Dutasteride for the Treatment of Androgenetic Alopecia: An Updated Review.

BACKGROUND: Androgenetic alopecia (AGA) is a common skin disease characterized by progressive hair loss, with negative psychological impacts on patients, especially young people. The primary pathogenesis of AGA involves the action of 5α-reductase converting testosterone to dihydrotestosterone, leading to gradual miniaturization of genetically susceptible hair follicles. Finasteride inhibits type II 5α-reductase, while dutasteride simultaneously inhibits type I and type II 5α-reductase. Currently, finasteride is approved by the Food and Drug Administration (FDA) for the treatment of AGA, but its efficacy remains poor in some patients. OBJECTIVES: This article aims to review the treatment of androgenetic alopecia with dutasteride. Oral dutasteride, intradermal injection of dutasteride (mesotherapy) and other related treatment methods are included. METHODS: We performed a Medical Subject Heading search in the PubMed database using "androgenetic alopecia" and "dutasteride". CONCLUSIONS: Compared to finasteride, oral dutasteride has better efficacy and comparable tolerability, and most adverse events are mild and reversible, making it an effective treatment option for AGA. Mesotherapy with dutasteride is a therapeutic option to reduce the systemic adverse effects of the drug, but there are no standardized treatment protocols and large-scale clinical trials. Microneedling combined with dutasteride solution also has its own unique efficacy for treating AGA. Liposomes or nanoparticles of dutasteride are still under development and may become a more optimized topical formulation in the future.

TRPV4 Blockage Inhibits the Neurogenesis in the Adult Hippocampal Dentate Gyrus Following Pilocarpine­Induced Status Epilepticus.

Aberrant neurogenesis in the adult hippocampal dentate gyrus (DG) contributes to synapse remodeling during temporal lobe epilepsy (TLE). Transient receptor potential vanilloid 4 (TRPV4) is involved in the pathogenesis of TLE. Activation of TRPV4 can modulate neurogenesis in the adult hippocampal DG. The present study examined whether TRPV4 is responsible for the aberrant neurogenesis in the adult hippocampal DG during TLE. Herein, administration of a TRPV4-specific antagonist, HC-067047, attenuated the enhanced neural stem cell proliferation in the adult hippocampal DG in mice following pilocarpine­induced status epilepticus (PISE). HC-067047 reduced the heightened hippocampal protein levels of cyclin-dependent kinase (CDK) 2, CDK6, cyclin E1, cyclin A2, and phosphorylated retinoblastoma (p-Rb) observed following PISE. Meanwhile, HC-067047 inhibited the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) pathways that were enhanced and responsible for the increased proliferation of stem cells and higher levels of CDKs, cyclins, and p-Rb protein. HC-067047 reduced the 28-day-old BrdU+ cells but increased the ratio of 28-day-old BrdU+ cells to 1-day-old BrdU+ cells, indicating that TRPV4 blockage reduced the number but increased the survival rate of newborn cells following PISE. Finally, HC-067047 increased the Akt signaling that was inhibited and responsible for the decreased survival rate of newborn cells following PISE. It is concluded that TRPV4 blockage inhibits stem cell proliferation in the hippocampal DG following PISE, likely through inhibiting ERK1/2 and p38 MAPK signaling to decrease cell cycle-related protein expression, and increases newborn cell survival rate likely through increasing phosphoinositide 3 kinase-Akt signaling.

New natural protein tyrosine phosphatase 1B inhibitors from Gynostemma pentaphyllum.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease mainly caused by insulin resistance, which can lead to a series of complications such as cardiovascular disease, retinopathy, and its typical clinical symptom is hyperglycaemia. Glucosidase inhibitors, including Acarbose, Miglitol, are commonly used in the clinical treatment of hypoglycaemia. In addition, Protein tyrosine phosphatase 1B (PTP1B) is also an important promising target for the treatment of T2DM. Gynostemma pentaphyllum is a well-known oriental traditional medicinal herbal plant, and has many beneficial effects on glucose and lipid metabolism. In the present study, three new and nine known dammarane triterpenoids isolated from G. pentaphyllum, and their structures were elucidated by spectroscopic methods including HR-ESI-MS,1H and 13C NMR and X-ray crystallography. All these compounds were evaluated for inhibitory activity against α-glucosidase, α-amylase and PTP1B. The results suggested that compounds 7∼10 were potential antidiabetic agents with significantly inhibition activity against PTP1B in a dose-dependent manner.

Causal effects of genetically determined metabolites on androgenetic alopecia: A two-sample Mendelian randomization analysis.

BACKGROUND: Androgenic alopecia (AGA) is the most common non-scarring alopecia disorder. Given its increasing incidence and onset during adolescence, AGA significantly impacts both the physical and psychological well-being of affected individuals. Emerging evidence suggests a pivotal role of metabolites in AGA. This study aims to elucidate the causal relationship between metabolites and AGA using Mendelian randomization (MR) analysis. METHODS: We conducted a two-sample Mendelian randomization (TSMR) analysis based on a genome-wide association study (GWAS) to assess the causality of 452 metabolites on AGA. The main approach employed for inferring causal effects was inverse variance weighted (IVW), which was complemented by MR-Egger regression, weighted median, as well as MR pleiotropy residual sum and outlier (MR-PRESSO) approaches. Additionally, sensitivity analyses were performed to ensure result robustness. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) in GWAS dataset comprising 452 metabolites. RESULTS: Notably, we identified Scyllo-inositol and Alpha-ketoglutarate as the most potent protective factors against AGA, while Heme* and 2-palmitoylglycerophosphocholine* emerged as significant risk factors for AGA. Furthermore, sensitivity analysis revealed no heterogeneity in these findings. CONCLUSIONS: Overall, our research suggests a potential causal link between metabolites and AGA, offering a more comprehensive insight into the pathogenesis of AGA and present additional strategies for prevention and treatment.

Acacetin alleviates autoimmune myocarditis by regulating CD4+ T cell mitochondrial respiration.

BACKGROUND: Myocarditis refers to an autoimmune inflammatory response of the myocardium with characterization of self-reactive CD4+ T cell activation, which lacks effective treatment and has a poor prognosis. Acacetin is a natural flavonoid product that has been reported to have anti-inflammatory effects. However, acacetin has not been investigated in myocarditis. METHODS: Oral acacetin treatment was administered in an experimental autoimmune myocarditis model established with myosin heavy chain-alpha peptide. Echocardiography, pathological staining, and RT-qPCR were used to detect cardiac function, myocardial injury, and inflammation levels. Flow cytometry was utilized to detect the effect of acacetin on CD4+ T cell function. RNA-seq, molecular docking, and microscale thermophoresis (MST) were employed to investigate potential mechanisms. Seahorse analysis, mitoSOX, JC-1, and mitotracker were utilized to detect the effect of acacetin on mitochondrial function. RESULTS: Acacetin attenuated cardiac injury and fibrosis as well as heart dysfunction, and reduced cardiac inflammatory cytokines and ratio of effector CD4+ T and Th17 cells. Acacetin inhibited CD4+ T cell activation, proliferation, and Th17 cell differentiation. Mechanistically, the effects of acacetin were related to reducing mitochondrial complex II activity thereby inhibiting mitochondrial respiration and mitochondrial reactive oxygen species in CD4+ T cells. CONCLUSION: Acacetin may be a valuable therapeutic drug in treating CD4+ T cell-mediated myocarditis.

Photodynamic therapy for the treatment of port-wine stains in phakomatosis pigmentovascularis.

BACKGROUND: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome. Only a few studies have reported the treatment of PPV, including a case using photodynamic therapy (PDT) to treat PPV-associated port-wine stains (PWS). OBJECTIVE: To investigating the efficacy and adverse effects of hemoporfin-PDT in PPV-associated PWS. METHODS: The efficacy and adverse effects in patients with PPV who underwent two sessions of hemoporfin-PDT from January 2019 to December 2022 were retrospectively analyzed. RESULTS: Twenty patients were included (13 females, 7 males, age range: 2-31 years; mean: 8.20 ± 8.92 years). Two, nine, seven, and two patients had PPV types Ia, IIa, IIb, and IIIa, respectively. After two treatments, the visual evaluation indicated the color of the PWS in 4, 5, 6, and 5 patients showed poor, fair, good, and excellent improvements, respectively. The combined good and excellent improvement rates in patients with PWS and pigmentary nevus overlapping in the same treatment area and in patients with PWS in the treatment areas only were 33.3% versus 87.5%, respectively, and were significantly different (p = 0.02). Minor side effects, such as edema, scabbing, hyperpigmentation, and blistering, were observed in some patients after PDT. CONCLUSION: Hemoporfin-PDT is an effective treatment for PPV-associated PWS. Patients with PWS and pigmentary nevus overlapping in the same treatment area showed poorer efficacy than patients with PWS in the treatment areas only.

Comparison of the efficacy and safety of benzbromarone and febuxostat in gout and hyperuricemia: a systematic review and meta-analysis.

OBJECTIVE: Urate-lowering therapy (ULT) is widely recognized as the primary treatment for hyperuricemia and gout. Xanthine oxidase inhibitors (XOI), particularly febuxostat, have gained popularity as a frontline approach. However, the divergent efficacy and safety between febuxostat and the traditional ULT drug, benzbromarone, remain poorly understood. This knowledge gap necessitates a comprehensive analysis and evidence update to guide drug selection for physicians and patients. METHOD: We conducted a systematic analysis by extracting relevant clinical studies from four medical literature databases. Forest plots, funnel plots, sensitivity analysis, Egger's test, and subgroup analysis were utilized to compare relevant indicators. RESULTS: The advantages and disadvantages of the two drugs were evaluated based on various indicators such as serum uric acid (SUA), triglyceride (TG), urinary uric acid (UUA), white blood cell count (WBC), total cholesterol (TC), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and serum creatinine (SC). Benzbromarone demonstrated better efficacy in rapidly reducing SUA levels and inhibiting inflammation for hyperuricemia and gout patients. Febuxostat was slightly less effective in lowering SUA, but there was no significant difference in its impact on liver and kidney function after long-term use. CONCLUSION: This study highlights the superiority of benzbromarone in rapidly reducing SUA and inhibiting inflammation. Febuxostat shows comparable effects on liver and kidney function after long-term use. These findings provide valuable insights for clinicians and patients in drug selection. Key Points • Benzbromarone stands out as a highly effective treatment for hyperuricemia and gout, offering rapid reduction of serum uric acid levels and potent anti-inflammatory effects. • When it comes to long-term use, febuxostat demonstrates comparable effects on liver and kidney function. This provides reassurance for patients who require extended treatment duration. • Moreover, our study goes beyond previous research by presenting a more comprehensive and detailed analysis.

Construction of in vitro liver-on-a-chip models and application progress.

The liver is the largest internal organ of the human body. It has a complex structure and function and plays a vital role in drug metabolism. In recent decades, extensive research has aimed to develop in vitro models that can simulate liver function to demonstrate changes in the physiological and pathological environment of the liver. Animal models and in vitro cell models are common, but the data obtained from animal models lack relevance when applied to humans, while cell models have limited predictive ability for metabolism and toxicity in humans. Recent advancements in tissue engineering, biomaterials, chip technology, and 3D bioprinting have provided opportunities for further research in in vitro models. Among them, liver-on-a-Chip (LOC) technology has made significant achievements in reproducing the in vivo behavior, physiological microenvironment, and metabolism of cells and organs. In this review, we discuss the development of LOC and its research progress in liver diseases, hepatotoxicity tests, and drug screening, as well as chip combinations. First, we review the structure and the physiological function of the liver. Then, we introduce the LOC technology, including general concepts, preparation materials, and methods. Finally, we review the application of LOC in disease modeling, hepatotoxicity tests, drug screening, and chip combinations, as well as the future challenges and directions of LOC.

Causal Effects of Lipids-Related Metabolites on Androgenic Alopecia: A Mendelian Randomization Study.

Purpose: To investigate whether increased levels of lipids-related metabolites (LRMs) result in androgenic alopecia (AGA). Patients and Methods: A two-sample Mendelian randomization (MR) study was designed, and single nucleotide polymorphisms (SNPs) respectively related to nine LRMs were selected from the genome-wide association study (GWAS) dataset. An MR analysis was performed to assess the causal association between LRMs and AGA. Results: Through the fixed-effect inverse variance weighting (IVW) method, MR analysis indicated that Apolipoprotein B (ApoB), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) had a causal relationship with AGA. No obvious heterogeneity or pleiotropy was observed. Conclusion: The risk of AGA increases significantly when the serum levels of ApoB, LDL, and VLDL increase. This causal relationship is solid and free of interference from confounding factors.

Effectiveness and safety of baricitinib in patients with moderate-to-severe refractory alopecia areata in real world: An open-label, single-center study.

PURPOSE: Baricitinib is a small-molecular drug that selectively inhibits the Janus Kinase (JAK) 1 and 2. However, it showed various efficiency and safety in treating moderate-to-severe alopecia areata (AA). This study was to describe the real-world effectiveness of baricitinib in treating moderate-to-severe refractory AA. METHODS: Patients who were affected by moderate-to-severe AA and reported no shrinkage in the alopecia area after 6 months of conventional treatment were enrolled in the retrospective study. The patients were treated with baricitinib orally for at least 24 weeks. The severity of alopecia was evaluated at the end of 4, 12, and 24 weeks of treatment. RESULTS: The 32 patients included 23 females and nine males, with a median duration of AA of 14.5 months. Among them, 28 patients received baricitinib 2 mg per day for 24 weeks while the other four patients increased the daily dose from 2 to 4 mg after the first 12 weeks due to the unobvious hair restoration. SALT value showed a significant decrease from baseline at week 12 and 24 (64.45 [44.68-100.00] vs. 26.80 [13.40-62.32], p < 0.0001 and 64.45 [44.68-100] vs. 9.40 [4.85-34.95], p < 0.0001). After 24 weeks of treatment, 50% of patients had an improvement of ≥2 points in IGA scores from the baseline, and IGA scores of 68.75% of patients were less than 2. CONCLUSION: This 24-week research showed that baricitinib had favorable clinical efficacy and safety in treating moderate-to-severe AA, which is worthy of attention and expectation.

New dammarane-type triterpenoids from hydrolyzate of total Gynostemma pentaphyllum saponins with protein tyrosine phosphatase 1B inhibitory activity.

Protein tyrosine phosphatase 1B (PTP1B) is a key factor and regulator of glucose, lipid metabolism throughout the body, and a promising target for treatment of type 2 diabetes mellitus (T2DM). Gynostemma pentaphyllum is a famous oriental traditional medicinal herbal plant and functional food, which has shown many beneficial effects on glucose and lipid metabolism. The aim of the present study is to assess the inhibitory activity of five new and four known dammarane triterpenoids isolated from the hydrolysate product of total G. pentaphyllum saponins. The bioassay data showed that all the compounds exhibited significant inhibitory activity against PTP1B. The structure-activity relationship showed that the strength of PTP1B inhibitory activity was mainly related to the electron-donating group on its side chain. Molecular docking analysis suggested that its mechanism may be due to the formation of competitive hydrogen bonding between the electron-donating moiety and the Asp48 amino acid residues on the PTP1B protein.

The role of telomerase in hair growth and relevant disorders: A review.

BACKGROUND: Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini-organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti-aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported. METHODS: In this study, we reviewed the role of telomerase in hair growth and the effects of hair disorders through literature search and analysis. RESULTS: There is growing evidence that telomerase plays an important role in maintaining hair follicle function and proliferation. Changes in telomerase levels in hair follicles have also been found in a variety of hair disorders. CONCLUSION: Telomerase plays a positive role in hair growth and is expected to become a new target for the treatment of alopecia or other hair diseases in the future.

Transient receptor potential vanilloid 4 (TRPV4) in neutrophils enhances myocardial ischemia/reperfusion injury.

The Ca2+-permeable TRPV4 cation channel is expressed in neutrophils and contributes to myocardial ischemia/reperfusion injury. Here we tested the hypotheses that TRPV4 promotes neutrophil activation and subsequently aggregates myocardial ischemia/reperfusion injury. TRPV4 protein was confirmed in neutrophils, and its function was assessed by the current and intracellular Ca2+ concentration elevations evoked by TRPV4 agonists. Furthermore, TRPV4 agonists dose-dependently promoted migration toward fMLP, reactive oxygen species production, and myeloperoxidase release, which were prevented by pretreatment with a selective TRPV4 antagonist, in neutrophils from TRPV4 knockout mice, Ca2+-free medium, or BAPTA-AM + Ca2+-free medium. Blockade of TRPV4 also inhibited the effects of commonly used neutrophil activators fMLP and PMA. Mechanically, TRPV4 regulated neutrophil activation, particularly reactive oxygen species production, by affecting PKCα, P38, and AKT via Ca2+ signaling. In addition, isolated hearts infused with neutrophils from wild-type mice showed additional myocardial ischemia/reperfusion injuries but not those infused with TRPV4 knockout. Our study reveals that TRPV4-mediated neutrophil activation enhances myocardial ischemia/reperfusion injury, and it might be a novel therapeutic target for myocardial ischemia/reperfusion injury and other neutrophil-mediated inflammatory diseases.

Advances in basic and translational research in atrial fibrillation.

Atrial fibrillation (AF) is a very common cardiac arrhythmia with an estimated prevalence of 33.5 million patients globally. It is associated with an increased risk of death, stroke and peripheral embolism. Although genetic studies have identified a growing number of genes associated with AF, the definitive impact of these genetic findings is yet to be established. Several mechanisms, including electrical, structural and neural remodelling of atrial tissue, have been proposed to contribute to the development of AF. Despite over a century of exploration, the molecular and cellular mechanisms underlying AF have not been fully established. Current antiarrhythmic drugs are associated with a significant rate of adverse events and management of AF using ablation is not optimal, especially in cases of persistent AF. This review discusses recent advances in our understanding and management of AF, including new concepts of epidemiology, genetics and pathophysiological mechanisms. We review the current status of antiarrhythmic drug therapy for AF, new potential agents, as well as mechanism-based AF ablation. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Gypenosides ameliorate high-fat diet-induced nonalcoholic fatty liver disease in mice by regulating lipid metabolism.

Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.

The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review.

Introduction: Androgenetic alopecia (AGA) has negative impacts on both men and women in terms of appearance and mental stress. Spironolactone is a synthetic aldosterone receptor antagonist known to stimulate hair growth and has been widely used by dermatologists to treat AGA. Objective: To conduct a systematic review evaluating the efficacy and safety of topical and oral spironolactone in AGA treatment. Methods: We searched PubMed, Embase, the Cochrane Library, and the Web of Science until October 23rd, 2022, for human studies evaluating the efficacy of spironolactone for the treatment of AGA, regardless of doses and routes. Results: We retrieved 784 papers and ultimately 7 articles matched our inclusion criteria and comprised 618 AGA patients (65 men, 553 women), 414 of them received spironolactone treatment. Oral spironolactone doses ranged from 25mg to 200mg daily, with the vast majority between 80mg and 110 mg. Dosage forms for topical spironolactone use include gels of 1% and solutions of 5% twice daily. Both oral and topical spironolactone have been shown efficacy for alopecia recovery, but topical use has significantly fewer side effects and is suitable for any gender. It showed better efficacy in combination with other therapies such as oral or topical minoxidil compared with monotherapy. Conclusion: Spironolactone is an effective and safe treatment of androgenic alopecia which can enhance the efficacy when combined with other conventional treatments such as minoxidil. Topical spironolactone is safer than oral administration and is suitable for both male and female patients, and is expected to become a common drug for those who do not have a good response to minoxidil. Furthermore, more high-quality clinical randomized controlled studies should be performed.

Inhibition of phosphoglycerate kinase 1 attenuates autoimmune myocarditis by reprogramming CD4+ T cell metabolism.

AIMS: CD4+ T cells are the major drivers of cardiac-specific autoimmunity in myocarditis, specifically Th1, Treg, and most significant Th17 cells. But the molecular mechanisms of their activation remain unclear. We aimed to elucidate the regulatory role of phosphoglycerate kinase 1 (PGK1) in CD4+ T cells and experimental autoimmune myocarditis (EAM). METHODS AND RESULTS: EAM was induced in BALB/c mice by subcutaneous injections with alpha myosin heavy chain peptide emulsified in complete Freund's adjuvant. Single-cell sequencing analysis found that glycolysis and PGK1 expression were elevated in cardiac CD4+ T and Th17 cells from myocarditis mice. Mice treated with PGK1 inhibitor NG52 showed less cardiac inflammation and fibrosis and better contractile function, as well as reduced cardiac infiltrating Th17 and Th1 cells and increased proportion of Treg. NG52 suppressed CD4+ T cell activation and differentiation of mice and myocarditis patients in vitro. Mechanistically, inhibition of PGK1 suppressed glycolytic activity and decreased pyruvate dehydrogenase kinase 1 (PDHK1) phosphorylation, thereby increasing reactive oxygen species (ROS) production in mitochondria and thus preventing Th17 cell differentiation. CONCLUSION: PGK1 may act as a key metabolic regulator of CD4+ T cell differentiation and regulates Th17 cell differentiation by regulating glycolysis and the PDHK1-ROS axis. Targeting PGK1 might be a promising strategy for the treatment of myocarditis.

Identification of Human UDP-Glucuronosyltransferase Involved in Gypensapogenin C Glucuronidation and Species Differences.

Gypensapogenin C (GPC) is one of the important aglycones of Gynostemma pentaphyllum (GP), which is structurally glucuronidated and is highly likely to bind to UGT enzymes in vivo. Due to the important role of glucuronidation in the metabolism of GPC, the UDP-glucuronosyltransferase metabolic pathway of GPC in human and other species' liver microsomes is investigated in this study. In the present study, metabolites were detected using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that GPC could generate a metabolite through glucuronidation in the human liver microsomes (HLMs). Additionally, chemical inhibitors combined with recombinant human UGT enzymes clarified that UGT1A4 is the primary metabolic enzyme for GPC glucuronidation in HLMs according to the kinetic analysis of the enzyme. Metabolic differential analysis in seven other species indicated that rats exhibited the most similar metabolic rate to that of humans. In conclusion, UGT1A4 is a major enzyme responsible for the glucuronidation of GPC in HLMs, and rats may be an appropriate animal model to evaluate the GPC metabolism.

Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus.

The blockage of transient receptor potential vanilloid 4 (TRPV4) inhibits inflammation and reduces hippocampal neuronal injury in a pilocarpine-induced mouse model of temporal lobe epilepsy. However, the underlying mechanisms remain largely unclear. NF-κB signaling pathway is responsible for the inflammation and neuronal injury during epilepsy. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1ß, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. Therefore, TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. We conclude that blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the anti-inflammatory response and neuroprotective ability of TRPV4 blockage in mice with PISE.