Berberine alleviated contrast-induced acute kidney injury by mitophagy-mediated NLRP3 inflammasome inactivation in a mice model.

The incidence of contrast-induced acute kidney injury (CI-AKI) has escalated to become the third most prevalent cause of hospital-acquired AKI, with a lack of efficacious interventions. Berberine (BBR) possesses diverse pharmacological effects and exhibits renoprotective properties; however, limited knowledge exists regarding its impact on CI-AKI. Therefore, our study aimed to investigate the protective effects and underlying mechanisms of BBR on CI-AKI in a mice model, focusing on the nucleotide-binding oligomerization domain-like pyrin domain-containing protein 3 (NLRP3) inflammasome and mitophagy. The CI-AKI mice model was established by administering NG-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg), indomethacin (10 mg/kg), and iohexol (11 g/kg) following water deprivation. A pretreatment of 100 mg/kg of BBR was orally administered to the mice for two weeks. Renal injury markers, damage-associated molecular patterns (DAMPs), renal histopathology, mitochondrial morphology, autophagosomes, and potential mechanisms were investigated. BBR effectively reduced levels of renal injury biomarkers such as serum cystatin C, urea nitrogen, and creatinine, downregulated the protein level of kidney injury molecule 1 (KIM1), and mitigated renal histomorphological damage. Moreover, BBR reduced DAMPs, including high mobility group box-1 (HMGB1), heat shock protein 70 (HSP70), and uric acid (UA). It also alleviated oxidative stress and inflammatory factors such as monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1ß). Furthermore, the activation of NLRP3 inflammasome was attenuated in the BBR pretreatment group, as evidenced by both mRNA and protein levels. Electron microscopy and western blotting examination revealed that BBR mitigated mitochondrial damage and enhanced mitophagy. Additionally, BBR increased the P-AMPK/AMPK ratio. These findings indicated that BBR exerted a protective effect against CI-AKI by suppressing NLRP3 inflammasome activation and modulating mitophagy, providing a potential therapeutic strategy for its prevention.

Berberine prevents against myocardial injury induced by acute ß-adrenergic overactivation in rats.

The overactivation of ß-adrenergic receptors (ß-ARs) can result in acute myocardial ischemic injury, culminating in myocardial necrosis. Berberine (BBR) has exhibited promising potential for prevention and treatment in various heart diseases. However, its specific role in mitigating myocardial injury induced by acute ß-AR overactivation remains unexplored. This study aimed to investigate the effects and underlying mechanisms of BBR pretreatment in a rat model of acute ß-AR overactivation induced by a single dose of the nonselective ß-adrenergic agonist isoprenaline (ISO). Rats were pretreated with saline or BBR (100 mg/kg/day) via gavage for 14 consecutive days, followed by a subcutaneous injection of ISO or saline on the 14th day. The findings indicated that BBR pretreatment significantly attenuated myocardial injury in ISO-stimulated rats, as evidenced by reduced pathological inflammatory infiltration, necrosis, and serum markers of myocardial damage. Additionally, BBR decreased oxidative stress and inflammation in the system and heart. Furthermore, BBR pretreatment enhanced myocardial ATP levels, improved mitochondrial dysfunction through increased Drp1 phosphorylation, and augmented myocardial autophagy. In a CoCl2-induced H9c2 cell hypoxic injury model, BBR pretreatment mitigated cellular injury, apoptosis, and oxidative stress while upregulating Drp1 and autophagy-associated proteins. Mechanistically, BBR pretreatment activated AKT, AMPK, and LKB1 both in vivo and in vitro, implicating the involvement of the AKT and LKB1/AMPK signaling pathways in its cardioprotective effects. Our study demonstrated the protective effects of BBR against myocardial injury induced by acute ß-AR overactivation in rats, highlighting the potential of BBR as a preventive agent for myocardial injury associated with ß-adrenergic overactivation.

Identification of Potent Zika Virus NS5 RNA-Dependent RNA Polymerase Inhibitors Combining Virtual Screening and Biological Assays.

The Zika virus (ZIKV) epidemic poses a significant threat to human health globally. Thus, there is an urgent need for developing effective anti-ZIKV agents. ZIKV non-structural protein 5 RNA-dependent RNA polymerase (RdRp), a viral enzyme for viral replication, has been considered an attractive drug target. In this work, we screened an anti-infection compound library and a natural product library by virtual screening to identify potential candidates targeting RdRp. Then, five selected candidates were further applied for RdRp enzymatic analysis, cytotoxicity, and binding examination by SPR. Finally, posaconazole (POS) was confirmed to effectively inhibit both RdRp activity with an IC50 of 4.29 µM and the ZIKV replication with an EC50 of 0.59 µM. Moreover, POS was shown to reduce RdRp activity by binding with the key amino acid D666 through molecular docking and site-directed mutation analysis. For the first time, our work found that POS could inhibit ZIKV replication with a stronger inhibitory activity than chloroquine. This work also demonstrated fast anti-ZIKV screening for inhibitors of RdRp and provided POS as a potential anti-ZIKV agent.

STING agonists induce an innate antiviral immune response against hepatitis B virus.

Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted.

The antituberculosis antibiotic capreomycin inhibits protein synthesis by disrupting interaction between ribosomal proteins L12 and L10.

Capreomycin is a second-line drug for multiple-drug-resistant tuberculosis (TB). However, with increased use in clinics, the therapeutic efficiency of capreomycin is decreasing. To better understand TB resistance to capreomycin, we have done research to identify the molecular target of capreomycin. Mycobacterium tuberculosis ribosomal proteins L12 and L10 interact with each other and constitute the stalk of the 50S ribosomal subunit, which recruits initiation and elongation factors during translation. Hence, the L12-L10 interaction is considered to be essential for ribosomal function and protein synthesis. Here we provide evidence showing that capreomycin inhibits the L12-L10 interaction by using an established L12-L10 interaction assay. Overexpression of L12 and/or L10 in M. smegmatis, a species close to M. tuberculosis, increases the MIC of capreomycin. Moreover, both elongation factor G-dependent GTPase activity and ribosome-mediated protein synthesis are inhibited by capreomycin. When protein synthesis was blocked with thiostrepton, however, the bactericidal activity of capreomycin was restrained. All of these results suggest that capreomycin seems to inhibit TB by interrupting the L12-L10 interaction. This finding might provide novel clues for anti-TB drug discovery.

The role of inflammation in silicosis.

Silicosis is a chronic illness marked by diffuse fibrosis in lung tissue resulting from continuous exposure to SiO2-rich dust in the workplace. The onset and progression of silicosis is a complicated and poorly understood pathological process involving numerous cells and molecules. However, silicosis poses a severe threat to public health in developing countries, where it is the most prevalent occupational disease. There is convincing evidence supporting that innate and adaptive immune cells, as well as their cytokines, play a significant role in the development of silicosis. In this review, we describe the roles of immune cells and cytokines in silicosis, and summarize current knowledge on several important inflammatory signaling pathways associated with the disease, aiming to provide novel targets and strategies for the treatment of silicosis-related inflammation.

Benefits of Puerarin on Metabolic Syndrome and Its Associated Cardiovascular Diseases in Rats Fed a High-Fat/High-Sucrose Diet.

Metabolic syndrome (MetS) is a cluster of risk factors for cardiovascular diseases (CVDs) that has become a global public health problem. Puerarin (PUE), the principal active compound of Pueraria lobata, has the effects of regulating glucose and lipid metabolism and protecting against cardiovascular damage. This study aimed to investigate whether dietary supplementation with PUE could ameliorate MetS and its associated cardiovascular damage. Rats were randomly divided into three groups: the normal diet group (NC), the high-fat/high-sucrose diet group (HFHS), and the HFHS plus PUE diet group (HFHS-PUE). The results showed that PUE-supplemented rats exhibited enhanced glucose tolerance, improved lipid parameters, and reduced blood pressure compared to those on the HFHS diet alone. Additionally, PUE reversed the HFHS-induced elevations in the atherogenic index (AI) and the activities of serum lactate dehydrogenase (LDH) and creatine kinase (CK). Ultrasonic evaluations indicated that PUE significantly ameliorated cardiac dysfunction and arterial stiffness. Histopathological assessments further confirmed that PUE significantly mitigated cardiac remodeling, arterial remodeling, and neuronal damage in the brain. Moreover, PUE lowered systemic inflammatory indices including C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and systemic immune-inflammation index (SII). In conclusion, dietary supplementation with PUE effectively moderated metabolic disorders, attenuated systemic inflammation, and minimized cardiovascular damage in rats with MetS induced by an HFHS diet. These results provide novel insights into the potential benefits of dietary PUE supplementation for the prevention and management of MetS and its related CVDs.

Cancer Differentiation Inducer Chlorogenic Acid Suppresses PD-L1 Expression and Boosts Antitumor Immunity of PD-1 Antibody.

As immune checkpoint inhibitors have shown good clinical efficacy, immune checkpoint blockade has become a vital strategy in cancer therapy. However, approximately only 12.5% patients experience benefits from immunotherapy. Herein, we identified the cancer differentiation inducer chlorogenic acid (CGA, now in the phase II clinical trial in China for glioma treatment) to be a small-molecular immune checkpoint inhibitor that boosted the antitumor effects of the anti-PD-1 antibody. CGA suppressed the expression of PD-L1 induced by interferon-γ in tumor cell culture through inhibition of the p-STAT1-IRF1 pathway and enhanced activity of activated T-cells. In two murine tumor xenografts, combination therapy of CGA with anti-PD-1 antibody decreased the expression of PD-L1 and IRF1 and increased the inhibitory effect of the anti-PD-1 antibody on tumor growth. Particularly, the activity of tumor infiltrated T cells was enhanced by CGA. CGA improved the gene expression of granzymes in tumor-infiltrated immune cells. In conclusion, through induction of differentiation, CGA appeared to suppress the expression of PD-L1 on cancer cells, effectively promoting infiltrated T cells in the tumor and boosting the antitumor effect of the anti-PD-1 antibody. Thus, CGA might serve as a promising agent to enhance anticancer immunotherapy if combined with anti-PD-1 antibodies.

Synergistic Activity and Mechanism of Sanguinarine with Polymyxin B against Gram-Negative Bacterial Infections.

Compounds that potentiate the activity of clinically available antibiotics provide a complementary solution, except for developing novel antibiotics for the rapid emergence of multidrug-resistant Gram-negative bacteria (GNB). We sought to identify compounds potentiating polymyxin B (PMB), a traditional drug that has been revived as the last line for treating life-threatening GNB infections, thus reducing its nephrotoxicity and heterogeneous resistance in clinical use. In this study, we found a natural product, sanguinarine (SA), which potentiated the efficacy of PMB against GNB infections. The synergistic effect of SA with PMB was evaluated using a checkerboard assay and time-kill curves in vivo and the murine peritonitis model induced by Escherichia coli in female CD-1 mice in vivo. SA assisted PMB in accelerating the reduction in bacterial loads both in vitro and in vivo, improving the inflammatory responses and survival rate of infected animals. The subsequent detection of the intracellular ATP levels, membrane potential, and membrane integrity indicated that SA enhanced the bacterial-membrane-breaking capacity of PMB. A metabolomic analysis showed that the inhibition of energy metabolism, interference with nucleic acid biosynthesis, and the blocking of L-Ara4N-related PMB resistance may also contribute to the synergistic effect. This study is the first to reveal the synergistic activity and mechanism of SA with PMB, which highlights further insights into anti-GNB drug development.

Alleviation of allergic asthma by rosmarinic acid via gut-lung axis.

BACKGROUND: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PURPOSE: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. METHODS: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. RESULTS: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. CONCLUSIONS: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.

Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells promote alveolar bone regeneration by regulating macrophage polarization.

Alveolar bone regeneration has been strongly linked to macrophage polarization. M1 macrophages aggravate alveolar bone loss, whereas M2 macrophages reverse this process. Berberine (BBR), a natural alkaloid isolated and refined from Chinese medicinal plants, has shown therapeutic effects in treating metabolic disorders. In this study, we first discovered that culture supernatant (CS) collected from BBR-treated human bone marrow mesenchymal stem cells (HBMSCs) ameliorated periodontal alveolar bone loss. CS from the BBR-treated HBMSCs contained bioactive materials that suppressed the M1 polarization and induced the M2 polarization of macrophages in vivo and in vitro. To clarify the underlying mechanism, the bioactive materials were applied to different animal models. We discovered macrophage colony-stimulating factor (M-CSF), which regulates macrophage polarization and promotes bone formation, a key macromolecule in the CS. Injection of pure M-CSF attenuated experimental periodontal alveolar bone loss in rats. Colony-stimulating factor 1 receptor (CSF1R) inhibitor or anti-human M-CSF (M-CSF neutralizing antibody, Nab) abolished the therapeutic effects of the CS of BBR-treated HBMSCs. Moreover, AKT phosphorylation in macrophages was activated by the CS, and the AKT activator reversed the negative effect of the CSF1R inhibitor or Nab. These results suggest that the CS of BBR-treated HBMSCs modulates macrophage polarization via the M-CSF/AKT axis. Further studies also showed that CS of BBR-treated HBMSCs accelerated bone formation and M2 polarization in rat teeth extraction sockets. Overall, our findings established an essential role of BBR-treated HBMSCs CS and this might be the first report to show that the products of BBR-treated HBMSCs have active effects on alveolar bone regeneration.

The antiviral effect of 7-hydroxyisoflavone against Enterovirus 71 in vitro.

Enterovirus 71 (EV71) is the major causative agent of hand foot and mouth disease. And EV71 causes epidemics worldwide, particularly in the Asia-Pacific region. Unfortunately, currently there is no approved vaccine or antiviral drug for EV71-induced disease prevention and therapy. In screening for anti-EV71 candidates, we found that 7-hydroxyisoflavone was active against EV71. 7-Hydroxyisoflavone exhibited strong antiviral activity against three different EV71 strains. The 50% inhibitory concentration range was between 3.25 and 4.92 µM by cytopathic effect assay. 7-Hydroxyisoflavone could reduce EV71 viral RNA and protein synthesis in a dose-dependent manner. Time course study showed that treatment of Vero cells with 7-hydroxyisoflavone at indicated times after EV71 inoculation (0-6 h) resulted in significant antiviral activity. Results showed that 7-hydroxyisoflavone acted at an early step of EV71 replication. 7-Hydroxyisoflavone also exhibited strong antiviral activity against coxsackievirus B2, B3, and B6. In short, 7-hydroxyisoflavone may be used as a lead compound for anti-EV71 drug development.

The common neurological basis and targeted therapeutic approaches for chronic pain and opioid addiction.

Chronic pain and drug addiction seriously threaten human health and generate a large loss of labor. Most highly addictive drugs are derived from opioids, which have severe side effects and are difficult to quit completely. On the other hand, opioid analgesics are widely used in detoxification for opioid addiction. These opioids are effective for controlling acute withdrawal symptoms, but can be problematic under long-term usage as maintenance therapy. Both chronic pain and opioid abuse are related to neurotransmitters and central reward pathways in the brain. As to provide new weapons for defending human health, this article summarized the similarities and differences between chronic pain and opioid addiction, based on their common neurobiological basis, and discussed the breakthroughs in targeted therapeutic approaches. Furthermore, we have brought out an innovative and integrative therapeutic scheme by combining drugs, medical devices, and phycological / behavioral therapies, according to the patient's individual situation, aiming at achieving better effects against these two types of diseases.

Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe.

Tuberculosis (TB) is one of the deadly diseases caused by Mycobacterium tuberculosis (Mtb), which presents a significant public health challenge. Treatment of TB relies on the combination of several anti-TB drugs to create shorter and safer regimens. Therefore, new anti-TB agents working by different mechanisms are urgently needed. FtsZ, a tubulin-like protein with GTPase activity, forms a dynamic Z-ring in cell division. Most of FtsZ inhibitors are designed to inhibit GTPase activity. In Mtb, the function of Z-ring is modulated by SepF, a FtsZ binding protein. The FtsZ/SepF interaction is essential for FtsZ bundling and localization at the site of division. Here, we established a yeast two-hybrid based screening system to identify inhibitors of FtsZ/SepF interaction in M. tuberculosis. Using this system, we found compound T0349 showing strong anti-Mtb activity but with low toxicity to other bacteria strains and mice. Moreover, we have demonstrated that T0349 binds specifically to SepF to block FtsZ/SepF interaction by GST pull-down, fluorescence polarization (FP), surface plasmon resonance (SPR) and CRISPRi knockdown assays. Furthermore, T0349 can inhibit bacterial cell division by inducing filamentation and abnormal septum. Our data demonstrated that FtsZ/SepF interaction is a promising anti-TB drug target for identifying agents with novel mechanisms.

Erratum to "Identification of anti-Mycobacterium tuberculosis agents targeting the interaction of bacterial division proteins FtsZ and SepFe" [Acta Pharmaceutica Sinica B 13 (2023) 2056-2070].

[This corrects the article DOI: 10.1016/j.apsb.2023.01.022.].

Microbiota-derived short-chain fatty acids mediate the effects of dengzhan shengmai in ameliorating cerebral ischemia via the gut-brain axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Dengzhan shengmai (DZSM) formula, composed of four herbal medicines (Erigeron breviscapus, Panax ginseng, Schisandra chinensis, and Ophiopogon japonicus), is widely used in the recovery period of ischemic cerebrovascular diseases; however, the associated molecular mechanism remains unclear. AIM OF THE STUDY: The purpose of this study was to uncover the links between the microbiota-gut-brain axis and the efficacy of DZSM in ameliorating cerebral ischemic diseases. MATERIALS AND METHODS: The effects of DZSM on the gut microbiota community and bacteria-derived short-chain fatty acid (SCFA) production were evaluated in vivo using a rat model of cerebral ischemia and in vitro through the anaerobic incubation with fresh feces derived from model animals. Subsequently, the mechanism underlying the role of SCFAs in the DZSM-mediated treatment of cerebral ischemia was explored. RESULTS: We found that DZSM treatment significantly altered the composition of the gut microbiota and markedly enhanced SCFA production. The consequent increase in SCFA levels led to the upregulation of the expression of monocarboxylate transporters and facilitated the transportation of intestinal SCFAs into the brain, thereby inhibiting the apoptosis of neurocytes via the regulation of the PI3K/AKT/caspase-3 pathway. The increased intestinal SCFA levels also contributed to the repair of the 2VO-induced disruption of gut barrier integrity and inhibited the translocation of lipopolysaccharide from the intestine to the brain, thus attenuating neuroinflammation. Consequently, cerebral neuropathy and oxidative stress were significantly improved in 2VO model rats, leading to the amelioration of cerebral ischemia-induced cognitive dysfunction. Finally, fecal microbiota transplantation could reproduce the beneficial effects of DZSM on SCFA production and cerebral ischemia. CONCLUSIONS: Our findings suggested that SCFAs mediate the effects of DZSM in ameliorating cerebral ischemia via the gut microbiota-gut-brain axis.

Berberine is a potential alternative for metformin with good regulatory effect on lipids in treating metabolic diseases.

Metformin (MTF) and berberine (BBR) share several therapeutic benefits in treating metabolic-related disorders. However, as the two agents have very different chemical structure and bioavailability in oral route, the goal of this study is to learn their characteristics in treating metabolic disorders. The therapeutic efficacy of BBR and MTF was systemically investigated in the high fat diet feeding hamsters and/or ApoE(-/-) mice; in parallel, gut microbiota related mechanisms were studied for both agents. We discovered that, although both two drugs had almost identical effects on reducing fatty liver, inflammation and atherosclerosis, BBR appeared to be superior over MTF in alleviating hyperlipidemia and obesity, but MTF was more effective than BBR for the control of blood glucose. Association analysis revealed that the modulation of intestinal microenvironment played a crucial role in the pharmacodynamics of both drugs, in which their respective superiority on the regulation of gut microbiota composition and intestinal bile acids might contribute to their own merits on lowering glucose or lipids. This study shows that BBR may be a good alternative for MTF in treating diabetic patients, especially for those complicated with dyslipidemia and obesity.

Bacterial butyrate mediates the anti-atherosclerotic effect of silybin.

Silybin (SIL) is a versatile bioactive compound used for improving liver damage and lipid disorders and is also thought to be beneficial for atherosclerosis (AS). The goal of this study was to investigate the efficacy of SIL in the treatment of AS in ApoE-/-mice fed a high-fat diet and explore the mechanism underlying treatment outcomes. We found that SIL significantly alleviated AS-related parameters, including the extent of aortic plaque formation, hyperlipidemia, and adhesion molecule secretion in the vascular endothelium. 16 S rRNA gene sequencing analysis, together with the application of antibiotics, showed that intestinal butyrate-producing bacteria mediated the ameliorative effect of SIL on AS. Further analysis revealed that SIL facilitated butyrate production by increasing the level of butyryl-CoA: acetate CoA-transferase (BUT). The increased expression of monocarboxylic acid transporter-1 (MCT1) induced by butyrate and MCT4 induced by SIL in the apical and basolateral membranes of colonocytes, respectively, resulted in enhanced absorption of intestinal butyrate into the circulation, leading to the alleviation of arterial endothelium dysfunction. Moreover, the SIL-mediated increase in intestinal butyrate levels restored gut integrity by upregulating the expression of tight junction proteins and promoting gut immunity, thus inhibiting the AS-induced inflammatory response. This is the first study to show that SIL can alleviate AS by modulating the production of bacterial butyrate and its subsequent absorption.

Host apolipoprotein B messenger RNA-editing enzyme catalytic polypeptide-like 3G is an innate defensive factor and drug target against hepatitis C virus.

UNLABELLED: Host cellular factor apolipoprotein B messenger RNA (mRNA)-editing enzyme catalytic polypeptide-like 3G (hA3G) is a cytidine deaminase that inhibits a group of viruses including human immunodeficiency virus-1 (HIV-1). In the continuation of our research on hA3G, we found that hA3G stabilizing compounds significantly inhibited hepatitis C virus (HCV) replication. Therefore, this study investigated the role of hA3G in HCV replication. Introduction of external hA3G into HCV-infected Huh7.5 human hepatocytes inhibited HCV replication; knockdown of endogenous hA3G enhanced HCV replication. Exogenous HIV-1 virion infectivity factor (Vif) decreased intracellular hA3G and therefore enhanced HCV proliferation, suggesting that the presence of Vif might be an explanation for the HIV-1/HCV coinfection often observed in HIV-1(+) individuals. Treatment of the HCV-infected Huh7.5 cells with RN-5 or IMB-26, two known hA3G stabilizing compounds, increased intracellular hA3G and accordingly inhibited HCV replication. The compounds inhibit HCV through increasing the level of hA3G incorporated into HCV particles, but not through inhibiting HCV enzymes. However, G/A hypermutation in the HCV genome were not detected, suggesting a new antiviral mechanism of hA3G in HCV, different from that in HIV-1. Stabilization of hA3G by RN-5 was safe in vivo. CONCLUSION: hA3G appears to be a cellular restrict factor against HCV and could be a potential target for drug discovery.

Berberine exerts protective effects on cardiac senescence by regulating the Klotho/SIRT1 signaling pathway.

Berberine (BBR), an isoquinoline alkaloid, exerts protective effects on various cardiac injuries, and also extends the lifespan of individuals. However, the cardioprotective effect of BBR on cardiac senescence remains unknown. This study investigated the effects of BBR on cardiac senescence and its underlying mechanism. Senescent H9c2 cells induced by doxorubicin (DOX) and naturally aged rats were used to evaluate the protective effects of BBR on cardiac senescence. The results showed that BBR protected H9c2 cells against DOX-induced senescence. Exogenous Klotho (KL) exerts similar effects to those of BBR. BBR significantly increased in protein expression of KL, while transfection with KL-specific siRNA (siKL) inhibited the protective effect of BBR against senescence. Both BBR and exogenous KL decreased the levels of reactive oxygen species, inhibited apoptosis, and alleviated mitochondrial dysfunction in these cells; and transfection with siKL attenuated these effects of BBR. In naturally aged rats, BBR indeed protected the animals from cardiac aging, at least partially, through lowering the levels of cardiac hypertrophy markers, and increased the expression of KL in cardiac tissue. Additionally, BBR markedly reversed downregulation of sirtuin1 (SIRTI) in the aged heart. In vitro experiments revealed that BBR and exogenous KL also increased the expression of SIRT1, whereas siKL limited this effect of BBR in senescent H9c2 cell. In summary, BBR upregulated KL expression and prevented heart from cardiac senescence through anti-oxidative and anti-apoptotic effects, as well as alleviation of mitochondrial dysfunction. These effects may be mediated via regulation of the Klotho/SIRT1 signaling pathway.