Neuron stem cell NLRP6 sustains hippocampal neurogenesis to resist stress-induced depression.

Neurogenesis decline in hippocampal dentate gyrus (DG) participates in stress-induced depressive-like behaviors, but the underlying mechanism remains poorly understood. Here, we observed low-expression of NOD-like receptor family pyrin domain containing 6 (NLRP6) in hippocampus of stress-stimulated mice, being consistent with high corticosterone level. NLRP6 was found to be abundantly expressed in neural stem cells (NSCs) of DG. Both Nlrp6 knockout (Nlrp6-/-) and NSC-conditional Nlrp6 knockout (Nlrp6CKO) mice were susceptible to stress, being more likely to develop depressive-like behaviors. Interestingly, NLRP6 was required for NSC proliferation in sustaining hippocampal neurogenesis and reinforcing stress resilience during growing up. Nlrp6 deficiency promoted esophageal cancer-related gene 4 (ECRG4) expression and caused mitochondrial dysfunction. Corticosterone as a stress factor significantly down-regulated NLRP6 expression, damaged mitochondrial function and suppressed cell proliferation in NSCs, which were blocked by Nlrp6 overexpression. ECRG4 knockdown reversed corticosterone-induced NSC mitochondrial function and cell proliferation disorders. Pioglitazone, a well-known clinical drug, up-regulated NLRP6 expression to inhibit ECRG4 expression in its protection against corticosterone-induced NSC mitochondrial dysfunction and proliferation restriction. In conclusion, this study demonstrates that NLRP6 is essential to maintain mitochondrial homeostasis and proliferation in NSCs, and identifies NLRP6 as a promising therapeutic target for hippocampal neurogenesis decline linked to depression.

Polydatin Ameliorates High Fructose-Induced Podocyte Oxidative Stress via Suppressing HIF-1α/NOX4 Pathway.

Long-term high fructose intake drives oxidative stress, causing glomerular podocyte injury. Polydatin, isolated from Chinese herbal medicine Polygonum cuspidatum, is used as an antioxidant agent that protects kidney function. However, it remains unclear how polydatin prevents oxidative stress-driven podocyte damage. In this study, polydatin attenuated high fructose-induced high expression of HIF-1α, inhibited NOX4-mediated stromal cell-derived factor-1α/C-X-C chemokine receptor type 4 (SDF-1α/CXCR4) axis activation, reduced reactive oxygen species (ROS) production in rat glomeruli and cultured podocytes. As a result, polydatin up-regulated nephrin and podocin, down-regulated transient receptor potential cation channel 6 (TRPC6) in these animal and cell models. Moreover, the data from HIF-1α siRNA transfection showed that high fructose increased NOX4 expression and aggravated SDF-1α/CXCR4 axis activation in an HIF-1α-dependent manner, whereas polydatin down-regulated HIF-1α to inhibit NOX4 and suppressed SDF-1α/CXCR4 axis activation, ameliorating high fructose-induced podocyte oxidative stress and injury. These findings demonstrated that high fructose-driven HIF-1α/NOX4 pathway controlled podocyte oxidative stress damage. Intervention of this disturbance by polydatin could help the development of the therapeutic strategy to combat podocyte damage associated with high fructose diet.

Short-Chain Fatty Acids Ameliorate Depressive-like Behaviors of High Fructose-Fed Mice by Rescuing Hippocampal Neurogenesis Decline and Blood-Brain Barrier Damage.

Excessive fructose intake is associated with the increased risk of mental illness, such as depression, but the underlying mechanisms are poorly understood. Our previous study found that high fructose diet (FruD)-fed mice exhibited neuroinflammation, hippocampal neurogenesis decline and blood-brain barrier (BBB) damage, accompanied by the reduction of gut microbiome-derived short-chain fatty acids (SCFAs). Here, we found that chronic stress aggravated these pathological changes and promoted the development of depressive-like behaviors in FruD mice. In detail, the decreased number of newborn neurons, mature neurons and neural stem cells (NSCs) in the hippocampus of FruD mice was worsened by chronic stress. Furthermore, chronic stress exacerbated the damage of BBB integrity with the decreased expression of zonula occludens-1 (ZO-1), claudin-5 and occludin in brain vasculature, overactivated microglia and increased neuroinflammation in FruD mice. These results suggest that high fructose intake combined with chronic stress leads to cumulative negative effects that promote the development of depressive-like behaviors in mice. Of note, SCFAs could rescue hippocampal neurogenesis decline, improve BBB damage and suppress microglia activation and neuroinflammation, thereby ameliorate depressive-like behaviors of FruD mice exposed to chronic stress. These results could be used to develop dietary interventions to prevent depression.

A narrative review of COVID-19: magnesium isoglycyrrhizinate as a potential adjuvant treatment.

Coronavirus disease 2019 (COVID-19) has become a global pandemic affecting more than 200 countries with 87 million patients worldwide as of January 7, 2021. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) replicates in a large amount and reaches high-titer levels in a short time after the infection. COVID-19 caused by SARS-CoV-2 shows clinical symptoms mainly including fever, fatigue, dry cough, and dyspnea. In more severe COVID-19 patients, viral pneumonia characterized by bilateral ground glass or patchy opacity, may lead to acute respiratory distress syndrome (ARDS), cytokine storm, multi-organ damage, and even death. Unfortunately, there is no effective therapy for COVID-19 until now. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-α glycyrrhizic acid stereoisomer, belongs to the fourth generation of glycyrrhizic acid preparation. MgIG has various pharmacological activities including anti-inflammation, anti-oxidation, anti-virus, and immunoregulation, showing the protection against the injury of the vital organs (such as kidney, heart, and lung). Clinically, MgIG injection is usually used as a hepatoprotective agent to treat liver diseases. This narrative review summarizes the research and application of MgIG, and provides the evidence supporting the recommended MgIG as supportive therapy in the "Management Standard for Mild and Common Patients of Coronavirus Disease 2019 (COVID-19) (Second Edition)", which is jointly issued by National Health Commission of People's Republic of China and National Administration of Traditional Chinese Medicine.

Positive effect of Astragaloside IV on neurite outgrowth via talin-dependent integrin signaling and microfilament force.

Integrin plays a prominent role in neurite outgrowth by transmitting both mechanical and chemical signals. Integrin expression is closely associated with Astragaloside IV (AS-IV), the main component extracted from Astragali radix, which has a positive effect on neural-protection. However, the relationship between AS-IV and neurite outgrowth has not been studied exhaustively to date. The present study investigated the underlying mechanism of AS-IV on neurite outgrowth. Longer neurites have been observed in SH-SY5Y cells or cortical neurons after AS-IV treatment. Furthermore, AS-IV not only increased the expression of integrin ß but also activated it. The AS-IV-induced increased integrin activity was attributed to the integrin-activating protein talin. Application of the actin force probe showed that AS-IV led to an increase in intracellular microfilament force during neurite growth. Furthermore, in response to AS-IV, the microfilament force was regulated by talin and integrin activity during neurite growth. These results suggest that AS-IV has the ability to increase intracellular structural force and facilitate neurite elongation by integrin signaling, which highlights its therapeutic potential for neurite outgrowth.

Possibility of magnesium supplementation for supportive treatment in patients with COVID-19.

Magnesium as an enzymatic activator is essential for various physiological functions such as cell cycle, metabolic regulation, muscle contraction, and vasomotor tone. A growing body of evidence supports that magnesium supplementation (mainly magnesium sulfate and magnesium oxide) prevents or treats various types of disorders or diseases related to respiratory system, reproductive system, nervous system, digestive system, and cardiovascular system as well as kidney injury, diabetes and cancer. The ongoing pandemic coronavirus disease 19 (COVID-19) characterized by respiratory tract symptoms with different degrees of important organ and tissue damages has attracted global attention. Particularly, effective drugs are still lacking in the COVID-19 therapy. In this review, we find and summarize the effectiveness of magnesium supplementation on the disorders or diseases, and provide a reference to the possibility of magnesium supplementation for supportive treatment in patients with COVID-19.

Protective effect of Ganoderic acid A on adjuvant-induced arthritis.

The purpose of the experiment was to explore the effect of Ganoderic acid A (GAA) on adjuvant-induced arthritis in rats. In this study, the rat model of collagen-induced rheumatoid arthritis (CIA) was established with type II collagen plus Freund's complete adjuvant. Arthritis index, joint pathology, toe swelling, hemorheology, synovial cell apoptosis, related cytokines and JAK3/STAT3 and nuclear factor-κB (NF-κB) signaling pathway were measured in rats. We found that GAA can significantly inhibit the arthritis index, improve joint pathology, reduce toe swelling, improve blood rheology, improve synovial cell apoptosis, and restore related cytokine negative regulation JAK3/STAT3 and NF-κB signaling pathways. In conclusion, GAA has an obvious therapeutic effect on joint inflammation of toes in CIA model rats, which may be due to the regulation of JAK3/STAT3 and NF-κB signaling pathway.

Chronic exposure to low dose of bisphenol A causes follicular atresia by inhibiting kisspeptin neurons in anteroventral periventricular nucleus in female mice.

Bisphenol-A (BPA) is an estrogenic chemical extensively used in industrial and household applications. The present study was conducted to investigate the effect of chronic exposure to BPA on the adult female neuroendocrine system. Herein, we found that expose of adult female mice to BPA (50 µg/kg) by oral gavage for 60 days (BPA mice) prolonged diestrus and decreased serum 17ß-estradiol (E2) concentration by reducing the number of antral follicles and corpora luteum. In comparison with controls, the levels of serum luteinizing hormone (LH), follicle stimulating hormone (FSH), hypothalamic gonadotrophin releasing hormone (GnRH) and the expression of kisspeptin in anteroventral periventricular nucleus (AVPV) decreased in BPA mice, which could be reversed by injecting kisspeptin-10 (i.c.v.). Treatment with BPA or estrogen receptor α (ERα) antagonist MPP, but not ERß antagonist PHTPP inhibited E2-induced AVPV-kisspeptin expression in ovariectomized mice. Use of ERα agonist PPT rather than ERß agonist DPN enhanced AVPV-kisspepetin expression, which decreased after treatment with BPA. The amplitude of the proestrus LH surge decreased in mice exposed to BPA, but was recovered by administering kisspeptin-10. The present study provides in vivo evidence that chronic exposure to a low dose of BPA suppressed ERα-induced activation of AVPV-kisspeptin neurons, leading to prolonged diestrus and reduced ovulation in adult female mice.

NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease.

Background: Inflammation and steatosis are the main pathological features of alcoholic liver disease (ALD), in which, inflammation is one of the critical drivers for the initiation and development of alcoholic steatosis. NIK, an inflammatory pathway component activated by inflammatory cytokines, was suspected to link inflammation to hepatic steatosis during ALD. However, the underlying pathogenesis is not well-elucidated. Methods: Alcoholic steatosis was induced in mice by chronic-plus-binge ethanol feeding. Both the loss- and gain-of-function experiments by the hepatocyte-specific deletion, pharmacological inhibition and adenoviral transfection of NIK were utilized to elucidate the role of NIK in alcoholic steatosis. Rate of fatty acid oxidation was assessed in vivo and in vitro. PPARα agonists or antagonists of MEK1/2 and ERK1/2 were used to identify the NIK-induced regulation of PPARα, MEK1/2, and ERK1/2. The potential interactions between NIK, MEK1/2, ERK1/2 and PPARα and the phosphorylation of PPARα were clarified by immunoprecipitation, immunoblotting and far-western blotting analysis. Results: Hepatocyte-specific deletion of NIK protected mice from alcoholic steatosis by sustaining hepatic fatty acid oxidation. Moreover, overexpression of NIK contributed to hepatic lipid accumulation with disrupted fatty acid oxidation. The pathological effect of NIK in ALD may be attributed to the suppression of PPARα, the main controller of fatty acid oxidation in the liver, because PPARα agonists reversed NIK-mediated hepatic steatosis and malfunction of fatty acid oxidation. Mechanistically, NIK recruited MEK1/2 and ERK1/2 to form a complex that catalyzed the inhibitory phosphorylation of PPARα. Importantly, pharmacological intervention against NIK significantly attenuated alcoholic steatosis in ethanol-fed mice. Conclusions: NIK targeting PPARα via MEK1/2 and ERK1/2 disrupts hepatic fatty acid oxidation and exhibits high value in ALD therapy.

Sirt6 deletion in hepatocytes increases insulin sensitivity of female mice by enhancing ERα expression.

Sirtuin 6 (Sirt6), a NAD+ -dependent protein deacetylase, is involved in hepatic glucose metabolism and insulin sensitivity, which impact metabolic homeostasis. In this paper, we discover that Sirt6 affects the insulin sensitivity of mice in a gender-dependent manner; few studies have been conducted on this issue. Based on reports revealing the influences of sex hormones on insulin signaling, this investigation explores the mechanism by which Sirt6 regulates the estrogen pathway and disrupts insulin signal transduction. Hepatocyte-specific Sirt6 knockout (Sirt6HKO) mice were generated to investigate the function of Sirt6 in hepatocytes. Mice were castrated or spayed to eliminate sex hormones. Insulin sensitivity was assessed via an insulin tolerance test (ITT) in vivo. The interaction of Sirt6 with the estrogen pathway and their impacts on insulin signal transduction were revealed by immunoblot and immunoprecipitation. Sirt6 deletion in hepatocytes significantly enhanced insulin sensitivity and signal transduction in female mice but not in male or spayed female mice as demonstrated by ITT and the phosphorylation level of Akt in the liver. We also identified upregulation of p300, ERα, and interaction of ERα with p85 in the liver of female Sirt6HKO mice. Additionally, Sirt6 was found to inhibit ERα protein stability in a p300-dependent manner without interacting directly with ERα. Our findings show that hepatic Sirt6 downregulates the ERα protein level in a p300-dependent manner and thus disturbs estrogen-induced improvement in insulin sensitivity in the liver, which may partially explain the gender difference in insulin sensitivity.

Crocetin attenuates DHT-induced polycystic ovary syndrome in mice via revising kisspeptin neurons.

Polycystic ovarian syndrome (PCOS), the most common endocrine disorder of women in reproductive age, is typical with hyperandrogenism and disturbance of the hypothalamus-pituitary-ovary (HPO) axis, i.e. abnormal expression of hypothalamic gonadotropin-releasing hormone (GnRH) followed by the elevated ratio of serum luteinizing hormone (LH) level to follicle-stimulating hormone (FSH) level. This derangement might have a close relationship with hypothalamic kisspeptin expression that is thought to be a key regulator of GnRH. Crocetin, one of the main components of Saffron clinically used as traditional medicine in gynecology diseases, was evaluated for its therapeutic effects on PCOS induced by prenatally exposure to dihydrotestosterone (DHT) in mice. Herein, we found that DHT-treated mice showed a similar phenotype to human PCOS such as heavier ovary, prolonged diestrus, multiple enlarged follicles with fewer corpus luteum, and higher LH and testosterone levels. Kisspeptin expression was lower in anteroventral periventricular nucleus (AVPV) but higher in arcuate nucleus (ARC). Treatment of crocetin prevented the prolongation of diestrus and reduction in corpora luteum, recover the levels of GnRH, FSH, LH, progesterone (P4), estradiol (E2) and testosterone (T), and increase the kisspeptin level in AVPV but reduce that in ARC. The present study provides in vivo evidence that crocetin improved the PCOS in mice via increasing AVPV-kisspeptin and reducing ARC-kisspeptin expression.

Wogonin Attenuates Isoprenaline-Induced Myocardial Hypertrophy in Mice by Suppressing the PI3K/Akt Pathway.

Many studies have focused on identifying therapeutic targets of myocardial hypertrophy for the treatment of correlative cardiac events. Wogonin is a natural flavonoid compound that displays a potent anti-hypertrophic effect. Knowledge of its pharmacological mechanisms might reveal an effective way to search for therapeutic targets. Myocardial hypertrophy was replicated by the subcutaneous implantation of an isoprenaline mini-pump in mice or isoprenaline treatment of H9C2 cells. Pathologic changes in cardiac structure were assessed by echocardiographic and histological examinations. The signaling transduction in hypertrophy-promoting pathways and the genes involved were detected by western blot and RT-qPCR. Wogonin significantly attenuated isoprenaline-induced myocardial hypertrophy in vivo and in vitro by suppressing phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) hypertrophy-promoting pathway. Wogonin promoted the ubiquitination and degradation of PI3K catalytic subunit alpha (Pik3ca), the catalytic subunit of PI3K, which was upregulated by isoprenaline treatment. Wogonin also increased the expression of neural precursor cells expressing developmentally down-regulated gene 4-like (Nedd4l), the ubiquitin E3 ligase of Pik3ca. Therefore, wogonin targets Nedd4l to induce the degradation of Pik3ca, which reverses the over-activation of the PI3K/Akt pathway and consequently relieves the isoprenaline-induced myocardial hypertrophy.

Impact of Perfluorooctane Sulfonate on Reproductive Ability of Female Mice through Suppression of Estrogen Receptor α-Activated Kisspeptin Neurons.

Perfluorooctane sulfonate (PFOS) is used extensively in industrial and household applications. High exposure to PFOS has been associated with increased odds of irregular and long menstrual cycles in women. However, the underlying mechanisms remain to be elucidated. Herein, we show that adult female mice appeared prolongation of diestrus and reduction of corpora luteum within a week of oral administration of PFOS (10 mg/kg), which are associated with decreases in the levels of serum progesterone, LH and hypothalamic GnRH. The number of AVPV-kisspeptin neurons and the AVPV-kisspeptin expression were increased in proestrus mice or OVX-mice treated with high-dose estradiol benzoate (0.05 mg/kg), which were suppressed by the administration of PFOS. The administration of PFOS or GPR54 antagonist P234 prevented the generation of LH-surge in OVX-mice treated with high-dose E2. In hypothalamic slices incubated in 100 nM E2 for 4 h, the AVPV-kisspeptin expression was significantly enhanced, which was inhibited by PFOS in a dose-dependent manner or estrogen receptor α (ERα) antagonist MPP, but not ERß antagonist PHTPP. The incubation of ERα agonist PPT rather than ERß agonist DPN could increase the level of AVPV-kisspeptin expression, which was sensitive to the treatment with PFOS. The administration of GPR54 agonist kisspeptin-10 in PFOS-mice could correct the prolongation of diestrus and reduction of corpora luteum, and recover the LH-surge and the levels of LH and GnRH. The results indicate that exposure to PFOS suppressed ERα-induced activation of AVPV-kisspeptin neurons leads to diestrus prolongation and ovulation reduction.

Withdrawal Notice: Targeting lncRNAs for Cardiovascular Therapeutics in Coronary Artery Disease

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