Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice.

Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.

Insights into targeting cellular senescence with senolytic therapy: The journey from preclinical trials to clinical practice.

Interconnected, fundamental aging processes are central to many illnesses and diseases. Cellular senescence is a mechanism that halts the cell cycle in response to harmful stimuli. Senescent cells (SnCs) can emerge at any point in life, and their persistence, along with the numerous proteins they secrete, can negatively affect tissue function. Interventions aimed at combating persistent SnCs, which can destroy tissues, have been used in preclinical models to delay, halt, or even reverse various diseases. Consequently, the development of small-molecule senolytic medicines designed to specifically eliminate SnCs has opened potential avenues for the prevention or treatment of multiple diseases and age-related issues in humans. In this review, we explore the most promising approaches for translating small-molecule senolytics and other interventions targeting senescence in clinical practice. This discussion highlights the rationale for considering SnCs as therapeutic targets for diseases affecting individuals of all ages.

Epigenetics in obesity: Mechanisms and advances in therapies based on natural products.

Obesity is a major risk factor for morbidity and mortality because it has a close relationship to metabolic illnesses, such as diabetes, cardiovascular diseases, and some types of cancer. With no drugs available, the mainstay of obesity management remains lifestyle changes with exercise and dietary modifications. In light of the tremendous disease burden and unmet therapeutics, fresh perspectives on pathophysiology and drug discovery are needed. The development of epigenetics provides a compelling justification for how environmental, lifestyle, and other risk factors contribute to the pathogenesis of obesity. Furthermore, epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms. Therefore, understanding epigenetic modifications to target the primary cause of obesity and the epigenetic mechanisms of anti-obesity effects with certain phytochemicals can prove rational strategies to prevent the disease and develop novel therapeutic interventions. Thus, the current review aimed to summarize the epigenetic mechanisms and advances in therapies for obesity based on natural products to provide evidence for the development of several potential anti-obesity drug targets.

Neutral polysaccharide from Gastrodia elata alleviates cerebral ischemia-reperfusion injury by inhibiting ferroptosis-mediated neuroinflammation via the NRF2/HO-1 signaling pathway.

AIMS: The crosstalk between ferroptosis and neuroinflammation considerably impacts the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). Neutral polysaccharide from Gastrodia elata (NPGE) has shown significant effects against oxidative stress and inflammation. This study investigated the potential effects of NPGE on CIRI neuropathology. METHODS: The effects of NPGE were studied in a mouse model of ischemic stroke (IS) and in oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cells. RESULTS: NPGE treatment decreased neurological deficits, reduced infarct volume, and alleviated cerebral edema in IS mice, and promoted the survival of OGD/R-induced HT22 cells. Mechanistically, NPGE treatment alleviated neuronal ferroptosis by upregulating GPX4 levels, lowering reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ excessive hoarding, and meliorating GSH levels and SOD activity. Additionally, it inhibited neuroinflammation by down-regulating the level of IL-1ß, IL-6, TNF-α, NLRP3, and HMGB1. Meanwhile, NPGE treatment alleviated ferroptosis and inflammation in erastin-stimulated HT22 cells. Furthermore, NPGE up-regulated the expression of NRF2 and HO-1 and promoted the translocation of NRF2 into the nucleus. Using the NRF2 inhibitor brusatol, we verified that NRF2/HO-1 signaling mediated the anti-ferroptotic and anti-inflammatory properties of NPGE. CONCLUSION: Collectively, our results demonstrate the protective effects of NPGE and highlight its therapeutic potential as a drug component for CIRI treatment.

Neuroprotective Potential of Punicalagin, a Natural Component of Pomegranate Polyphenols: A Review.

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD), are major health problems worldwide. To date, available remedies against NDs are limited. In fact, current treatment options include drug intervention and nutritional therapy, which mainly focus on the repair of neuronal damage and functional monitoring. However, these treatments do not completely alleviate disease symptoms. Recently, eliminating harmful molecules, such as reactive oxygen species, and inhibiting neuroinflammation have become potential strategies recommended by many researchers. Accordingly, remarkable interest has been generated in recent years regarding natural products, including polyphenols, that provide neuroprotective effects. In this review, we aimed to provide experimental evidence of the therapeutic potential of punicalagin (PUN), a prevailing compound in pomegranate polyphenols with antioxidant activity. Overall, the chemistry, methods of determination, characteristics of metabolism, transformation mechanisms of action, and neuroprotective effects of PUN on NDs are summarised to provide a scientific basis for elucidating the therapeutic mechanisms and targets of NDs.

Recent advancement in bioeffect, metabolism, stability, and delivery systems of apigenin, a natural flavonoid compound: challenges and perspectives.

Apigenin is a bioflavonoid compound that is widely present in dietary plant foods and possesses biological activities that protect against immune, cardiovascular, and neurodegenerative diseases and cancer. Therefore, apigenin is widely used in food and medicine, and increasing attention has been drawn to developing new delivery systems for apigenin. This review highlights the biological effects, metabolism, stability, and bioactivity of apigenin. In addition, we summarized advancements in the delivery of apigenin, which provides some references for its widespread use in food and medicine. Better stability of apigenin may enhance digestion and absorption and provide health benefits. Constructing delivery systems (such as emulsions, nanostructured lipid carriers, hydrogels, and liposomes) for apigenin is an effective strategy to improve its bioavailability, but more animal and cell experiments are needed to verify these findings. Developing apigenin delivery systems for food commercialization is still challenging, and further research is needed to promote their in-depth development and utilization.

Disease-Associated Oligodendrocyte: New Player in Alzheimer's Disease and CNS Pathologies.

Considerable evidence has shown that the breakdown of myelin has been linked to Alzheimer's disease (AD). Considering the vulnerability of oligodendrocytes to Alzheimer's disease, the myelin sheath breakdown and degeneration are easily induced, suggesting that dysfunction of the oligodendrocytes could be the first step in the progression at the early AD before the occurrence of amyloid and tau pathology. It is considered that amyloid ß-peptide (Aß)-mediated oligodendrocyte dysfunction and demyelination could be manifested through neuroinflammation, oxidative stress, and neuronal ferroptosis. With the development of single-cell sequencing technology, an oligodendrocyte state that increased in association with central nervous system brain pathology (designated as disease-associated oligodendrocytes) has been identified. In the current review, we examine the possible roles of oligodendrocytes in cognitive decline and their molecular characteristics in AD. Altogether, our findings elucidate that targeting oligodendrocytes may be a novel treatment or prevention option for AD.

Pomegranate polyphenol punicalagin improves learning memory deficits, redox homeostasis, and neuroinflammation in aging mice.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder characterized by loss of memory and cognitive dysfunction in the aged. Despite remarkable advances in drug therapy, effective pharmacological interventions are rare. Punicalagin (PU) is an active antioxidant polyphenol found in pomegranates, raspberries, blueberries, and chestnuts that has attracted considerable attention owing to its strong antioxidant and anti-inflammatory properties. The current study focused on the neuroprotective effect of PU on aging mice and its potential mechanisms. In this study, we first evaluated the protective effect of PU on neuro-2a (N2a) cell damage mediated by BV2 microglia-induced neuroinflammation. The in vivo D-galactose (D-gal)-induced brain aging model demonstrated that PU ameliorated deficits in learning and memory and prevented neuroinflammation, which was evident from the decrease in microglial activation and astrocytosis. Furthermore, PU reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and inhibited NLRP3 inflammasome activation, reducing the levels of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), interleukin-18 (IL-18), and interleukin-1 beta (IL-1ß) in both accelerated aging and naturally senescent mouse models. PU effectively improved neuroinflammation, learning and memory deficits, and redox homeostasis in aging mice, and it could be a potential therapeutic agent for AD.

Dihydrokaempferol attenuates CCl4-induced hepatic fibrosis by inhibiting PARP-1 to affect multiple downstream pathways and cytokines.

The pathophysiological mechanism of hepatic fibrosis (HF) is related to the excessive activation of the DNA repair enzyme poly ADP-ribose polymerase-1 (PARP-1). The drugs, targeting PARP-1, are scarce. Therefore, the lead compound, moderately inhibiting PARP-1, with anti-HF properties should be identified. This study screened dihydrokaempferol (DHK) from herbs based on preliminary studies to intervene in a CCl4-induced liver injury and HF model in mice. In vitro, the expression levels of PARP-1-regulated related proteins and phosphorylation were examined. The binding pattern of DHK and PARP-1 was analyzed using molecular docking and molecular dynamics platforms. The results showed that DHK could significantly attenuate CCl4-induced liver injury and HF in mice. Moreover, it could also attenuate the toxic effects of CCl4 on HepG2 and inhibit α-SMA and Collagen 1/3 synthesis of LX-2 cells in-vitro. Molecular docking revealed that DHK could competitively bind to the Glu-988 and His-862 residues of the upstream DNA repair enzyme PARP-1, moderately inhibiting its overactivation. This led to maintaining NAD+ levels and energy metabolism in hepatocytes and inhibiting the activation of PARP-1-regulated downstream signaling pathways (TGF-ß1, etc.), related proteins (p-Smd2/3, etc.), and inflammatory mediators while acting indirectly. Thus, DHK could attenuate CCl4-induced liver injury and HF in mice in a different mechanism from those of the existing reported flavonoids. It was associated with inhibiting the expression of downstream pathways and related cytokines by competitively binding to PARP-1. This study might provide a basis and direction for the design and exploration of anti-HF lead compounds.

Insight into the role of adult hippocampal neurogenesis in aging and Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia and seriously affects the quality of life of the elderly. Neurodegeneration is closely related to hippocampal dysfunction in AD patients. The hippocampus is key to creating new memories and is also one of the first areas of the brain to deteriorate with age. Mammalian neurogenesis occurs mainly in the hippocampus. Recent studies have confirmed that neurogenesis in the hippocampus is sustainable but decreases with age, which seriously affects the learning and memory function of AD patients. At present, our understanding of neurogenesis is still relatively shallow, especially pertaining to the influence and role of neurogenesis during aging and cognitive deficits in AD patients. Interestingly, many recent studies have described the characteristics of neurogenesis in animal models. This article reviews the progress of neurogenesis research in the context of aging and AD to provide new insights into neurogenesis.

Molecular Mechanisms of Luteolin Against Atopic Dermatitis Based on Network Pharmacology and in vivo Experimental Validation.

Purpose: To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation. Methods: TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB). Results: A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin. Conclusion: Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.

Development and evaluation of an online training program based on the O-AMAS teaching model for community pharmacists in the post-COVID-19 era.

Background: Formerly, the community pharmacists' work was mainly focused on drug supply. However, during the COVID-19 epidemic outbreak, community pharmacists in Wuhan played an important role in control and prevention of SARS-CoV-2 and in providing pharmaceutical care. Due to a lack of adequate knowledge and skills, many community pharmacists were not able to cope with healthcare work timely and efficiently. To improve community pharmacists' specialized knowledge and enhance their professional competence through systemic training in the post-COVID-19 era. Methods: Based on the O-AMAS (Objective, Activation, Multi-learning, Assessment and Summary) teaching model and flipped classroom, an online continuing training program containing four sections was developed. It was a semi-experimental study with no control group. Quantitative tests before and after training as well as questionnaire were used to evaluate the outcome of this training program for community pharmacists. Results: A total of twenty-six community pharmacists were invited to participate in continuing education, and twenty-five trainees finished this training program with a completion rate of 96.2 %. Quantitative tests before and after training and anonymous questionnaires were carried out to comprehensively evaluate the outcomes of this training program. Compared with the test scores before training (61.6 ± 6.6), the score after training was statistically higher, reaching 80.9 ± 7.5 (P < 0.001). Twenty-three questionnaires were received (returns ratio, 92.0%). Notably, most of the pharmacists were satisfied with the training program. The percentage of positive responses for each item in this anonymous questionnaire was more than 85 %. Conclusion: It was suggested that the O-AMAS model and the flipped classroom-based continuing educational program achieved the expected training effects. It is a promising on-the-job training approach for pharmacy continuing education. Moreover, our study also demonstrated that online learning had advantages of no geographic constraints, flexible learning beyond time and easy interaction, over traditional face-to-face training style, especially in the post-pandemic era.

Tryptophan-5-HT pathway disorder was uncovered in the olfactory bulb of a depression mice model by metabolomic analysis.

Major depression (MD) is a severe mental illness that creates a heavy social burden, and the potential molecular mechanisms remain largely unknown. Lots of research demonstrate that the olfactory bulb is associated with MD. Recently, gas chromatography-mass spectrometry-based metabolomic studies on depressive rats indicated that metabolisms of purine and lipids were disordered in the olfactory bulb. With various physicochemical properties and extensive concentration ranges, a single analytical technique could not completely cover all metabolites, hence it is necessary to adopt another metabolomic technique to seek new biomarkers or molecular mechanisms for depression. Therefore, we adopted a liquid chromatography-mass spectrometry metabonomic technique in the chronic mild stress (CMS) model to investigate significant metabolic changes in the olfactory bulb of the mice. We discovered and identified 16 differential metabolites in the olfactory bulb of the CMS treatments. Metabolic pathway analysis by MetaboAnalyst 5.0 was generated according to the differential metabolites, which indicated that the tryptophan metabolism pathway was the core pathogenesis in the olfactory bulb of the CMS depression model. Further, the expressions of tryptophan hydroxylase (TpH) and aromatic amino acid decarboxylase (AAAD) were detected by western blotting and immunofluorescence staining. The expression of TpH was increased after CMS treatment, and the level of AAAD was unaltered. These results revealed that abnormal metabolism of the tryptophan pathway in the olfactory bulb mediated the occurrence of MD.

Recent Advances and Perspectives on the Health Benefits of Urolithin B, A Bioactive Natural Product Derived From Ellagitannins.

Urolithin (Uro) B is a natural compound produced by gut bacteria from ingested ellagitannins (ETs) and ellagic acid (EA), complex polyphenols abundant in foods such as pomegranates, raspberries, blueberries and chestnuts. Uro B has recently garnered considerable attention owing to its wide range of nutraceutical effects and relatively high potency. According to several studies, Uro B prevents the development of hyperlipidemia, cardiovascular disease (CVD) and tumors due to its strong antioxidant and anti-inflammatory properties. Many reviews have systematically summarized the health benefits and pharmacological activities of ETs, EA and urolithins (especially Uro A) while available reviews or detailed summaries on the positive impact of Uro B are rarer. Here, we sought to review the pharmacological activity, mechanism of action, regulation of immune function and its associated diseases and preventive potential of Uro B to elucidate its function as a nutritional agent in humans.

Understanding the Role of Glia-Neuron Communication in the Pathophysiology of Epilepsy: A Review.

Epilepsy is a chronic brain disorder that causes repeated seizures. It affects 65 million people worldwide and is a major burden on individuals and health systems. It has been reported that factors leading to ion channel disfuntion, neuronal damage and are all involved in the pathogenesis of epilepsy. The exact etipathogenic mechanism is unknown and appropriate therapeutic targets remain elusive. Recent studies point to a significant contribution by non-neuronal cells, the glia-especially astrocytes and microglia-in the pathophysiology of epilepsy. This review critically evaluates the role of glia-induced hyperexcitability in the pathogenesis of epilepsy to provide a better understanding of the contribution of glia to epilepsy.

Serum Metabolomics Analysis of the Anti-Inflammatory Effects of Gallic Acid on Rats With Acute Inflammation.

Background: Gallic acid (GA) is a natural small-molecule polyphenol having a wide range of pharmacological activities. Until now, some works have studied the effect and the mechanisms of GA against inflammation. However, whether or how gallic acid regulates the downstream metabolic disorder against acute inflammation remains unclear. The present study explored the protective effect and the potential mechanism of GA on acute inflammation through the metabolomics approach. Methods: An acute inflammation rat model was induced by local injection of carrageenin. Local swelling on paw and serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) were assessed in Control, Model and Gallic acid groups, respectively. Serum metabolomics based on high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) was also established to collect rats' metabolic profiles and explore the metabolic changes related to GA pretreatment. Results: Compared to the Modal group, local pain, redness, and swelling induced by carrageenin were significantly alleviated in GA groups in addition to the dose-dependent decreases of TNF-α and IL-6. Metabolomics analysis found significant alterations in metabolic signatures between the carrageenin-induced inflammation and control groups. Twelve potential biomarkers were further identified in acute inflammation by principal component analysis (PCA) and partial least squares discrimination analysis (PLS-DA). In addition, when rats were pretreated with gallic acid, serum levels of eleven biomarkers were observed to restore partially. Metabolic pathway and networks analysis revealed that GA might invert the pathological process of acute inflammation by regulating the key biomarkers involved in linoleic acid metabolism, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and arachidonic acid (AA) metabolism pathways. Conclusion: The study elucidates the protective effect of gallic acid against acute inflammation and its possible regulating mechanism from a metabolomic perspective. These results could provide a theoretical basis for clarifying gallic acid's mechanism and potential medicinal value in curing inflammation disorder in the clinic.

Urolithin A alleviates acute kidney injury induced by renal ischemia reperfusion through the p62-Keap1-Nrf2 signaling pathway.

Acute kidney injury (AKI) induced by renal ischemia reperfusion (RIR) is typically observed in renal surgeries and is a leading cause of renal failure. However, there is still an unmet medical need currently in terms of clinical treatments. Herein, we report the effect of Urolithin A (UA) in a mouse RIR model, wherein we demonstrated its underlying mechanism both in vitro and in vivo. The expression levels of p62 and Keap1 significantly decreased, while that of nuclear Nrf2 increased in vitro in a hypoxia cell model after UA treatment. Furthermore, the apoptosis of tubular cells was attenuated and the reactive oxygen species (ROS) levels were reduced in the kidneys in a mouse RIR model after UA administration. In this study, we demonstrated that UA can alleviate oxidative stress and promote autophagy by activating the p62-Keap1-Nrf2 signaling pathway, which could protect the kidneys from ischemia reperfusion injury.

Correction: Gut microbial metabolite urolithin B attenuates intestinal immunity function in vivo in aging mice and in vitro in HT29 cells by regulating oxidative stress and inflammatory signalling.

Correction for 'Gut microbial metabolite urolithin B attenuates intestinal immunity function in vivo in aging mice and in vitro in HT29 cells by regulating oxidative stress and inflammatory signalling' by Peng Chen et al., Food Funct., 2021, 12, 11938-11955, DOI: 10.1039/D1FO02440J.

The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice.

Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.