, Alistipes, Odoribacter, and Parabacteroides and improving the gut epithelial protection against the metabolic imbalances associated with dysbiosis in diabetes knock-out mice [95]. Another study showed that resveratrol treatment reduced the proportion of harmful bacteria such as Desulfovibrio and Lachnospiraceae in the guts of animals with hepatic steatosis [96], and Bilophila and Ruminococcus in the guts of animals with high fat diet-induced metabolic imbalance conditions [97]. Other studies mention that resveratrol helps the gut to maintain the gut barrier integrity and function and inhibits inflammation in the gut [98,99] (Figure 2).
Based on these findings, we assume that resveratrol could help to reduce harmful gut microbes in patients with HE, thus supporting the suggestion that resveratrol has therapeutic potential for HE and that its therapeutic effect might be mediated by improvements in the gut microbiome and gut barrier function following metabolic imbalance.

4. Resveratrol and Brain Edema in HE

Brain edema is defined as an excessive accumulation of water in the intra- and extracellular spaces in the brain and is a common feature in HE [100]. Vasogenic edema leads to the breakdown of the BBB via the loss of tight junction proteins and raises the intracranial pressure [101], while cytosolic edema increases BBB permeability via the intracellular swelling of the astrocytes and also increases brain volume [102]. Cytotoxic edema triggers an increase in the water permeability of the cell membrane via changes in the expression of water transport membrane proteins such as aquaporins [103]. This is especially true for aquaporin 4 (AQP4), which is the most common water channel protein in the CNS and is found in high quantities in both the perivascular area and astrocyte end-feet [103].
Astrocytes function as a component of the BBB and exhibit a higher capacity for water permeability than the other parts of the BBB [104]. Their swelling is commonly associated with the regulation of osmo-intracellular pathways such as calcium signaling and the alteration of aquaporin protein expression in the water transport and ion channels [104,105,106,107]. Increases in the expression of aquaporins, such as AQP4, correlate with the progression of brain edema [108,109]. The majority of HE-associated brain edema cases can be described as cytosolic edema and are closely associated with astrocyte swelling [110,111]. Many acute HE patients demonstrate brain edema accompanied by intracranial pressure increases [110,111], and some studies have linked the excessive brain edema associated with liver failure models to changes in the regulation of the brain tissues [100,112,113].
Therefore, the modulation of the water permeability in HE brains is an important consideration for therapeutic intervention, as this edema often determines the degree of neuropathological damage in these tissues. Resveratrol has been known to ameliorate ischemic brain edema through the inhibition of AQP4 expression [114] (Figure 1A). In addition, resveratrol suppresses cerebral edema by inhibiting the Na+ channel-related SUR1 expression in the brain and subsequently influences osmotic cell swelling [115]. Further, SIRT1 activation following the addition of resveratrol decreased BBB breakdown by protecting against the loss of tight junction proteins through improved SIRT1/p53 signaling and ultimately decreased brain edema [116]. Another study showed that the intra-arterial administration of resveratrol exerted a beneficial effect on cerebral ischemic edema in rats [117].
A recent study demonstrated that resveratrol could alleviate astrocyte swelling in response to ammonia-induced oxidative stress [118]. In this study, however, it was also shown that resveratrol can enhance ammonia-induced cell swelling under certain concentrations. Thus, caution is recommended when resveratrol is used for the treatment of the neurological conditions associated with brain edema. Therefore, more studies are required to confirm the beneficial role of resveratrol on brain edema.
Matrix metalloproteinase (MMP) is a key extracellular matrix component responsible for the maintenance of the BBB [119,120]. Resveratrol suppresses the increased expression of MMP linked to the occurrence of cerebral edema events [121]. Resveratrol was also shown to maintain BBB integrity by controlling the MMP-9/TIMP-1 balance after cerebral ischemia-reperfusion in rats [122]. This protective effect was then confirmed again in an additional study using an animal model of cerebral ischemic injury [123]. It was also reported that resveratrol reduces the level of MMP-9 in the BBB and blocks BBB disruption [124,125]. In addition, resveratrol pre-treatment improved BBB breakdown via its interactions with the YAP/TAZ signaling pathway in the brain [126], Moreover, resveratrol protected BBB integrity and improved cognitive function in AD rats [127]. A recent study demonstrated that resveratrol restores the tight junction protein expression in the BBB and helps to inhibit severe neuropathology in response to hyperammonemia in mice with liver cirrhosis [128].
Given these data, we surmise that resveratrol may prevent brain edema by protecting the BBB and facilitating the maintenance of its integrity. Although more studies are required to prove the safety of using resveratrol for the treatment of brain edema, many studies emphasize the fact that resveratrol could be used as an inhibitor of brain edema in response to HE.

5. Resveratrol and Ammonia-Induced Neuroinflammation in HE

Ammonia (NH3 and NH4+) is a critical factor in several important cellular functions in the CNS, including the secretion of excitatory and inhibitory neurotransmitters [129], mitochondrial permeability [130,131], ion homeostasis [132], inflammatory responses [133], and oxidative stress [134,135]. Ammonia is the critical factor in the development of HE, and a high level of these ions (hyperammonemia) leads to astrocyte swelling [107], BBB breakdown [136], high levels of ROS [137], neuronal cell death [138], energy deficits [139], glutamine synthetase inactivity [132,140], nitrogen species production [141], and impaired cognition [142]. The redox imbalance caused by a high level of ammonia induces the oxidation of many biomolecules and the inactivation of the antioxidant enzymes [141]. In HE, hyperammonemia triggers oxidative stress and the excessive generation of ROS, inducing various neuroinflammatory responses [143,144], accelerating the activation of the microglia and astrocytes, and amplifying neuroinflammation [142,145,146] (Figure 1B).
Resveratrol has been shown to alleviate the brain damage associated with hepatic ischemic stress by decreasing the activity of aminotransferase [147] and reducing the expression of interleukin (IL)-1 beta and IL-6 [148]. Recent studies also suggest that a supplementation with resveratrol inhibits mitochondrial dysfunction in response to increased levels of ammonia and improves cellular redox in astrocytes affected by ammonia-mediated toxicity [149,150]. Another study showed that resveratrol suppresses ammonia levels in the brain and prevents the severe exacerbation of HE from increased liver cirrhosis [128]. Some studies mention that resveratrol inhibits DNA damage in the neurons and protects against cell death in response to ammonia toxicity [151,152]. Another study suggested that resveratrol promotes DNA repair in response to oxidative stress [153].
Additionally, resveratrol treatment improved the antioxidant capacity and induced mitochondrial biogenesis during oxidative stress [154]. Resveratrol can also prevent neuronal damage during ammonia-induced oxidative stress [8]. Given these data, we can conclude that resveratrol has strong potential as a treatment for HE and that this therapeutic effect is likely mediated, at least in some part, by its inhibition of the inflammatory response and the inhibition of neuronal damage.

6. Conclusions

Here, we reviewed the therapeutic potential of resveratrol in the treatment of HE, focusing on gut microbiota, brain edema, and neuroinflammation. Our review supports the assertion that resveratrol is beneficial in reducing harmful gut microbes and maintaining the gut barrier integrity in response to metabolic imbalances. It also demonstrates that resveratrol reduces brain edema via the regulation of both water permeability in the BBB and astrocyte swelling. Finally, these data clearly show that resveratrol alleviates neuroinflammatory responses by activating antioxidant enzymes and inhibiting DNA damage in response to oxidative stress. Given the fact that previous clinical studies have tried to use resveratrol supplementation as a treatment in liver injury [155,156,157], we also emphasize the therapeutic potential of resveratrol in liver failure and suggest that resveratrol therapy may be a promising clinical approach for HE. A recent study demonstrating the improvement in the neuropathology of HE patients treated with resveratrol further supports these observations [158].
However, we also note that there are still debates on the use of resveratrol for therapeutic purposes. One of the issues is the low bioavailability of resveratrol [159]. Moreover, there is another issue related to ammonia-induced cell swelling under certain concentrations, as described above [118]. Moreover, there were meta-analyses suggesting that the effect of resveratrol on the cognitive effects of the human brain may be limited [35,36]. Although more studies are required to scrutinize these points, resveratrol is still expected to be a promising candidate for the treatment of HE, according to its diverse effects related to HE described in this review.
Taken together, this review emphasizes that resveratrol has multiple therapeutic potentials for the treatment of HE. Since the effects and mechanisms of resveratrol in HE patients are not fully elucidated, further studies need to be undertaken to help explain the specific mechanism underlying the therapeutic effects of resveratrol in HE patients. Given that resveratrol is a natural compound, we suggest that resveratrol may be a promising agent with fewer side effects for the treatment of HE.

Author Contributions

J.S. collected references and wrote the first draft. Y.-K.K. prepared the figures. Y.-K.K. and J.S. revised the draft. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education (grant number: NRF-2019R1F1A1054111 to J.S.), and an NRF grant funded by the Korean government (MSIT) (grant number: NRF-2021R1A2B5B02001501 to Y-K.K.).

Conflicts of Interest

The authors have no conflict of interest to declare.

References

  1. Bajaj, J.S. Hepatic encephalopathy: Classification and treatment. J. Hepatol. 2018, 68, 838–839. [Google Scholar] [CrossRef] [PubMed]
  2. Patidar, K.R.; Bajaj, J.S. Covert and Overt Hepatic Encephalopathy: Diagnosis and Management. Clin. Gastroenterol. Hepatol. 2015, 13, 2048–2061. [Google Scholar] [CrossRef] [PubMed]
  3. Elsaid, M.I.; Rustgi, V.K. Epidemiology of Hepatic Encephalopathy. Clin. Liver Dis. 2020, 24, 157–174. [Google Scholar] [CrossRef] [PubMed]
  4. Montagnese, S.; Russo, F.P.; Amodio, P.; Burra, P.; Gasbarrini, A.; Loguercio, C.; Marchesini, G.; Merli, M.; Ponziani, F.R.; Riggio, O.; et al. Hepatic encephalopathy 2018: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig. Liver Dis. 2019, 51, 190–205. [Google Scholar] [CrossRef]
  5. Yanny, B.; Winters, A.; Boutros, S.; Saab, S. Hepatic Encephalopathy Challenges, Burden, and Diagnostic and Therapeutic Approach. Clin. Liver Dis. 2019, 23, 607–623. [Google Scholar] [CrossRef]
  6. Kircheis, G.; Wettstein, M.; Timmermann, L.; Schnitzler, A.; Häussinger, D. Critical flicker frequency for quantification of low-grade hepatic encephalopathy. Hepatology 2002, 35, 357–366. [Google Scholar] [CrossRef]
  7. Lazar, M.; Butz, M.; Baumgarten, T.J.; Füllenbach, N.-D.; Jördens, M.S.; Häussinger, D.; Schnitzler, A.; Lange, J. Impaired Tactile Temporal Discrimination in Patients With Hepatic Encephalopathy. Front. Psychol. 2018, 9, 2059. [Google Scholar] [CrossRef]
  8. Bobermin, L.D.; Wartchow, K.M.; Flores, M.P.; Leite, M.C.; Quincozes-Santos, A.; Gonçalves, C.-A. Ammonia-induced oxidative damage in neurons is prevented by resveratrol and lipoic acid with participation of heme oxygenase 1. NeuroToxicology 2015, 49, 28–35. [Google Scholar] [CrossRef]
  9. Häussinger, D.; Butz, M.; Schnitzler, A.; Görg, B. Pathomechanisms in hepatic encephalopathy. Biol. Chem. 2021, 402, 1087–1102. [Google Scholar] [CrossRef]
  10. Bajaj, J.S. Review article: The modern management of hepatic encephalopathy. Aliment. Pharmacol. Ther. 2010, 31, 537–547. [Google Scholar] [CrossRef]
  11. Riggio, O.; Ridola, L.; Pasquale, C.; Pentassuglio, I.; Nardelli, S.; Moscucci, F.; Merli, M.; Montagnese, S.; Amodio, P.; Merkel, C. A Simplified Psychometric Evaluation for the Diagnosis of Minimal Hepatic Encephalopathy. Clin. Gastroenterol. Hepatol. 2011, 9, 613–616.e1. [Google Scholar] [CrossRef]
  12. Baur, J.; Sinclair, D. Therapeutic potential of resveratrol: The in vivo evidence. Nat. Rev. Drug Discov. 2006, 5, 493–506. [Google Scholar] [CrossRef]
  13. Carrizzo, A.; Forte, M.; Damato, A.; Trimarco, V.; Salzano, F.; Bartolo, M.; Maciag, A.; Puca, A.A.; Vecchione, C. Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem. Toxicol. 2013, 61, 215–226. [Google Scholar] [CrossRef] [PubMed]
  14. Švajger, U.; Jeras, M. Anti-inflammatory Effects of Resveratrol and Its Potential Use in Therapy of Immune-mediated Diseases. Int. Rev. Immunol. 2012, 31, 202–222. [Google Scholar] [CrossRef]
  15. Pennisi, M.; Bertino, G.; Gagliano, C.; Malaguarnera, M.; Bella, R.; Borzì, A.M.; Madeddu, R.; Drago, F.; Malaguarnera, G. Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-α-2b and Ribavirin Reduces Sleep Disturbance. Nutrients 2017, 9, 897. [Google Scholar] [CrossRef]
  16. Salehi, B.; Mishra, A.P.; Nigam, M.; Sener, B.; Kilic, M.; Sharifi-Rad, M.; Fokou, P.V.T.; Martins, N.; Sharifi-Rad, J. Resveratrol: A Double-Edged Sword in Health Benefits. Biomedicines 2018, 6, 91. [Google Scholar] [CrossRef] [PubMed]
  17. Truong, V.-L.; Jun, M.; Jeong, W.-S. Role of resveratrol in regulation of cellular defense systems against oxidative stress. BioFactors 2017, 44, 36–49. [Google Scholar] [CrossRef] [PubMed]
  18. Borra, M.T.; Smith, B.; Denu, J.M. Mechanism of Human SIRT1 Activation by Resveratrol. J. Biol. Chem. 2005, 280, 17187–17195. [Google Scholar] [CrossRef] [PubMed]
  19. Krishnan, V.; Nestler, E.J. The molecular neurobiology of depression. Nature 2008, 455, 894–902. [Google Scholar] [CrossRef] [PubMed]
  20. Zhang, F.; Wang, S.; Gan, L.; Vosler, P.S.; Gao, Y.; Zigmond, M.J.; Chen, J. Protective effects and mechanisms of sirtuins in the nervous system. Prog. Neurobiol. 2011, 95, 373–395. [Google Scholar] [CrossRef] [PubMed]
  21. Denissova, N.G.; Nasello, C.M.; Yeung, P.L.; Tischfield, J.; Brenneman, M.A. Resveratrol protects mouse embryonic stem cells from ionizing radiation by accelerating recovery from DNA strand breakage. Carcinogenesis 2011, 33, 149–155. [Google Scholar] [CrossRef]
  22. Agbele, A.T.; Fasoro, O.J.; Fabamise, O.M.; Oluyide, O.O.; Idolor, O.R.; Bamise, E.A. Protection Against Ionizing Radiation-Induced Normal Tissue Damage by Resveratrol: A Systematic Review. Eurasian J. Med. 2020, 52, 298–303. [Google Scholar] [CrossRef] [PubMed]
  23. Perez-Pinzon, M.A.; Koronowski, K. Sirt1 in cerebral ischemia. Brain Circ. 2015, 1, 69–78. [Google Scholar] [CrossRef] [PubMed]
  24. Ramadori, G.; Lee, C.E.; Bookout, A.L.; Lee, S.; Williams, K.; Anderson, J.; Elmquist, J.K.; Coppari, R. Brain SIRT1: Anatomical Distribution and Regulation by Energy Availability. J. Neurosci. 2008, 28, 9989–9996. [Google Scholar] [CrossRef]
  25. Asher, G.; Gatfield, D.; Stratmann, M.; Reinke, H.; Dibner, C.; Kreppel, F.; Mostoslavsky, R.; Alt, F.W.; Schibler, U. SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation. Cell 2008, 134, 317–328. [Google Scholar] [CrossRef]
  26. Khanna, A.; Anamika; Chakraborty, S.; Tripathi, S.J.; Acharjee, A.; Bs, S.R.; Trigun, S.K. SIRT1 activation by resveratrol reverses atrophy of apical dendrites of hippocampal CA1 pyramidal neurons and neurobehavioral impairments in moderate grade hepatic encephalopathy rats. J. Chem. Neuroanat. 2020, 106, 101797. [Google Scholar] [CrossRef]
  27. Lange, K.W.; Li, S. Resveratrol, pterostilbene, and dementia. Biofactors 2018, 44, 83–90. [Google Scholar] [CrossRef]
  28. Moore, A.; Beidler, J.; Hong, M.Y. Resveratrol and Depression in Animal Models: A Systematic Review of the Biological Mechanisms. Molecules 2018, 23, 2197. [Google Scholar] [CrossRef] [PubMed]
  29. Virgili, M.; Contestabile, A. Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci. Lett. 2000, 281, 123–126. [Google Scholar] [CrossRef]
  30. Wang, Q.; Xu, J.; Rottinghaus, G.E.; Simonyi, A.; Lubahn, D.; Sun, G.Y.; Sun, A.Y. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res. 2002, 958, 439–447. [Google Scholar] [CrossRef]
  31. Hu, J.; Han, H.; Cao, P.; Yu, W.; Yang, C.; Gao, Y.; Yuan, W. Resveratrol improves neuron protection and functional recovery through enhancement of autophagy after spinal cord injury in mice. Am. J. Transl. Res. 2017, 9, 4607–4616. [Google Scholar] [PubMed]
  32. Michán, S.; Li, Y.; Chou, M.M.-H.; Parrella, E.; Ge, H.; Long, J.M.; Allard, J.S.; Lewis, K.; Miller, M.; Xu, W.; et al. SIRT1 Is Essential for Normal Cognitive Function and Synaptic Plasticity. J. Neurosci. 2010, 30, 9695–9707. [Google Scholar] [CrossRef]
  33. Cao, Y.; Yan, Z.; Zhou, T.; Wang, G. SIRT1 Regulates Cognitive Performance and Ability of Learning and Memory in Diabetic and Nondiabetic Models. J. Diabetes Res. 2017, 2017, 1–11. [Google Scholar] [CrossRef] [PubMed]
  34. Farzaei, M.H.; Rahimi, R.; Nikfar, S.; Abdollahi, M. Effect of resveratrol on cognitive and memory performance and mood: A meta-analysis of 225 patients. Pharmacol. Res. 2018, 128, 338–344. [Google Scholar] [CrossRef] [PubMed]
  35. Marx, W.; Kelly, J.; Marshall, S.; Cutajar, J.; Annois, B.; Pipingas, A.; Tierney, A.; Itsiopoulos, C. Effect of resveratrol supplementation on cognitive performance and mood in adults: A systematic literature review and meta-analysis of randomized controlled trials. Nutr. Rev. 2018, 76, 432–443. [Google Scholar] [CrossRef]
  36. Khorshidi, F.; Poljak, A.; Liu, Y.; Lo, J.W.; Crawford, J.D.; Sachdev, P.S. Resveratrol: A “miracle” drug in neuropsychiatry or a cognitive enhancer for mice only? A systematic review and meta-analysis. Ageing Res. Rev. 2020, 65, 101199. [Google Scholar] [CrossRef]
  37. Ferenci, P. Hepatic encephalopathy. Gastroenterol. Rep. 2017, 5, 138–147. [Google Scholar] [CrossRef]
  38. Wijdicks, E.F. Hepatic Encephalopathy. N. Engl. J. Med. 2016, 375, 1660–1670. [Google Scholar] [CrossRef]
  39. Weiss, N.; Jalan, R.; Thabut, M. Understanding hepatic encephalopathy. Intensiv. Care Med. 2017, 44, 231–234. [Google Scholar] [CrossRef]
  40. Poordad, F.F. Review article: The burden of hepatic encephalopathy. Aliment. Pharmacol. Ther. 2007, 25, 3–9. [Google Scholar] [CrossRef]
  41. Montgomery, J.Y.; Bajaj, J.S. Advances in the Evaluation and Management of Minimal Hepatic Encephalopathy. Curr. Gastroenterol. Rep. 2010, 13, 26–33. [Google Scholar] [CrossRef] [PubMed]
  42. Felipo, V.; Urios, A.; Montesinos, E.; Molina, I.; Garcia-Torres, M.L.; Civera, M.; Olmo, J.A.D.; Ortega, J.; Martinez-Valls, J.; Serra, M.A.; et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab. Brain Dis. 2011, 27, 51–58. [Google Scholar] [CrossRef]
  43. Shawcross, D.L.; Shabbir, S.S.; Taylor, N.J.; Hughes, R.D. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010, 51, 1062–1069. [Google Scholar] [CrossRef] [PubMed]
  44. Sawhney, R.; Holland-Fischer, P.; Rosselli, M.; Mookerjee, R.; Agarwal, B.; Jalan, R. Role of ammonia, inflammation, and cerebral oxygenation in brain dysfunction of acute-on-chronic liver failure patients. Liver Transplant. 2016, 22, 732–742. [Google Scholar] [CrossRef] [PubMed]
  45. Albrecht, J.; Jones, E. Hepatic encephalopathy: Molecular mechanisms underlying the clinical syndrome. J. Neurol. Sci. 1999, 170, 138–146. [Google Scholar] [CrossRef]
  46. Limón, I.D.; Angulo-Cruz, I.; Sánchez-Abdon, L.; Patricio-Martínez, A. Disturbance of the Glutamate-Glutamine Cycle, Secondary to Hepatic Damage, Compromises Memory Function. Front. Neurosci. 2021, 15, 578922. [Google Scholar] [CrossRef]
  47. Martinez, R.G.; Córdoba, J. Acute-on-chronic liver failure: The brain. Curr. Opin. Crit. Care 2011, 17, 177–183. [Google Scholar] [CrossRef] [PubMed]
  48. Albrecht, J.; Faff, L. Astrocyte-Neuron Interactions in Hyperammonemia and Hepatic Encephalopathy. Adv. Exp. Med. Biol. 1994, 368, 45–54. [Google Scholar] [CrossRef] [PubMed]
  49. Benarroch, E.E. Neuron-Astrocyte Interactions: Partnership for Normal Function and Disease in the Central Nervous System. Mayo Clin. Proc. 2005, 80, 1326–1338. [Google Scholar] [CrossRef] [PubMed]
  50. Nguyen, J.H.; Yamamoto, S.; Steers, J.; Sevlever, D.; Lin, W.; Shimojima, N.; Castanedes-Casey, M.; Genco, P.; Golde, T.; Richelson, E.; et al. Matrix metalloproteinase-9 contributes to brain extravasation and edema in fulminant hepatic failure mice. J. Hepatol. 2006, 44, 1105–1114. [Google Scholar] [CrossRef]
  51. Cauli, O.; López–Larrubia, P.; Rodrigo, R.; Agusti, A.; Boix, J.; Nieto–Charques, L.; Cerdán, S.; Felipo, V. Brain Region-Selective Mechanisms Contribute to the Progression of Cerebral Alterations in Acute Liver Failure in Rats. Gastroenterology 2011, 140, 638–645. [Google Scholar] [CrossRef]
  52. Lv, S.; Song, H.-L.; Zhou, Y.; Li, L.-X.; Cui, W.; Wang, W.; Liu, P. Tumour necrosis factor-α affects blood-brain barrier permeability and tight junction-associated occludin in acute liver failure. Liver Int. 2010, 30, 1198–1210. [Google Scholar] [CrossRef]
  53. Godichaud, S.; Krisa, S.; Couronné, B.; Dubuisson, L.; Mérillon, J.-M.; Desmoulière, A.; Rosenbaum, J. Deactivation of cultured human liver myofibroblasts byTrans-resveratrol, a grapevine-derived polyphenol. Hepatology 2000, 31, 922–931. [Google Scholar] [CrossRef]
  54. Shang, J.; Chen, L.-L.; Xiao, F.-X.; Sun, H.; Ding, H.-C.; Xiao, H. Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol. Sin. 2008, 29, 698–706. [Google Scholar] [CrossRef]
  55. Souza, I.C.; Martins, L.A.M.; Coelho, B.P.; Grivicich, I.; Guaragna, R.M.; Gottfried, C.; Borojevic, R.; Guma, F.C.R. Resveratrol inhibits cell growth by inducing cell cycle arrest in activated hepatic stellate cells. Mol. Cell. Biochem. 2008, 315, 1–7. [Google Scholar] [CrossRef] [PubMed]
  56. Choi, H.Y.; Chong, S.A.; Nam, M.J. Resveratrol induces apoptosis in human SK-HEP-1 hepatic cancer cells. Cancer Genom. Proteom. 2009, 6, 263–268. [Google Scholar]
  57. Wang, D.-H.; Ootsuki, Y.; Fujita, H.; Miyazaki, M.; Yie, Q.; Tsutsui, K.; Sano, K.; Masuoka, N.; Ogino, K. Resveratrol Inhibited Hydroquinone-Induced Cytotoxicity in Mouse Primary Hepatocytes. Int. J. Environ. Res. Public Health 2012, 9, 3354–3364. [Google Scholar] [CrossRef] [PubMed]
  58. Rubiolo, J.A.; Mithieux, G.; Vega, F.V. Resveratrol protects primary rat hepatocytes against oxidative stress damage: Activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur. J. Pharmacol. 2008, 591, 66–72. [Google Scholar] [CrossRef] [PubMed]
  59. Gallis, J.-L.; Serhan, N.; Gin, H.; Couzigou, P.; Beauvieux, M.-C. Resveratrol plus ethanol counteract the ethanol-induced impairment of energy metabolism: 31P NMR study of ATP and sn-glycerol-3-phosphate on isolated and perfused rat liver. Pharmacol. Res. 2012, 65, 387–395. [Google Scholar] [CrossRef]
  60. Wu, S.-L.; Yu, L.; Pan, C.-E.; Jiao, X.-Y.; Lv, Y.; Fu, J.; Meng, K.-W. Apoptosis of lymphocytes in allograft in a rat liver transplantation model induced by resveratrol. Pharmacol. Res. 2006, 54, 19–23. [Google Scholar] [CrossRef]
  61. Burgess, T.A.; Robich, M.P.; Chu, L.M.; Bianchi, C.; Sellke, F.W. Improving glucose metabolism with resveratrol in a swine model of metabolic syndrome through alteration of signaling pathways in the liver and skeletal muscle. Arch. Surg. 2011, 146, 556–564. [Google Scholar] [CrossRef]
  62. Farghali, H.; Černý, D.; Kameníková, L.; Martínek, J.; Horinek, A.; Kmoníčková, E.; Zídek, Z. Resveratrol attenuates lipopolysaccharide-induced hepatitis in d-galactosamine sensitized rats: Role of nitric oxide synthase 2 and heme oxygenase-1. Nitric Oxide 2009, 21, 216–225. [Google Scholar] [CrossRef]
  63. Chan, C.-C.; Cheng, L.-Y.; Lin, C.-L.; Huang, Y.-H.; Lin, H.-C.; Lee, F.-Y. The protective role of natural phytoalexin resveratrol on inflammation, fibrosis and regeneration in cholestatic liver injury. Mol. Nutr. Food Res. 2011, 55, 1841–1849. [Google Scholar] [CrossRef]
  64. Sebai, H.; Sani, M.; Yacoubi, M.T.; Aouani, E.; Ghanem-Boughanmi, N.; Ben-Attia, M. Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver. Ecotoxicol. Environ. Saf. 2010, 73, 1078–1083. [Google Scholar] [CrossRef] [PubMed]
  65. MacPherson, A.J.; Geuking, M.B.; McCoy, K.D. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria. Immunology 2005, 115, 153–162. [Google Scholar] [CrossRef] [PubMed]
  66. Sender, R.; Fuchs, S.; Milo, R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell 2016, 164, 337–340. [Google Scholar] [CrossRef] [PubMed]
  67. Suk, K.T.; Kim, D.J. Gut microbiota: Novel therapeutic target for nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 2019, 13, 193–204. [Google Scholar] [CrossRef] [PubMed]
  68. Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C.; Rinninella, E.; Raoul, P.; Cintoni, M.; et al. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms 2019, 7, 14. [Google Scholar] [CrossRef] [PubMed]
  69. Wu, H.-J.; Wu, E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012, 3, 4–14. [Google Scholar] [CrossRef]
  70. Ubeda, C.; Djukovic, A.; Isaac, S. Roles of the intestinal microbiota in pathogen protection. Clin. Transl. Immunol. 2017, 6, e128. [Google Scholar] [CrossRef]
  71. Lynch, S.V.; Pedersen, O. The Human Intestinal Microbiome in Health and Disease. N. Engl. J. Med. 2016, 375, 2369–2379. [Google Scholar] [CrossRef]
  72. Tripathi, A.; Debelius, J.; Brenner, D.A.; Karin, M.; Loomba, R.; Schnabl, B.; Knight, R. The gut–liver axis and the intersection with the microbiome. Nat. Rev. Gastroenterol. Hepatol. 2018, 15, 397–411. [Google Scholar] [CrossRef]
  73. Ji, Y.; Yin, Y.; Sun, L.; Zhang, W. The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement. Int. J. Mol. Sci. 2020, 21, 3066. [Google Scholar] [CrossRef] [PubMed]
  74. Chen, Y.; Qin, N.; Guo, J.; Qian, G.; Fang, D.; Shi, D.; Xu, M.; Yang, F.; He, Z.; Van Nostrand, J.D.; et al. Functional gene arrays-based analysis of fecal microbiomes in patients with liver cirrhosis. BMC Genom. 2014, 15, 1–13. [Google Scholar] [CrossRef][Green Version]
  75. Fukui, H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J. Hepatol. 2015, 7, 425–442. [Google Scholar] [CrossRef]
  76. Arab, J.P.; Martin-Mateos, R.; Shah, V.H. Gut–liver axis, cirrhosis and portal hypertension: The chicken and the egg. Hepatol. Int. 2017, 12, 24–33. [Google Scholar] [CrossRef] [PubMed]
  77. Xu, L.; Zheng, X.; Wang, Y.; Fan, Q.; Zhang, M.; Li, R.; Ye, J.; Wu, X.; Zhao, W.; Zhang, Y. Berberine protects acute liver failure in mice through inhibiting inflammation and mitochondria-dependent apoptosis. Eur. J. Pharmacol. 2018, 819, 161–168. [Google Scholar] [CrossRef]
  78. Bull, M.J.; Plummer, N.T. Part 1: The Human Gut Microbiome in Health and Disease. Integr. Med. Encinitas Calif. 2014, 13, 17–22. [Google Scholar]
  79. Fukui, H. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far? Diseases 2019, 7, 58. [Google Scholar] [CrossRef]
  80. Quigley, E.M.; Stanton, C.; Murphy, E.F. The gut microbiota and the liver. Pathophysiological and clinical implications. J. Hepatol. 2012, 58, 1020–1027. [Google Scholar] [CrossRef]
  81. Tandon, P.; Garcia-Tsao, G. Bacterial Infections, Sepsis, and Multiorgan Failure in Cirrhosis. Semin. Liver Dis. 2008, 28, 026–042. [Google Scholar] [CrossRef] [PubMed]
  82. Bajaj, J.S.; Hylemon, P.B.; Ridlon, J.M.; Heuman, D.M.; Daita, K.; White, M.B.; Monteith, P.; Noble, N.A.; Sikaroodi, M.; Gillevet, P.M. Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am. J. Physiol. Liver Physiol. 2012, 303, G675–G685. [Google Scholar] [CrossRef] [PubMed]
  83. Chen, Y.; Yang, F.; Lu, H.; Wang, B.; Chen, Y.; Lei, D.; Wang, Y.; Zhu, B.; Li, L. Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 2011, 54, 562–572. [Google Scholar] [CrossRef] [PubMed]
  84. Bajaj, J.S.; Salzman, N.H.; Acharya, C.; Sterling, R.K.; White, M.B.; Gavis, E.A.; Fagan, A.; Hayward, M.; Holtz, M.L.; Matherly, S.; et al. Fecal Microbial Transplant Capsules Are Safe in Hepatic Encephalopathy: A Phase 1, Randomized, Placebo-Controlled Trial. Hepatology 2019, 70, 1690–1703. [Google Scholar] [CrossRef] [PubMed]
  85. Qin, N.; Yang, F.; Li, A.; Prifti, E.; Chen, Y.; Shao, L.; Guo, J.; Le Chatelier, E.; Yao, J.; Wu, L.; et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 2014, 513, 59–64. [Google Scholar] [CrossRef] [PubMed]
  86. Pessione, E. Lactic acid bacteria contribution to gut microbiota complexity: Lights and shadows. Front. Cell. Infect. Microbiol. 2012, 2, 86. [Google Scholar] [CrossRef]
  87. Dhiman, R.K.; Rana, B.; Agrawal, S.; Garg, A.; Chopra, M.; Thumburu, K.K.; Khattri, A.; Malhotra, S.; Duseja, A.; Chawla, Y.K. Probiotic VSL#3 Reduces Liver Disease Severity and Hospitalization in Patients With Cirrhosis: A Randomized, Controlled Trial. Gastroenterology 2014, 147, 1327–1337.e3. [Google Scholar] [CrossRef]
  88. Bajaj, J.S.; Heuman, D.M.; Hylemon, P.B.; Sanyal, A.J.; Puri, P.; Sterling, R.K.; Luketic, V.; Stravitz, R.T.; Siddiqui, M.S.; Fuchs, M.; et al. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment. Pharmacol. Ther. 2014, 39, 1113–1125. [Google Scholar] [CrossRef]
  89. Xia, X.; Chen, J.; Xia, J.; Wang, B.; Liu, H.; Yang, L.; Wang, Y.; Ling, Z. Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis. J. Int. Med. Res. 2018, 46, 3596–3604. [Google Scholar] [CrossRef] [PubMed]
  90. Davani-Davari, D.; Negahdaripour, M.; Karimzadeh, I.; Seifan, M.; Mohkam, M.; Masoumi, S.J.; Berenjian, A.; Ghasemi, Y. Prebiotics: Definition, Types, Sources, Mechanisms, and Clinical Applications. Foods 2019, 8, 92. [Google Scholar] [CrossRef]
  91. Vidot, H.; Cvejic, E.; Finegan, L.J.; Shores, E.A.; Bowen, D.G.; Strasser, S.I.; McCaughan, G.W.; Carey, S.; Allman-Farinelli, M.; Shackel, N.A. Supplementation with Synbiotics and/or Branched Chain Amino Acids in Hepatic Encephalopathy: A Pilot Randomised Placebo-Controlled Clinical Study. Nutrients 2019, 11, 1810. [Google Scholar] [CrossRef]
  92. Poh, Z.; Chang, P.E. A Current Review of the Diagnostic and Treatment Strategies of Hepatic Encephalopathy. Int. J. Hepatol. 2012, 2012, 1–10. [Google Scholar] [CrossRef] [PubMed]
  93. Ahluwalia, V.; Wade, J.B.; Heuman, D.M.; Hammeke, T.A.; Sanyal, A.J.; Sterling, R.K.; Stravitz, R.T.; Luketic, V.; Siddiqui, M.S.; Puri, P.; et al. Enhancement of functional connectivity, working memory and inhibitory control on multi-modal brain MR imaging with Rifaximin in Cirrhosis: Implications for the gut-liver-brain axis. Metab. Brain Dis. 2014, 29, 1017–1025. [Google Scholar] [CrossRef] [PubMed]
  94. Liu, Q.; Duan, Z.P.; Ha, D.K.; Bengmark, S.; Kurtovic, J.; Riordan, S.M. Synbiotic modulation of gut flora: Effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004, 39, 1441–1449. [Google Scholar] [CrossRef] [PubMed]
  95. Cai, T.-T.; Ye, X.-L.; Li, R.-R.; Chen, H.; Wang, Y.-Y.; Yong, H.-J.; Pan, M.-L.; Lu, W.; Tang, Y.; Miao, H.; et al. Resveratrol Modulates the Gut Microbiota and Inflammation to Protect Against Diabetic Nephropathy in Mice. Front. Pharmacol. 2020, 11, 1249. [Google Scholar] [CrossRef] [PubMed]
  96. Wang, P.; Wang, J.; Li, D.; Ke, W.; Chen, F.; Hu, X. Targeting the gut microbiota with resveratrol: A demonstration of novel evidence for the management of hepatic steatosis. J. Nutr. Biochem. 2020, 81, 108363. [Google Scholar] [CrossRef]
  97. Chen, K.; Zhao, H.; Shu, L.; Xing, H.; Wang, C.; Lu, C.; Song, G. Effect of resveratrol on intestinal tight junction proteins and the gut microbiome in high-fat diet-fed insulin resistant mice. Int. J. Food Sci. Nutr. 2020, 71, 965–978. [Google Scholar] [CrossRef]
  98. Chen, M.; Hou, P.; Zhou, M.; Ren, Q.; Wang, X.; Huang, L.; Hui, S.; Yi, L.; Mi, M. Resveratrol attenuates high-fat diet-induced non-alcoholic steatohepatitis by maintaining gut barrier integrity and inhibiting gut inflammation through regulation of the endocannabinoid system. Clin. Nutr. 2019, 39, 1264–1275. [Google Scholar] [CrossRef]
  99. Wang, P.; Li, D.; Ke, W.; Liang, D.; Hu, X.; Chen, F. Resveratrol-induced gut microbiota reduces obesity in high-fat diet-fed mice. Int. J. Obes. 2019, 44, 213–225. [Google Scholar] [CrossRef]
  100. Bémeur, C.; Cudalbu, C.; Dam, G.; Thrane, A.S.; Cooper, A.J.L.; Rose, C.F. Brain edema: A valid endpoint for measuring hepatic encephalopathy? Metab. Brain Dis. 2016, 31, 1249–1258. [Google Scholar] [CrossRef]
  101. Bosoi, C.R.; Rose, C. Brain edema in acute liver failure and chronic liver disease: Similarities and differences. Neurochem. Int. 2013, 62, 446–457. [Google Scholar] [CrossRef]
  102. Norenberg, M.D.; Rao, K.V.R.; Jayakumar, A.R. Mechanisms of Ammonia-Induced Astrocyte Swelling. Metab. Brain Dis. 2005, 20, 303–318. [Google Scholar] [CrossRef] [PubMed]
  103. Francesca, B.; Rezzani, R. Aquaporin and Blood Brain Barrier. Curr. Neuropharmacol. 2010, 8, 92–96. [Google Scholar] [CrossRef] [PubMed]
  104. Papadopoulos, M.; Verkman, A.S. Aquaporin water channels in the nervous system. Nat. Rev. Neurosci. 2013, 14, 265–277. [Google Scholar] [CrossRef]
  105. Thrane, A.S.; Thrane, V.R.; Nedergaard, M. Drowning stars: Reassessing the role of astrocytes in brain edema. Trends Neurosci. 2014, 37, 620–628. [Google Scholar] [CrossRef] [PubMed]
  106. Rao, K.V.R.; Norenberg, M.D. Aquaporin-4 in hepatic encephalopathy. Metab. Brain Dis. 2007, 22, 265–275. [Google Scholar] [CrossRef]
  107. Jayakumar, A.; Rao, K.R.; Murthy, C.; Norenberg, M. Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem. Int. 2006, 48, 623–628. [Google Scholar] [CrossRef] [PubMed]
  108. Solenov, E.; Watanabe, H.; Manley, G.T.; Verkman, A.S. Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am. J. Physiol. Physiol. 2004, 286, C426–C432. [Google Scholar] [CrossRef] [PubMed]
  109. Papadopoulos, M.; Verkman, A.S. Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis. J. Biol. Chem. 2005, 280, 13906–13912. [Google Scholar] [CrossRef]
  110. Scott, T.R.; Kronsten, V.T.; Hughes, R.D.; Shawcross, D.L. Pathophysiology of cerebral oedema in acute liver failure. World J. Gastroenterol. 2013, 19, 9240–9255. [Google Scholar] [CrossRef]
  111. Rao, K.V.R.; Jayakumar, A.R.; Norenberg, M.D. Brain edema in acute liver failure: Mechanisms and concepts. Metab. Brain Dis. 2014, 29, 927–936. [Google Scholar] [CrossRef]
  112. Rao, K.V.R.; Verkman, A.; Curtis, K.; Norenberg, M.D. Aquaporin-4 deletion in mice reduces encephalopathy and brain edema in experimental acute liver failure. Neurobiol. Dis. 2013, 63, 222–228. [Google Scholar] [CrossRef]
  113. Jayakumar, A.; Bethea, J.; Tong, X.; Gomez, J.; Norenberg, M. NF-κB in the mechanism of brain edema in acute liver failure: Studies in transgenic mice. Neurobiol. Dis. 2011, 41, 498–507. [Google Scholar] [CrossRef]
  114. Changlin, H.; Tan, C.; Liu, Y.; Liu, X.; Wang, X.; Gui, Y.; Qin, L.; Deng, F.; Yuejiang, G.; Hu, C.; et al. Resveratrol ameliorates oxidative stress and inhibits aquaporin 4 expression following rat cerebral ischemia-reperfusion injury. Mol. Med. Rep. 2015, 12, 7756–7762. [Google Scholar] [CrossRef]
  115. Burgos, I.M.A.; Ortiz-Plata, A.; Franco-Pérez, J.; Millán, A.; Aguilera, P. Resveratrol reduces cerebral edema through inhibition of de novo SUR1 expression induced after focal ischemia. Exp. Neurol. 2020, 330, 113353. [Google Scholar] [CrossRef]
  116. Qian, C.; Jin, J.; Chen, J.; Li, J.; Yu, X.; Mo, H.; Chen, G. SIRT1 activation by resveratrol reduces brain edema and neuronal apoptosis in an experimental rat subarachnoid hemorrhage model. Mol. Med. Rep. 2017, 16, 9627–9635. [Google Scholar] [CrossRef]
  117. Lu, X.; Dong, J.; Zheng, D.; Li, X.; Ding, D.; Xu, H. Reperfusion combined with intraarterial administration of resveratrol-loaded nanoparticles improved cerebral ischemia–reperfusion injury in rats. Nanomed. Nanotechnol. Biol. Med. 2020, 28, 102208. [Google Scholar] [CrossRef] [PubMed]
  118. Taherian, M.; Norenberg, M.D.; Panickar, K.S.; Shamaladevi, N.; Ahmad, A.; Rahman, P.; Jayakumar, A.R. Additive Effect of Resveratrol on Astrocyte Swelling Post-exposure to Ammonia, Ischemia and Trauma In Vitro. Neurochem. Res. 2020, 45, 1156–1167. [Google Scholar] [CrossRef] [PubMed]
  119. Hamann, G.F.; Liebetrau, M.; Martens, H.; Burggraf, D.; Kloss, C.U.A.; Bültemeier, G.; Wunderlich, N.; Jäger, G.; Pfefferkorn, T. Microvascular Basal Lamina Injury after Experimental Focal Cerebral Ischemia and Reperfusion in the Rat. Br. J. Pharmacol. 2002, 22, 526–533. [Google Scholar] [CrossRef] [PubMed]
  120. Nagaoka, I.; Hirota, S. Increased expression of matrix metalloproteinase-9 in neutrophils in glycogen-induced peritoneal inflammation of guinea pigs. Inflamm. Res. 2000, 49, 55–62. [Google Scholar] [CrossRef]
  121. Pandey, A.K.; Patnaik, R.; Bhattacharya, P.; Shukla, S.C.; Paul, S. Resveratrol inhibits matrix metalloproteinases to attenuate neuronal damage in cerebral ischemia: A molecular docking study exploring possible neuroprotection. Neural Regen. Res. 2015, 10, 568–575. [Google Scholar] [CrossRef]
  122. Wei, H.; Wang, S.; Zhen, L.; Yang, Q.; Wu, Z.; Lei, X.; Lv, J.; Xiong, L.; Xue, R. Resveratrol Attenuates the Blood-Brain Barrier Dysfunction by Regulation of the MMP-9/TIMP-1 Balance after Cerebral Ischemia Reperfusion in Rats. J. Mol. Neurosci. 2014, 55, 872–879. [Google Scholar] [CrossRef] [PubMed]
  123. Dou, Z.; Rong, X.; Zhao, E.; Zhang, L.; Lv, Y. Neuroprotection of Resveratrol Against Focal Cerebral Ischemia/Reperfusion Injury in Mice Through a Mechanism Targeting Gut-Brain Axis. Cell. Mol. Neurobiol. 2019, 39, 883–898. [Google Scholar] [CrossRef] [PubMed]
  124. Dong, W.; Gao, D.; Lin, H.; Zhang, X.; Li, N.; Li, F. New insights into mechanism for the effect of resveratrol preconditioning against cerebral ischemic stroke: Possible role of matrix metalloprotease-9. Med. Hypotheses 2008, 70, 52–55. [Google Scholar] [CrossRef] [PubMed]
  125. Gao, D.; Zhang, X.; Jiang, X.; Peng, Y.; Huang, W.; Cheng, G.; Song, L. Resveratrol reduces the elevated level of MMP-9 induced by cerebral ischemia–reperfusion in mice. Life Sci. 2006, 78, 2564–2570. [Google Scholar] [CrossRef] [PubMed]
  126. Hong, G.; Yan, Y.; Zhong, Y.; Chen, J.; Tong, F.; Ma, Q. Combined Ischemic Preconditioning and Resveratrol Improved Bloodbrain Barrier Breakdown via Hippo/YAP/TAZ Signaling Pathway. CNS Neurol. Disord. Drug Targets 2020, 18, 713–722. [Google Scholar] [CrossRef]
  127. Zhao, H.; Li, N.; Wang, Q.; Cheng, X.; Li, X.; Liu, T. Resveratrol decreases the insoluble Aβ1–42 level in hippocampus and protects the integrity of the blood–brain barrier in AD rats. Neuroscience 2015, 310, 641–649. [Google Scholar] [CrossRef]
  128. Vairappan, B.; Sundhar, M.; Srinivas, B.H. Resveratrol Restores Neuronal Tight Junction Proteins Through Correction of Ammonia and Inflammation in CCl4-Induced Cirrhotic Mice. Mol. Neurobiol. 2018, 56, 4718–4729. [Google Scholar] [CrossRef]
  129. Bender, A.S.; Norenberg, M.D. Effect of ammonia on GABA uptake and release in cultured astrocytes. Neurochem. Int. 2000, 36, 389–395. [Google Scholar] [CrossRef]
  130. Bai, G.; Rao, K.R.; Murthy, C.; Panickar, K.; Jayakumar, A.; Norenberg, M. Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J. Neurosci. Res. 2001, 66, 981–991. [Google Scholar] [CrossRef]
  131. Alvarez, V.M.; Rao, K.V.R.; Brahmbhatt, M.; Norenberg, M.D. Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J. Neurosci. Res. 2011, 89, 2028–2040. [Google Scholar] [CrossRef]
  132. Kelly, T.; Kafitz, K.W.; Roderigo, C.; Rose, C.R. Ammonium-evoked alterations in intracellular sodium and pH reduce glial glutamate transport activity. Glia 2009, 57, 921–934. [Google Scholar] [CrossRef] [PubMed]
  133. Bobermin, L.D.; Quincozes-Santos, A.; Guerra, M.C.; Leite, M.C.; Souza, D.O.; Gonçalves, C.-A.; Gottfried, C. Resveratrol Prevents Ammonia Toxicity in Astroglial Cells. PLoS ONE 2012, 7, e52164. [Google Scholar] [CrossRef] [PubMed]
  134. Skowrońska, M.; Albrecht, J. Oxidative and nitrosative stress in ammonia neurotoxicity. Neurochem. Int. 2013, 62, 731–737. [Google Scholar] [CrossRef] [PubMed]
  135. Bosoi, C.R.; Rose, C.F. Identifying the direct effects of ammonia on the brain. Metab. Brain Dis. 2008, 24, 95–102. [Google Scholar] [CrossRef] [PubMed]
  136. Northrop, N.A.; Halpin, L.E.; Yamamoto, B.K. Peripheral ammonia and blood brain barrier structure and function after methamphetamine. Neuropharmacology 2016, 107, 18–26. [Google Scholar] [CrossRef]
  137. Yang, S.; Hao, D.; Jin, M.; Li, Y.; Liu, Z.; Huang, Y.; Chen, T.; Su, Y. Internal ammonium excess induces ROS-mediated reactions and causes carbon scarcity in rice. BMC Plant Biol. 2020, 20, 1–15. [Google Scholar] [CrossRef] [PubMed]
  138. Klejman, A.; Węgrzynowicz, M.; Szatmari, E.M.; Mioduszewska, B.; Hetman, M.; Albrecht, J. Mechanisms of ammonia-induced cell death in rat cortical neurons: Roles of NMDA receptors and glutathione. Neurochem. Int. 2005, 47, 51–57. [Google Scholar] [CrossRef]
  139. Schousboe, A.; Waagepetersen, H.; Leke, R.; Bak, L.K. Effects of hyperammonemia on brain energy metabolism: Controversial findings in vivo and in vitro. Metab. Brain Dis. 2014, 29, 913–917. [Google Scholar] [CrossRef]
  140. Ohara, K.; Aoyama, M.; Fujita, M.; Sobue, K.; Asai, K. Prolonged exposure to ammonia increases extracellular glutamate in cultured rat astrocytes. Neurosci. Lett. 2009, 462, 109–112. [Google Scholar] [CrossRef] [PubMed]
  141. Görg, B.; Qvartskhava, N.; Keitel, V.; Bidmon, H.J.; Selbach, O.; Schliess, F.; Häussinger, D. Ammonia induces RNA oxidation in cultured astrocytes and brainin vivo. Hepatology 2008, 48, 567–579. [Google Scholar] [CrossRef]
  142. Rodrigo, R.; Cauli, O.; Gomez–Pinedo, U.; Agusti, A.; Hernandez–Rabaza, V.; García-Verdugo, J.M.; Felipo, V. Hyperammonemia Induces Neuroinflammation That Contributes to Cognitive Impairment in Rats With Hepatic Encephalopathy. Gastroenterology 2010, 139, 675–684. [Google Scholar] [CrossRef]
  143. Kosenko, E.; Venediktova, N.; Kaminsky, Y.; Montoliu, C.; Felipo, V. Sources of oxygen radicals in brain in acute ammonia intoxication in vivo. Brain Res. 2003, 981, 193–200. [Google Scholar] [CrossRef]
  144. RamaRao, K.; Jayakumar, A.; Norenberg, M.; Rao, K.R. Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochem. Int. 2005, 47, 31–38. [Google Scholar] [CrossRef]
  145. Butterworth, R.F. Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology. Drugs 2019, 79, 17–21. [Google Scholar] [CrossRef] [PubMed]
  146. Aitbaev, K.A.; Murkamilov, I.T.; Fomin, V.V. Liver diseases: The pathogenetic role of the gut microbiome and the potential of treatment for its modulation. Terapevticheskii 2017, 89, 120–128. [Google Scholar] [CrossRef] [PubMed]
  147. Gedik, E.; Girgin, S.; Ozturk, H.; Obay, B.D.; Ozturk, H.; Buyukbayram, H. Resveratrol attenuates oxidative stress and histological alterations induced by liver ischemia/reperfusion in rats. World J. Gastroenterol. 2008, 14, 7101–7106. [Google Scholar] [CrossRef] [PubMed]
  148. Hassan-Khabbar, S.; Vamy, M.; Cottart, C.-H.; Wendum, D.; Vibert, F.; Savouret, J.-F.; Thérond, P.; Clot, J.-P.; Waligora, A.-J.; Nivet-Antoine, V. Protective effect of post-ischemic treatment with trans-resveratrol on cytokine production and neutrophil recruitment by rat liver. Biochimie 2010, 92, 405–410. [Google Scholar] [CrossRef]
  149. Bobermin, L.D.; Souza, D.; Gonçalves, C.-A.; Quincozes-Santos, A. Resveratrol prevents ammonia-induced mitochondrial dysfunction and cellular redox imbalance in C6 astroglial cells. Nutr. Neurosci. 2017, 21, 276–285. [Google Scholar] [CrossRef]
  150. Bobermin, L.D.; Hansel, G.; Scherer, E.B.; Wyse, A.T.; Souza, D.; Quincozes-Santos, A.; Gonçalves, C.-A. Ammonia impairs glutamatergic communication in astroglial cells: Protective role of resveratrol. Toxicol. Vitr. 2015, 29, 2022–2029. [Google Scholar] [CrossRef]
  151. Quincozes-Santos, A.; Andreazza, A.C.; Nardin, P.; Funchal, C.; Gonçalves, C.-A.; Gottfried, C. Resveratrol attenuates oxidative-induced DNA damage in C6 Glioma cells. Neurotoxicology 2007, 28, 886–891. [Google Scholar] [CrossRef]
  152. Liu, Y.; Li, Y.; Lu, X. Regulators in the DNA damage response. Arch. Biochem. Biophys. 2016, 594, 18–25. [Google Scholar] [CrossRef] [PubMed]
  153. Zaky, A.; Mohammad, B.; Moftah, M.; Kandeel, K.M.; Bassiouny, A.R. Apurinic/apyrimidinic endonuclease 1 is a key modulator of aluminum-induced neuroinflammation. BMC Neurosci. 2013, 14, 26. [Google Scholar] [CrossRef] [PubMed]
  154. Price, N.; Gomes, A.P.; Ling, A.J.; Duarte, F.V.; Martin-Montalvo, A.; North, B.J.; Agarwal, B.; Ye, L.; Ramadori, G.; Teodoro, J.; et al. SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function. Cell Metab. 2012, 15, 675–690. [Google Scholar] [CrossRef] [PubMed]
  155. Muriel, P.; Espinoza, Y.R. Beneficial drugs for liver diseases. J. Appl. Toxicol. 2008, 28, 93–103. [Google Scholar] [CrossRef]
  156. Bechmann, L.; Zahn, D.; Gieseler, R.K.; Fingas, C.D.; Marquitan, G.; Jochum, C.; Gerken, G.; Friedman, S.L.; Canbay, A. Resveratrol amplifies profibrogenic effects of free fatty acids on human hepatic stellate cells. Hepatol. Res. 2009, 39, 601–608. [Google Scholar] [CrossRef]
  157. Theodotou, M.; Fokianos, K.; Moniatis, D.; Kadlenic, R.; Chrysikou, A.; Aristotelous, A.; Mouzouridou, A.; Diakides, J.; Stavrou, E. Effect of resveratrol on non-alcoholic fatty liver disease. Exp. Ther. Med. 2019, 18, 559–565. [Google Scholar] [CrossRef] [PubMed]
  158. Malaguarnera, G.; Pennisi, M.; Bertino, G.; Motta, M.; Borzì, A.M.; Vicari, E.; Bella, R.; Drago, F.; Malaguarnera, M. Resveratrol in Patients with Minimal Hepatic Encephalopathy. Nutrients 2018, 10, 329. [Google Scholar] [CrossRef] [PubMed]
  159. Samuel, V.P.; Gupta, G.; Dahiya, R.; Jain, D.A.; Mishra, A.; Dua, K. Current Update on Preclinical and Clinical Studies of Resveratrol, a Naturally Occurring Phenolic Compound. Crit. Rev. Eukaryot. Gene Expr. 2019, 29, 529–537. [Google Scholar] [CrossRef]
Jcm 10 03819 g001
Figure 1. The pathogenic process of hepatic encephalopathy (HE) in the brain and the possible protective effects of resveratrol. (A) HE in the brain is linked to the development of several specific features including hyperammonemia, brain edema, neuroinflammation, and blood-brain barrier (BBB). Resveratrol may protect brain endothelial cells, astrocytes, and neurons against hyperammonemia-induced damage, and finally circumvents brain edema. (B) In addition, resveratrol may reduce neuroinflammation by suppressing inflammatory cytokine expression, and (C) protects against BBB disruption by helping to maintain a tight junction protein density within the BBB. Note that the protective effects of resveratrol shown in this figure are hypothetic effects based on the current empirical evidence and do not represent the proven effects of resveratrol on patients with HE. See text for details. IL: interleukin, TNF: tumor necrosis factor.
Figure 1. The pathogenic process of hepatic encephalopathy (HE) in the brain and the possible protective effects of resveratrol. (A) HE in the brain is linked to the development of several specific features including hyperammonemia, brain edema, neuroinflammation, and blood-brain barrier (BBB). Resveratrol may protect brain endothelial cells, astrocytes, and neurons against hyperammonemia-induced damage, and finally circumvents brain edema. (B) In addition, resveratrol may reduce neuroinflammation by suppressing inflammatory cytokine expression, and (C) protects against BBB disruption by helping to maintain a tight junction protein density within the BBB. Note that the protective effects of resveratrol shown in this figure are hypothetic effects based on the current empirical evidence and do not represent the proven effects of resveratrol on patients with HE. See text for details. IL: interleukin, TNF: tumor necrosis factor.
Jcm 10 03819 g001
Jcm 10 03819 g002
Figure 2. The pathogenesis of hepatic encephalopathy (HE) in the gut and possible therapeutic effects of resveratrol treatment. The gut microbiome is altered in response to hepatic encephalopathy, which increases the amount of toxins from harmful microorganisms within the system, exacerbating the pathogenesis of HE. HE reduces the integrity of the gut barrier, allowing for a systemic distribution of these toxic compounds, and increases inflammation and systemic disruption. However, the treatment with resveratrol may facilitate the recovery of the beneficial bacterial populations and improve the integrity of the gut barrier. It is also noted that the therapeutic effect of resveratrol shown in this figure is an assumption based on the current empirical evidence and not proven in patients with HE. See text for details.
Figure 2. The pathogenesis of hepatic encephalopathy (HE) in the gut and possible therapeutic effects of resveratrol treatment. The gut microbiome is altered in response to hepatic encephalopathy, which increases the amount of toxins from harmful microorganisms within the system, exacerbating the pathogenesis of HE. HE reduces the integrity of the gut barrier, allowing for a systemic distribution of these toxic compounds, and increases inflammation and systemic disruption. However, the treatment with resveratrol may facilitate the recovery of the beneficial bacterial populations and improve the integrity of the gut barrier. It is also noted that the therapeutic effect of resveratrol shown in this figure is an assumption based on the current empirical evidence and not proven in patients with HE. See text for details.
Jcm 10 03819 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Kim, Y.-K.; Song, J. Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation. J. Clin. Med. 2021, 10, 3819. https://doi.org/10.3390/jcm10173819

AMA Style

Kim Y-K, Song J. Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation. Journal of Clinical Medicine. 2021; 10(17):3819. https://doi.org/10.3390/jcm10173819

Chicago/Turabian Style

Kim, Young-Kook, and Juhyun Song. 2021. "Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation" Journal of Clinical Medicine 10, no. 17: 3819. https://doi.org/10.3390/jcm10173819

APA Style

Kim, Y.-K., & Song, J. (2021). Therapeutic Applications of Resveratrol in Hepatic Encephalopathy through Its Regulation of the Microbiota, Brain Edema, and Inflammation. Journal of Clinical Medicine, 10(17), 3819. https://doi.org/10.3390/jcm10173819

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop