Search Results (8,578)

Background: Xanthohumol (XN), a prenylated chalcone flavonoid derived from hops (Humulus lupulus), is increasingly recognized as a highly pleiotropic natural compound. Objective: We aimed to structure XN’s mechanistic hierarchy with emerging translational relevance across disease areas. Methods: We performed a comprehensive and integrative literature review of XN for its biological and translational effects across cancer, metabolic, neurological, cardiovascular, hepatic, renal, and dermatological disorders. Results: Mechanistically, XN exerts diverse bioactivities by inhibiting major pro-oncogenic and pro-inflammatory pathways, such as NF-κB, PI3K/Akt/mTOR, STAT3, HIF-1α, and selective MAPK cascades, while activating cytoprotective signaling, such as the Nrf2/ARE and AMPK pathways. Through these coordinated actions, XN modulates redox homeostasis, mitochondrial integrity, apoptosis, autophagy, ferroptosis, and inflammatory responses. In oncology, XN demonstrates broad-spectrum anticancer activity in preclinical models by inhibiting proliferation; inducing cell cycle arrest and apoptosis; suppressing epithelial–mesenchymal transition, angiogenesis, and metastasis; and restoring chemosensitivity in resistant cancers, including breast, lung, gastric, liver, and head-and-neck carcinomas. Beyond cancer, XN exhibits multi-organ protective bioactivities through antioxidative, antimicrobial, antiviral, and anti-inflammatory activities; inhibition of ferroptosis and excitotoxicity; and preservation of mitochondrial integrity. It shows beneficial effects in preclinical models of Parkinson’s disease, Alzheimer’s disease, hepatic steatosis and fibrosis, renal ischemia–reperfusion injury, cardiovascular dysfunction, skin photoaging, and atopic dermatitis. Human subject studies demonstrate that XN is safe and well tolerated, with observed reductions in oxidative DNA damage and inflammatory cytokine release. Recent advances in micellar formulations have improved XN’s systemic bioavailability and thus its translational feasibility. Conclusions: In summary, XN is a safe, multifunctional natural compound with strong potential for modulating disease-relevant biological pathways associated with cancer, neurodegenerative diseases, metabolic disorders, and inflammatory skin conditions. Continued efforts to enhance its bioavailability and conduct rigorous clinical trials are essential to fully establish its clinical relevance in patient populations. Full article

Background: Traumatic brain injury (TBI) imposes a substantial public health burden through long-term physical, cognitive, and psychiatric effects. This includes substance use disorders (SUDs) for which TBI is a demonstrated risk factor; however, prior studies have not comprehensively compared relative incidences of SUD subtypes post-TBI or differences between intracranial hemorrhage (ICH) and non-ICH TBI in patients without prior SUD history. This global retrospective analysis using the TriNetX database aims to quantify new-onset SUD incidence post-TBI in the largest cohort of patients evaluated to date, with cohorts stratified by SUD subtype and ICH versus non-ICH TBI, to highlight opportunities for post-injury care models to mitigate SUD risk. Methods: De-identified data from the TriNetX Research Network were used to select patients with TBI (n = 1,889,112) and define distinct cohorts based upon the presence (n = 420,868) or absence (n = 1,471,592) of ICH. Patients with previously diagnosed SUD before the date of TBI were excluded. Patient demographics and medical comorbidities were calculated for each group. The incidence of new SUD diagnosis over the lifetime and at 1-, 3-, and 5-years post-TBI were calculated and compared. Subtypes of SUD were defined and calculated based on the specific substance used. Propensity scores were calculated to create balanced matched ICH and non-ICH cohorts (n = 331,812 each) were used for comparisons of 5-year SUD incidence. Results: In the full TBI cohort, 5-year new SUD incidence was 4.2% overall, with nicotine (2.4%) and alcohol (1.1%) predominating, followed by cannabis (0.9%) and opioids (0.4%). Rates of SUDs increased over time, but attenuated beyond 5 years, with approximately 50% of those who would ultimately be diagnosed with SUD manifesting (lifetime) by 3 years post-TBI. After propensity matching, non-ICH TBI showed higher 5-year risk for any SUD (4.2% vs. 3.6%; risk difference −0.65%, p < 0.0001) and all subtypes (p < 0.05) except inhalants (p = 0.53). Conclusions: This largest-to-date analysis of new-onset SUD post-TBI demonstrates significantly higher rates of SUD in TBI patients; rates of nicotine, alcohol, cannabis, and opioid use disorders were most common. Non-ICH TBI patients demonstrated greater rates of SUD after injury than patients with ICH-associated TBI. Of patients suffering from TBI without ICH who would eventually be diagnosed with SUD, approximately 50% had obtained that diagnosis within 3 years of the injury. Taken together, these findings demonstrate the clinical need for routine SUD screening in post-TBI care, especially for 3 years post-injury. Such an intervention has the potential to significantly alleviate the public health burden and associated cost of care for TBI-associated substance use disorder patients. Full article

The authors hypothesize that idiopathic Parkinson’s disease may result from an alteration in microvascular flow at a “critical point” in the nervous system that is characterized by pigmented cells that express neuromelanin and/or lipofuscin. “Critical points” include the olfactory epithelium/bulb, the autonomic nervous system, the enteric nervous system, the prefrontal–cortico-pontine network, and the amygdala. Hypoxia–ischemia following blood flow disturbance would recruit and activate leukocytes and induce the infiltration of peripheral immune cells into neural tissue. The excess of toxic factors produced by hyperactive immune cells, such as myeloperoxidase and its derivatives, would cause the oxidation of lipids, proteins, and biogenic monoamines such as dopamine, which in turn would facilitate the accumulation and precipitation of neuromelanin, lipofuscin, and alpha-synuclein. In addition, neuromelanin and lipofuscin precipitates may accentuate the misfolding and aggregation of alpha-synuclein. This “amplification” mechanism could help explain the crucial role of pigmented neurons in the onset of Parkinson’s disease pathology, triggering abnormal neurotoxic alpha-synuclein spread throughout the nervous system from the “critical point” of origin, and enabling a self-perpetuating degenerative process. The proposed hypothesis may have implications for the identification of new therapeutic targets, early prevention strategies, and the development of vascular and/or immune biomarkers. Full article

Age-related macular degeneration (AMD) is an increasingly prevalent source of permanent visual impairment in the aging population and is widely accepted as a multi-factorial neurodegenerative disorder of the retina. While there has been significant progress in treating neovascular AMD, there are currently no effective disease-sparing treatments for dry AMD and geographic atrophy. To date, research has begun to reveal the complex relationship between the environment and genetic predisposition in AMD pathogenesis. Various environmental factors responsible for AMD include oxidative stress, mitochondrial dysfunction, inflammation, abnormal complement activation, and epigenetic regulation, which interact dynamically to drive disease progression. This review summarizes recent data and provides a comprehensive model for understanding how these interacting factors lead to the progression of AMD from an early stage to advanced stages with complications associated with the disease. We highlight the central role of retinal pigment epithelial mitochondrial failure and impaired stress resilience as upstream drivers that amplify inflammation and complement-mediated injuries. We also discuss how dysregulated miRNAs and proteomic network remodeling contribute to disease heterogeneity. Emerging therapeutic strategies are reviewed in the context of molecular endotyping and personalized intervention. Finally, we outline future directions toward precision medicine in AMD, emphasizing early disease modification, rational combination therapies, and the need to bridge the translational gaps between molecular discovery and clinical trial design. Full article

Microcin C7 (McC7) is a ribosomally synthesized antimicrobial peptide that has emerged as a promising candidate due to its dual antibacterial and immunomodulatory activities. This study evaluated the preventive effect of McC7 against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. An immunosuppression model was established by intraperitoneal CTX injection in mice, which were randomly allocated into five groups (n = 15): a negative control, a CTX model group, and three McC7 treatment groups receiving dietary McC7 at 100, 200, or 400 mg/kg both before and during CTX exposure. Body weight and feed intake were monitored throughout the study. Organ indices, serum biochemical parameters, immune and antioxidant markers, and intestinal morphology were assessed. Splenic T-cell subsets were analyzed by flow cytometry, and gut microbiota composition was evaluated by 16S rRNA sequencing. McC7 supplementation significantly attenuated the CTX-induced reduction in body weight, feed intake, and organ indices, ameliorated markers of hepatic and renal injury, and restored the splenic CD4⁺/CD8⁺ T-cell ratio. McC7 enhanced intestinal mucosal barrier integrity, increased the abundance of beneficial bacteria such as Candidatus Arthromitus and ASF356, and reduced the abundance of the potentially pathogenic genus Bilophila. In conclusion, our results demonstrate that McC7 alleviates CTX-induced immunosuppression by regulating T-cell differentiation, maintaining cytokine homeostasis, and modulating gut microbial composition to support intestinal health. Full article

Myocardial infarction (MI) triggers complex pathological processes, including inflammation, hypoxia, and fibrotic remodeling. MicroRNAs (miRNAs) have emerged as promising biomarkers for cardiovascular injury; however, their expression dynamics along processes remain underexplored. We used an in vivo rat model of permanent coronary occlusion to study the molecular alterations associated with MI and its resolution in a temporal mode, including five experimental groups with five animals in each: sham, PO 24 h, PO 72 h, PO 7 d, PO 1 month. Histological analysis, serum biomarkers, and miRNA/gene expression profiles were analyzed in a time-dependent manner post-occlusion. Subsequent analysis revealed early depletion of selected circulating miRNAs (PO 24 h). Transient upregulation in cardiac tissue miRNAs, inflammatory and fibrotic gene expression (Fibronectin, Collagen, Vimentin, E-Cadherin) were observed at PO 72 h. These molecular alterations correlated with histological evidence of myocardial injury and repair. Taken together, our findings delineate the molecular timeline of MI progression and resolution and identify candidate miRNAs as sensitive and time-dependent indicators of myocardial stress, including miR-107, miR-122-5p and miR-221-3p. This integrative approach supports the use of miRNA signatures for noninvasive monitoring of cardiac injury and resolution and unveils potential therapeutic targets to reduce pathological remodeling. Full article

The limited capacity for cardiomyocyte proliferation in the adult human heart restricts its ability to recover from injury. Building on discoveries in regenerative model systems, such as zebrafish and neonatal mice, reactivation of a latent potential for cardiomyocyte proliferation is a strategy to promote therapeutic heart regeneration. Although cardiomyocyte proliferation remains modest even with the most effective mitogenic stimuli identified to date, evidence for a potential functional benefit in pre-clinical model systems has led to the initiation of several early-phase clinical programs. Here, we review insights from model organisms that inform the potential efficacy and limitations of therapeutic cardiomyocyte proliferation, systems to study human cardiomyocyte proliferation, and the natural history of cardiomyocyte proliferation in the human heart. We also examine the translational trajectory of selected discoveries, including therapeutic delivery modalities, and attendant safety concerns. Finally, we discuss critical challenges that will need to be addressed to enable successful clinical translation. Full article

Kidney disease, be it acute or chronic, has a complex pathology and is a significant human health problem. Increasing interest has been focused on exploring therapeutic targets that can be used to safeguard kidney function under a variety of detrimental conditions. In this article, we review the protective effects of 5-methoxytryptophan (5-MTP), a tryptophan metabolite, on kidney injury. Published studies indicate that serum 5-MTP level is decreased in patients with chronic kidney disease (CKD), suggesting that 5-MTP is a biomarker for CKD and has therapeutic values. Indeed, rodent models of kidney injury induced by folic acid, lipopolysaccharide (LPS), unilateral ureteral obstruction (UUO), and ischemia/reperfusion all demonstrate that exogenous 5-MTP exhibits nephroprotective effects. The underlying mechanisms involve antioxidative damage via activating antioxidant systems such as heme oxygenase-1, anti-inflammation, anti-fibrosis, and enhanced mitophagy. To further explore the underlying mechanisms and the potential of 5-MTP as a kidney therapeutic compound, future studies need to include more rodent models of kidney injury induced by a variety of insults. Moreover, how to boost endogenous 5-MTP content and its potential synergistic effects with other therapeutic approaches aiming to combat kidney diseases also remain to be explored. Full article

Cisplatin is an effective chemotherapeutic agent, yet its clinical utility is limited by dose-dependent nephrotoxicity. Alpha-1 antitrypsin (AAT) has cytoprotective, anti-inflammatory, and antiapoptotic properties, but its therapeutic potential in cisplatin-induced acute kidney injury (AKI) remains unclear. A murine cisplatin–AKI model was used to evaluate whether AAT (80 mg/kg) ameliorates renal injury. Renal function, oxidative stress, NADPH oxidase (NOX) isoforms, mitochondrial metabolism, inflammatory mediators, apoptosis, and fibrosis-related markers were assessed using biochemical, histological, immunohistochemical, and Western blot analyses. Cisplatin markedly impaired renal function and induced tubular injury; meanwhile, AAT significantly reversed these changes. Cisplatin also induced severe oxidative stress and disrupted the balance of NOX isoforms; AAT restored redox homeostasis. Cisplatin upregulated CPT1A/PDK4 and suppressed CPT2, UCP3, PGC1α, and DRP1, inducing maladaptive mitochondrial changes, indicating impaired β-oxidation and defective mitochondrial dynamics; AAT reversed these alterations, restoring normal mitochondrial metabolism. IL-1β, IL-6R, OPN, and F4/80 expression, recovery of the Bax/Bcl-2 ratio, and MAPK activation were reduced, indicating decreased inflammation and apoptosis; profibrotic markers were also reduced. AAT confers multifaceted protection against cisplatin-induced AKI by restoring redox balance, mitochondrial homeostasis, and inflammatory and apoptotic signaling. These findings support AAT as a promising therapeutic agent for preventing cisplatin nephrotoxicity. Full article

Background: Approximately two-thirds of individuals with spinal cord injury (SCI) become overweight or obese. Weight loss surgery, including vertical sleeve gastrectomy (VSG), is one of the most effective long-term treatments for obesity and type 2 diabetes. Introduction: The main objective of this study was to test in our diet induced obesity rat model whether subjects respond to VSG in the same way as subjects with or without SCI. Methods: To address this question, male Wistar rats underwent either T3 contusion injuries or sham spinal surgeries (Sham). Following recovery, all rats were fed a high-energy, high-fat diet (HFD) for six weeks before undergoing VSG. Taste responsivity and preferences were assessed at multiple time points. Results: Prior to HFD exposure, SCI rats exhibited significantly reduced lick responses for sucrose at higher concentrations and increased licking for low concentrations of sodium, although 2BC sucrose preference was unchanged. HFD feeding in SCI rats enhanced salt and sucrose licking overall. Importantly, VSG reduced sucrose licking, with SCI rats showing greater sensitivity to this effect. cFos immunohistochemistry further revealed enhanced neuronal activation to sucrose ingestion in the dorsal vagal complex, including the rostral subnucleus of the nucleus of the solitary tract. Discussion and Conclusions: Together, these findings support the hypothesis that SCI alters taste functions, thereby increasing vulnerability to diet-induced obesity and that VSG may restore sweet taste responsivity even more effectively in SCI-associated obesity than in non-SCI obesity. Future studies are needed to clarify the neural and hormonal mechanisms mediating these effects and to determine their translational relevance to human SCI populations. Full article

Cerebral palsy (CP) is a developmental disability caused by injury to the fetal or infant brain, affecting between 1.6 to 3.7 per 1000 live births worldwide. Ambulatory patients with cerebral palsy experience various gait problems, for which they seek treatment from medical professionals. Varus foot deformities are among the most problematic for patients. Varus foot deformity is characterized by the inner border of the foot being tilted upward and the hindfoot inward, increasing weightbearing on the lateral aspect of the foot. This positioning increases weight-bearing pressure under the lateral (outside) of the foot and often under the fifth metatarsal head when walking. As such, varus foot deformity can contribute to in-toeing, make shoe and brace-wearing difficult and painful, compromise gait stability, and sometimes lead to metatarsal fractures. Current knowledge of CP etiology and classifications, as well as principles and advances in assessment and treatment decision making for varus foot deformities, are outlined in this narrative review. In younger children with flexible deformities, non-operative interventions such as bracing, botulinum toxin injection, and serial casting are effective. The literature and expert consensus suggest that, if possible, surgery should be delayed until after the age of 8 years. When surgery is indicated, soft tissue procedures are used for flexible deformities. In addition to the soft tissue procedures, bone surgery is needed for rigid deformities. Careful pre-operative foot assessment is needed, including assessment of deformity flexibility and range of motion, X-rays, and computerized gait analysis if possible. Strategies are presented for thorough assessment when gait analysis is not available or feasible. Research reports of surgical outcomes for soft tissue and bony correction are positive, but should be interpreted with caution. The quality of evidence on surgical outcomes is compromised by use of varying research design methods and selection of outcome measures, with few including measures of function or patient-reported outcomes. It is recommended that surgical outcome be assessed using standardized assessment tools, such as the Foot Posture Index, which have had their validity and reliability established. Recent advances in 3D kinematic foot model development and musculoskeletal modeling have the potential to greatly improve surgical outcomes for patients with CP. Full article

Controlled local hyperthermia supports postoperative wound healing in liver surgery by stimulating metabolism, angiogenesis, and immune responses through the induction of heat shock proteins (HSPs) and modulation of Damage-Associated Molecular Patterns (DAMPs). This study evaluates the impact of thermal modulation on immune processes during abdominal wound repair, specifically analyzing the role of HSPs and immune activation pathways. A narrative review of the literature from 2010 to 2025 was conducted to summarize molecular mechanisms regarding temperature, HSP activation, cytokine expression, and DAMPs, excluding studies conducted solely in animal models. The results indicate that precise local hyperthermia in postoperative abdominal wounds activates HSPs as well as inflammasome and Toll-like receptor (TLR) pathways, modulating immune and cytokine responses depending on the type and depth of tissue injury. Consequently, such thermoimmunomodulation stabilizes immune cell functions, optimizes the balance between inflammation and regeneration, and minimizes the risk of postoperative complications to support effective wound healing. Full article

Background: Colorectal liver metastases (CRLM) represent a major determinant of prognosis in patients with metastatic colorectal cancer and account for a substantial proportion of cancer-related mortality worldwide. Over the last decades, survival outcomes have improved significantly as a result of advances in systemic therapies, refinement of surgical techniques, and, most importantly, the widespread implementation of multidisciplinary management strategies. Within this evolving landscape, surgery remains the cornerstone of potentially curative treatment, although its optimal integration with systemic and locoregional therapies requires careful patient selection and individualized treatment planning. Methods: This narrative review explores the contemporary role of surgery within the multidisciplinary management of CRLM, emphasizing how surgical decision-making is integrated with medical oncology, radiology, interventional procedures, and emerging technologies. Results: The pivotal role of multidisciplinary team meetings in defining resectability, treatment sequencing, and therapeutic intent is highlighted. Key technical and oncological criteria guiding upfront resection, neoadjuvant or conversion strategies, and staged approaches are reviewed, including assessment of future liver remnant, optimization of liver volume and function, tumor burden, molecular profile, and dynamic prognostic models. In addition, the review summarizes current evidence supporting parenchyma-sparing liver surgery and the integration of local therapies such as thermal ablation, irreversible electroporation, stereotactic body radiotherapy, selective internal radiation therapy, and hepatic artery infusion chemotherapy within multimodal treatment algorithms. Complex clinical scenarios, including synchronous disease, extensive bilobar metastases, chemotherapy-associated liver injury, and the emerging role of liver transplantation in highly selected patients with liver-only disease, are also addressed. Conclusions: Modern CRLM management has evolved toward a highly individualized, biology-driven approach in which surgery is optimally integrated within a multidisciplinary framework to maximize curative potential and long-term survival. Full article

Background: Spinal cord injury (SCI) represents a form of traumatic damage to the central nervous system, and oligodendrocytes play a central role in SCI recovery. Ferroptosis is a major factor in the pathophysiological development of SCI symptoms. Pterostilbene (Pte) has antioxidant, anti-inflammatory, and neuroprotective effects. This study aims to investigate the potential role of Pte in SCI. Methods: A SCI model of rats was constructed. The BBB score assessment, the footprint test, EC staining, immunofluorescence (IF), and Western blot (WB) were conducted to observe the neuroprotective effects of Pte. The factors of ferroptosis, such as Glutathione (GSH), Malondialdehyde (MDA), Fe²⁺, solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), were assessed. Then, transcriptomic data, network pharmacology, molecular docking analysis, and the erastin-induced ferroptosis model of OLN-93 cell lines were used to investigate the mechanism of inhibiting ferroptosis by Pte. Results: Pte treatment restored motor function and spinal cord tissue in SCI rats. Furthermore, Pte dramatically decreased oligodendrocyte ferroptosis. Finally, we discovered that Pte can repair SCI by blocking ferroptosis via the Keap1/Nrf2/SLC7A11/GPX4 axis. Conclusions: Pte reduces lipid peroxidation via the Keap1/Nrf2/SLC7A11/GPX4 axis, which reduces the development of ferroptosis in oligodendrocytes and improves locomotor function in rats with SCI. Full article

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD (n = 176) and healthy controls (n = 8). We tested group differences using Mann–Whitney U or Kruskal–Wallis; determined diagnostic quality using ROC curves. Logistic regression was used to assess the relationship with decompensation. Associations with MELD and routine laboratory parameters were modeled using Spearman correlation and linear regression. We analyzed survival using Kaplan–Meier and Cox regression. Findings: IL-38 concentrations were found to be higher in decompensated (n = 94) than in compensated patients (n = 82) (p < 0.001). MELD was positively associated with IL-38 (p < 0.001; 95% CI 0.057–0.120). This corresponds to a 9.2% increase in IL-38 per 1-point increase in MELD (95% CI 5.9–12.7%). IL-38 correlated positively with the MELD score (p < 0.001) and with bilirubin/AST/LDH. In the combination model (MELD + IL-38 ± CRP), a very good AUC ≈ 0.92 was achieved. Conclusion: IL-38 reflects the severity of steatotic liver disease and is therefore a potentially predictive biomarker for early risk stratification and therapy monitoring. Full article