Search Results (108)

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK’s critical role in mediating E2’s actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2’s full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2’s protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Brassinosteroids, as unique plant steroid hormones that bear structural similarity to animal steroids, play a crucial role in modulating plant growth and development. These hormones have a positive impact on plant resistance and, under stressful conditions, stimulate photosynthesis and antioxidative systems (enzymatic and non-enzymatic), leading to a reduced impact of environmental cues on plant metabolism and growth. Although these plant hormones have been studied for several decades, most studies analyze the primary site of action of the brassinosteroid phytohormone, with a special emphasis on the activation of various genes (mainly nuclear) through different signaling processes that influence plant metabolism, growth, and development. This review explores another issue, the secondary influence (the so-called mode of action) of brassinosteroids on changes in growth, development, and chemical composition, as well as thermodynamic and energetic changes, mainly during the early growth of corn seedlings. The interactions of brassinosteroids with other phytohormones and physiologically active substances and the influence of these interactions on the mode of action of brassinosteroid phytohormones were also discussed. Seen from a cybernetic point of view, the approach can be labeled as “black box” or “gray box”. “Black box” and “gray box” are terms for cybernetic systems, for which we know the inputs and outputs (in an energetic, biochemical, kinetic, informational, or some other sense), but whose internal structure and/or organization are completely or partially unknown to us. The findings of many researchers have indicated an important role of reactive species, such as oxygen and nitrogen reactive species, in these processes. This ultimately results in the redistribution of matter and energy from source organs to sink organs, with a decrease in Gibbs free energy from the source to sink organs. This quantitative evidence speaks of the exothermic nature and spontaneity of early (corn) seedling development and growth under the influence of 24-epibrassinolide. Based on these findings and a review of the literature on the mode of action of brassinosteroids, a hypothesis was put forward about the secondary effects of BRs on germination and the early growth of plant seedlings. Full article

Background: It is true that vitamin D did not earn its title as the “sunshine vitamin” for nothing. In recent years, however, there has been a shift in the perception surrounding vitamin D to a type of hormone that boasts countless bioactivities and health advantages. Historically, vitamin D has been known to take care of skeletal integrity and the calcium–phosphorus balance in the body, but new scientific research displays a much larger spectrum of actions handled by this vitamin. Materials and Methods: A systematic literature search was performed using the following electronic databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library. Results: Many emerging new ideas, especially concerning alternative hormonal pathways and vitamin D analogs, are uniformly challenging the classic “one hormone–one receptor” hypothesis. To add more context to this, the vitamin D receptor (VDR) was previously assumed to be the only means through which the biologically active steroid 1,25-dihydroxyvitamin D3 could impact the body. Two other molecules apart from the active hormonal form of 1,25(OH)2D3 have gained interest in recent years, and these have reinvigorated research on D3 metabolism. These metabolites can interact with several other nuclear receptors (like related orphan receptor alpha—RORα, related orphan receptor gamma—RORγ, and aryl hydrocarbon receptor—AhR) and trigger various biological responses. Conclusions: This paper thus makes a case for placing vitamin D at the forefront of new holistic and dermatological health research by investigating the potential synergies between the canonical and noncanonical vitamin D pathways. This means that there are now plentiful new opportunities for manipulating and understanding the full spectrum of vitamin D actions, far beyond those related to minerals. Full article

Gonadotropins and progestins are the primary regulators of follicle maturation and ovulation in fish, and they require complex communication among the oocyte and somatic cells of the follicle. The major progestin and the maturation-inducing hormone in salmonids is 17α,20β-dihdroxy-4-pregnen-3-one (17,20βP), and traditional nuclear receptors and membrane steroid receptors for the progestin have been identified within the follicle. Herein, RNA-seq was used to conduct a comprehensive survey of changes in gene expression throughout the intact follicle in response to in vitro treatment with these hormones to provide a foundation for understanding the coordination of their actions in regulating follicle maturation and preparation for ovulation. A total of 5292 differentially expressed genes were identified from our transcriptome sequencing datasets comparing four treatments: fresh tissue; untreated control; 17,20βP-treated; and salmon pituitary homogenate-treated follicles. Extensive overlap in affected genes suggests many gonadotropin actions leading to the acquisition of maturational and ovulatory competence are mediated in part by gonadotropin induction of 17,20βP synthesis. KEGG analysis identified signaling pathways, including MAPK, TGFβ, FoxO, and Wnt signaling pathways, among the most significantly enriched pathways altered by 17,20βP treatment, suggesting pervasive influences of 17,20βP on actions of other endocrine and paracrine factors in the follicle complex. Full article

Metabolic-Associated Fatty Liver Disease (MAFLD) is a clinical–pathological scenario that occurs due to the accumulation of triglycerides in hepatocytes which is considered a significant cause of liver conditions and contributes to an increased risk of death worldwide. Even though the possible causes of MAFLD can involve the interaction of genetics, hormones, and nutrition, lifestyle (diet and sedentary lifestyle) is the most influential factor in developing this condition. Polyphenols comprise many natural chemical compounds that can be helpful in managing metabolic diseases. Therefore, the aim of this review was to investigate the impact of oxidative stress, inflammation, mitochondrial dysfunction, and the role of polyphenols in managing MAFLD. Some polyphenols can reverse part of the liver damage related to inflammation, oxidative stress, or mitochondrial dysfunction, and among them are anthocyanin, baicalin, catechin, curcumin, chlorogenic acid, didymin, epigallocatechin-3-gallate, luteolin, mangiferin, puerarin, punicalagin, resveratrol, and silymarin. These compounds have actions in reducing plasma liver enzymes, body mass index, waist circumference, adipose visceral indices, lipids, glycated hemoglobin, insulin resistance, and the HOMA index. They also reduce nuclear factor-KB (NF-KB), interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), blood pressure, liver fat content, steatosis index, and fibrosis. On the other hand, they can improve HDL-c, adiponectin levels, and fibrogenesis markers. These results show that polyphenols are promising in the prevention and treatment of MAFLD. Full article

The protein menin is encoded by the MEN1 gene and primarily serves as a nuclear scaffold protein, regulating gene expression through its interaction with and regulation of chromatin modifiers and transcription factors. While the scope of menin’s functions continues to expand, one area of growing investigation is the role of menin in cancer. Menin is increasingly recognized for its dual function as either a tumor suppressor or a tumor promoter in a highly tumor-dependent and context-specific manner. While menin serves as a suppressor of neuroendocrine tumor growth, as seen in the cancer risk syndrome multiple endocrine neoplasia type 1 (MEN1) syndrome caused by pathogenic germline variants in MEN1, recent data demonstrate that menin also suppresses cholangiocarcinoma, pancreatic ductal adenocarcinoma, gastric adenocarcinoma, lung adenocarcinoma, and melanoma. On the other hand, menin can also serve as a tumor promoter in leukemia, colorectal cancer, ovarian and endometrial cancers, Ewing sarcoma, and gliomas. Moreover, menin can either suppress or promote tumorigenesis in the breast and prostate depending on hormone receptor status and may also have mixed roles in hepatocellular carcinoma. Here, we review the rapidly expanding literature on the role and function of menin across a broad array of different cancer types, outlining tumor-specific differences in menin’s function and mechanism of action, as well as identifying its therapeutic potential and highlighting areas for future investigation. Full article

Cymbidium ensifolium, a prominent orchid species, is both highly valued for its ornamental qualities and commercially cultivated. However, the species has a considerable challenge in its breeding efforts due to the lengthy period of 7–8 years required for it to transition from seed germination to flowering. BBXs are multifunctional proteins that modulate the actions of critical regulators including HY5 and COP1 in response to blue light, ultimately impacting photomorphogenic processes. In this study, BBX proteins, known for their essential roles in regulating developmental processes under various light conditions, were chosen as the main subject of investigation. The outcome reveals the presence of 19 BBX genes in their genome. The genes are classified into four separate clades and dispersed among 12 out of the 20 chromosomes. Located in the nuclear, physicochemical properties of proteins, analysis of the promoter region reveals the existence of almost 800 cis-acting elements, highlighting the complex regulatory mechanisms that control the expression of the CeBBXs in various organs, as well as their response to light and hormone inputs. Moreover, the examination of differential expression under blue light therapy reveals their involvement in photomorphogenic reactions. The expression of CeBBXs exhibits substantial alterations as the duration of exposure to blue light increases. These findings contribute to a deeper understanding of the roles that BBX genes serve in C. ensifolium, providing a basis for future studies on the functions and regulatory mechanisms of BBX members in the context of floral initiation and development within this species. Full article

This review aims to gain insight into the major causes of hair graying (canities) and how plant-derived extracts and phytochemicals could alleviate this symptom. Research articles on human hair graying were searched and selected using the PubMed, Web of Science, and Google Scholar databases. We first examined the intrinsic and extrinsic factors associated with hair graying, such as the reduced capacity of melanin synthesis and transfer, exhaustion of melanocyte stem cells (MSCs) and melanocytes, genetics and epigenetics, race, gender, family history, aging, oxidative stress, stress hormones, systematic disorders, nutrition, smoking, alcohol consumption, lifestyle, medications, and environmental factors. We also examined various plants and phytochemicals that have shown a potential to interfere with the onset or progression of human hair graying at different levels from in vitro studies to clinical studies: the extract of Polygonum multiflorum and its major components, 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside and emodin; the extract of Eriodictyon angustifolium and its major flavonoid compounds, hydroxygenkwanin, sterubin, and luteolin; the extracts of Adzuki beans (Vigna angularis), Fuzhuan brick tea (Camellia sinensis), and Gynostemma pentaphyllum; bixin, a carotenoid compound found in Bixa orellana; and rhynchophylline, an alkaloid compound found in certain Uncaria species. Experimental evidence supports the notion that certain plant extracts and phytochemicals could alleviate hair graying by enhancing MSC maintenance or melanocyte function, reducing oxidative stress due to physiological and environmental influences, and managing the secretion and action of stress hormones to an appropriate level. It is suggested that hair graying may be reversible through the following tactical approaches: selective targeting of the p38 mitogen-activated protein kinase (MAPK)–microphthalmia-associated transcription factor (MITF) axis, nuclear factor erythroid 2-related factor 2 (NRF2), or the norepinephrine–β2 adrenergic receptor (β2AR)–protein kinase A (PKA) signaling pathway. Full article

Glyphosate, the active ingredient of several broad-spectrum herbicides, is widely used throughout the world, although many adverse effects are known. Among these, it has been recognized as an endocrine disruptor. This work aimed to test the effects and potential endocrine disrupting action of glyphosate on PNT1A human prostate cells, an immortalized non-tumor epithelial cell line, possessing both ERα and ERβ estrogen receptors. The results showed that glyphosate induces cytotoxicity, mitochondrial dysfunction, and rapid activation of ERα and ERβ via nuclear translocation. Molecular analysis indicated a possible involvement of apoptosis in glyphosate-induced cytotoxicology. The apoptotic process could be attributed to alterations in mitochondrial metabolism; therefore, the main parameters of mitochondrial functionality were investigated using the Seahorse analyzer. Impaired mitochondrial function was observed in glyphosate-treated cells, with reductions in ATP production, spare respiratory capacity, and proton leakage, along with increased efficiency of mitochondrial coupling. Finally, the results of immunofluorescence analysis demonstrated that glyphosate acts as an estrogen disruptor determining the nuclear translocation of both ERs. Nuclear translocation occurred independent of dose, faster than the specific hormone, and persisted throughout treatment. In conclusion, the results collected show that in non-tumor prostate cells glyphosate can cause cell death and acts as a xenoestrogen, activating estrogen receptors. The consequent alteration of hormonal functions can have negative effects on the reproductive health of exposed animals, compromising their fertility. Full article

This study summarizes new data on induced spawning of Steindachneridion parahybae, focusing on the aggressive behavior of females. This study characterizes the vasotocinergic system using immunohistochemistry, highlighting the potential influence of arginine-vasotocin (AVT) on reproductive physiology. Two experimental groups were proposed: (A) control, with one female in the aquarium, and (B) experimental, with two females in the same aquarium. Dominant (D) females presented a more aggressive behavior and did not show any injury. They apparently had a length and body mass higher than injured nondominant (ND) females. The analysis identified positive AVT immunoreactive (ir) neurons exclusively within the preoptic area, including parvocellular, magnocellular, and gigantocellular subpopulations, containing fibers-ir extending into the pituitary gland. Cellular and nuclear areas were greater in D compared to ND in the magnocellular subpopulation. There were no differences between parvocellular and gigantocellular subpopulations. There was a difference on the steroid plasma profile of cortisol (more in ND than in D) and 17α,20β-dihydroxy-4-pregnen-3-one (more in D than in ND). Furthermore, control and D females presented higher optical densities for AVT-ir, gonadotropin-releasing hormone-ir, and luteinizing hormone-ir than ND. In general, there were no differences in the results of female (control group) with D females. The AVT system is highly complex, possibly counting multiple sites of action during artificial reproduction and acting directly and/or indirectly associated with behavioral and physiological changes in S. parahybae females when induced to spawning. Full article

Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D₂ [ercalcitriol, 1,25(OH)₂D₂] and 1α,25-dihydroxyvitamin D₃ [calcitriol, 1,25(OH)₂D₃], which act as classical steroid hormones. 1,25(OH)₂D₃ exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)₂D₃ cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)₂D₃ and 1,25(OH)₂D₂ have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies. Full article

Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) buildup and neuronal degeneration. An association between low serum vitamin D levels and an increased risk of AD has been reported in several epidemiological studies. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, and is generated in the kidney and many other tissues/organs, including the brain. It is a steroid hormone that regulates important functions like calcium/phosphorous levels, bone mineralization, and immunomodulation, indicating its broader systemic significance. In addition, calcitriol confers neuroprotection by mitigating oxidative stress and neuroinflammation, promoting the clearance of Aβ, myelin formation, neurogenesis, neurotransmission, and autophagy. The receptors to which calcitriol binds (vitamin D receptors; VDRs) to exert its effects are distributed over many organs and tissues, representing other significant roles of calcitriol beyond sustaining bone health. The biological effects of calcitriol are manifested through genomic (classical) and non-genomic actions through different pathways. The first is a slow genomic effect involving nuclear VDR directly affecting gene transcription. The association of AD with VDR gene polymorphisms relies on the changes in vitamin D consumption, which lowers VDR expression, protein stability, and binding affinity. It leads to the altered expression of genes involved in the neuroprotective effects of calcitriol. This review summarizes the neuroprotective mechanism of calcitriol and the role of VDR polymorphisms in AD, and might help develop potential therapeutic strategies and markers for AD in the future. Full article

Colon cancer (CRC) is a prevalent malignancy that exhibits distinct differences in incidence, prognosis, and treatment responses between males and females. These disparities have long been attributed to hormonal differences, particularly the influence of oestrogen signalling. This review aims to provide a comprehensive analysis of recent advances in our understanding of the molecular mechanisms underlying sex differences in colon cancer and the protective role of membrane and nuclear oestrogen signalling in CRC development, progression, and therapeutic interventions. We discuss the epidemiological and molecular evidence supporting sex differences in colon cancer, followed by an exploration of the impact of oestrogen in CRC through various genomic and nongenomic signalling pathways involving membrane and nuclear oestrogen receptors. Furthermore, we examine the interplay between oestrogen receptors and other signalling pathways, in particular the Wnt/β-catenin proliferative pathway and hypoxia in shaping biological sex differences and oestrogen protective actions in colon cancer. Lastly, we highlight the potential therapeutic implications of targeting oestrogen signalling in the management of colon cancer and propose future research directions to address the current gaps in our understanding of this complex phenomenon. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD. Full article