Acetyl-11-Keto-Beta-Boswellic Acid Activates the Nrf2/HO-1 Signaling Pathway in Schwann Cells to Reduce Oxidative Stress and Promote Sciatic Nerve Injury Repair.

Boswellia is a traditional medicine for bruises and injuries. Its main active ingredient, acetyl-11-keto-beta-boswellic acid, has antioxidant and antiapoptotic effects. In this experiment, we used Sprague-Dawley rats to make a sciatic nerve injury model to detect the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway and apoptosis, combined with clinical indicators, for testing whether acetyl-11-keto-beta-boswellic acid can reduce oxidative stress and promote sciatic nerve repair. Our results showed that acetyl-11-keto-beta-boswellic acid administration promoted myelin regeneration and functional recovery in the rat sciatic nerve, reduced lipid peroxidation levels, upregulated the expression of various antioxidant enzymes and enhanced enzyme activity, decreased the expression levels of apoptosis-related proteins, and promoted nuclear translocation of the transcription factor NF-E2-related factor 2 protein. In vitro studies revealed that acetyl-11-keto-beta-boswellic acid reduced H2O2-induced reactive oxygen species production, restored mitochondrial membrane potential, upregulated the expression of various antioxidant enzymes, and downregulated apoptosis-related indicators in Schwann cells, and these therapeutic effects of acetyl-11-keto-beta-boswellic acid were reversed after ML385 treatment in Schwann cells. In summary, acetyl-11-keto-beta-boswellic acid alleviates oxidative stress and apoptosis caused by sciatic nerve injury in rats by activating the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway, promotes the recovery of sciatic nerve function in rats, and is a promising therapeutic agent to promote sciatic nerve repair by alleviating excessive oxidative stress.

The Potential Mechanism of Cannabidiol (CBD) Treatment of Epilepsy in Pentetrazol (PTZ) Kindling Mice Uncovered by Multi-Omics Analysis.

Cannabidiol (CBD) is the main active ingredient in the cannabis plant used for treating epilepsy and related diseases. However, how CBD ameliorates epilepsy and its effect on the hippocampus remains unknown. Herein, we evaluated how CBD ameliorates seizure degree in pentylenetetrazol (PTZ) induced epilepsy mice after being exposed to CBD (10 mg/kg p.o). In addition, transcriptome and metabolomic analysis were performed on the hippocampus. Our results suggested that CBD could alleviate PTZ-induced seizure, of which the NPTX2, Gprc5c, Lipg, and Stc2 genes were significantly down-regulated in mice after being exposed to PTZ. Transcriptome analysis showed 97 differently expressed genes (CBD) and the PTZ groups. Metabonomic analysis revealed that compared with the PTZ group, 41 up-regulated and 67 down-regulated metabolites were identified in the hippocampus of epileptic mice exposed to CBD. The correlation analysis for transcriptome and metabolome showed that (±) 15-HETE and carnitine C6:0 were at the core of the network and were involved in the positive or negative regulation of the related genes after being treated with CBD. In conclusion, CBD ameliorates epilepsy by acting on the metabolism, calcium signaling pathway, and tuberculosis pathways in the hippocampus. Our study provided a practical basis for the therapeutic potential of treating epilepsy using CBD.

Ligusticum chuanxiong promotes the angiogenesis of preovulatory follicles (F1-F3) in late-phase laying hens.

Ligusticum chuanxiong (CX) is a traditional Chinese medicine that is widely planted throughout the world. CX is one of the most important and commonly used drugs to enhance blood circulation. The preovulatory follicles in laying hens have a large number of blood arteries and meridians that feed the follicles' growth and maturation with nutrients, hormones, and cytokines. With the extension of laying time, preovulatory follicles angiogenesis decreased gradually. In this study, we studied the mechanism of CX on preovulatory follicles angiogenesis in late-phase laying hens. The results show that CX extract can increase the angiogenesis of preovulatory follicles (F1-F3) of late-phase laying hens. CX extract can promote vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation in preovulatory follicles theca layers, promote the proliferation, invasion and migration through PI3K/AKT and RAS/ERK signaling pathways in primary follicle microvascular endothelial-like cells (FMECs). In addition, CX extract can up-regulate the expression of hypoxia inducible factor α (HIF1α) in granulosa cells (GCs) and granulosa layers through PI3K/AKT and RAS/ERK signaling pathways, thereby promoting the secretion of vascular endothelial growth factor A (VEGFA). In conclusion, the current study confirmed the promoting effect of CX extract on the preovulatory follicles angiogenesis, which sets the stage for the design of functional animal feed for late-phase laying hens.

Grape seed extract proanthocyanidin antagonizes aristolochic acid I-induced liver injury in rats by activating PI3K-AKT pathway.

Aristolochic acid is internationally recognized as a carcinogen. It has been shown that the main toxic mechanism of aristolochic acid on the liver and kidney is the induction of ROS-induced oxidative stress damage. To investigate whether proanthocyanidins (GSPE), a natural antioxidant product from grape seed extract, could antagonize AA-I-induced liver injury. Thirty-two SD rats were selected and divided into aristolochic acid exposure group (AA-I), normal control group, GSPE group and GSPE intervention group. The protective effects of GSPE on AA-I liver injury were evaluated by examining the body weight, liver index, liver function and liver pathological sections of rats. The results of body weight, liver index, liver function and liver pathological sections of rats showed that GSPE had antagonistic effects on AA-I-induced liver injury. antioxidant enzyme activity in the GSPE intervention group was significantly higher than that in the aristolochic acid group, apoptotic cells were significantly lower than that in the aristolochic acid group, protein and mRNA expression of PI3K-AKT and BCL-2 were significantly higher than that in the aristolochic acid group, BAX, The protein and mRNA expression of BAX, CASPAES-3, CASPAES-9 were significantly lower than those of the aristolochic acid group. GSPE can antagonize aristolochic acid-induced hepatotoxicity, and its mechanism of action is to antagonize aristolochic acid I-induced liver injury by inhibiting PI3K-AKT pathway-mediated hepatocyte apoptosis.

Effect of Angelica Sinensis extract on the angiogenesis of preovulatory follicles (F1-F3) in late-phase laying hens.

In order to form follicles and ovulate normally, there must be abundant blood vessels. Angelica sinensis (Oliv.) Diels (AS), as a traditional Chinese medicinal herb, has the effects of tonifying the blood and activating the blood circulation. However, the effect of AS on angiogenesis in hen-follicles remains to be discovered. In this study, we identified vascular richness, granulosa layer thickness, expression of platelet endothelial cell adhesion molecule-1 (CD31) and the content of vascular endothelial growth factor A (VEGFA) in granulosa layers to elucidate the effect of AS extract on angiogenesis in preovulatory follicles (F1-F3) of late-phase laying hens (75 wk). Based on network pharmacology, we predicted beta-sitosterol, ferulic acid, and caffeic acid as the main active components of AS, and hypoxia-inducible factor-1α (HIF1α), vascular endothelial growth factor receptor 2 (VEGFR2) as hub targets of AS in angiogenesis. The intersection targets were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the hub targets were verified by immunofluorescence and western blot. Molecular docking of active components with hub targets was performed and verified in vitro. The results showed that AS extract promoted angiogenesis in preovulatory follicles and increased granulosa cell layer thickness, CD31 expression and content of VEGFA. Experiments in vitro and in vivo demonstrated that AS extract promoted the expression of HIF1α and VEGFA, up-regulated the phosphorylation levels of VEGFR2. These results further demonstrated the reliability of molecular docking and network pharmacology findings. In summary, AS extract can promote angiogenesis in the preovulatory follicles in late-phase laying hens.

A Comprehensive Description of Hypoxia-inducible Factor 2α Inhibitors as Anticancer Agents: A Mini-review.

Targeting the tumor microenvironment is a promising strategy to prevent metastasis, overcome acquired drug resistance, and improve the therapeutic effect. Hypoxia is one of the characteristics of the tumor microenvironment, which is mainly regulated by hypoxia-inducible factors. Hypoxia-inducible factors (HIFs) including HIF-1α, HIF-2α, and HIF-3α, of which HIF-2α has assumed a more important role in tumor hypoxia environment. It has been demonstrated that HIF-2α plays an important role in tumor diseases, including renal cell carcinoma, breast cancer, non-small cell lung cancer, and gastric cancer, among others. Therefore, targeting HIF-2α has become one of the important strategies for treating cancers. HIF-2α inhibitors can be divided into two categories: specific inhibitors and non-specific inhibitors. The former includes synthetic monomer compounds and traditional Chinese medicine extracts. In this review, we summarized, classified, and discussed current research on the structure, structure-activity relationship (SAR), and pharmacology of HIF-2α inhibitors, which is helpful to the rational design of effective drugs for various types of malignant tumors.

Aqueous extract of Artemisia capillaris improves non-alcoholic fatty liver and obesity in mice induced by high-fat diet.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases and is a nutritional metabolic disease. Artemisia capillaris (AC) is the above-ground dried part of Artemisia capillaris Thunb. or Artemisia scoparia Waldst. et Kit., a natural medicinal plant with pharmacological effects of heat-clearing and biliary-promoting. In order to evaluate the therapeutic effect of Artemisia capillaris on NAFLD and obesity, experiments were conducted using aqueous extracts of Artemisia capillaris (WAC) to intervene in NAFLD models in vivo and in vitro. In vivo experiments were performed using HFD-fed (high fat diet) C57BL/6 mice to induce NAFLD model, and in vitro experiments were performed using oleic acid to induce HepG2 cells to construct NAFLD cell model. H.E. staining and oil red O staining of liver tissue were used to observe hepatocytes. Blood biochemistry analyzer was used to detect serum lipid levels in mice. The drug targets and mechanism of action of AC to improve NAFLD were investigated by western blotting, qRT-PCR and immunofluorescence. The results showed that C57BL/6 mice fed HFD continuously for 16 weeks met the criteria for NAFLD in terms of lipid index and hepatocyte fat accumulation. WAC was able to reverse the elevation of serum lipid levels induced by high-fat diet in mice. WAC promoted the phosphorylation levels of PI3K/AKT and AMPK in liver and HepG2 cells of NAFLD mice, inhibited SREBP-1c expression, reduced TG and lipogenesis, and decreased lipid accumulation. In summary, WAC extract activates PI3K/AKT pathway, reduces SREBP-1c protein expression by promoting AMPK phosphorylation, and decreases fatty acid synthesis and TG content in hepatocytes. AC can be used as a potential health herb to improve NAFLD and obesity.

Exploration of the Components and Pharmacological Mechanisms of Keyin Pill-Induced Liver Injury Based on Network Pharmacology.

Background: Keyin pill (KP), a patented medicine in China, is used to treat psoriasis. However, KP has been reported to have liver toxicity, but its toxic substance basis and underlying mechanisms remain unclear. Therefore, this study aimed to explore the pharmacological mechanisms and components of KP-induced liver injury through animal experiments, UPLC-QTOF/MS combined with network pharmacology. Methods: Firstly, based on the immune stress mouse model, liver function parameters and hematoxylin-eosin (H&E) staining were detected to investigate KP-induced liver injury. The UPLC-QTOF/MS method was used to identify the components of KP. CTD database and literature mining were further applied to screen nonliver protective components. Subsequently, the nonliver protective components and their corresponding targets and targets of hepatotoxicity were analyzed by the method of network pharmacology. Finally, key targets from networked pharmacology were examined by the enzyme-linked immunosorbent assay (ELISA) and molecular docking. Results: Our results indicated that KP had hepatotoxicity in male Kunming mice, which could favor hepatocyte necrosis and infiltration of inflammatory cells. A total of 70 nonliver protective compounds were identified and screened. The results of network pharmacology illustrated that methoxsalen, obacunone, limonin, and dictamnine might be the main compounds that caused liver damage. The potential hepatotoxicity mechanisms of KP might be through the IL17 and apoptosis pathways to regulate IL6, TNFα, CASP3, and CASP8 targets, thereby causing inflammation, excessive release of factors, and hepatocyte necrosis. The results of the ELISA experiments indicated that KP could increase the release of IL6 and TNFα inflammatory factors in liver tissues. Molecular docking suggested that methoxsalen, obacunone, limonin, and dictamnine had moderate binding ability with CASP3 and CASP8. Conclusion: In this study, the material basis and potential pharmacological mechanisms of KP-induced liver injury were preliminarily explored. Our research provides the initial theoretical basis for reducing the toxicity of KP.

Mechanistic Investigation of Curcuma Protection against Oral Submucous Fibrosis.

Objective: Oral submucous fibrosis (OSMF) is a chronic, fibrotic disease that affects the oral cavity, showing a high rate of malignant transformation. Curcuma exerts therapeutic potentials in many diseases including OSMF. However, the potential targets and pathways to explain the therapeutic effects of curcuma on OSMF are outside the scope of present knowledge. Herein we intend to reveal the predictive targets and potential pathways of curcuma against OSMF by a network pharmacology-based approach followed by molecular docking technology. Methods: We searched the SymMap, GeneCards, and OMIM database to obtain curcuma and OSMF common targets. The protein-protein interaction (PPI) of curcuma and OSMF common targets were then analyzed, followed by functional enrichment analysis. The best binding mode of curcuma and target proteins was analyzed by molecular docking technology. Results: We collected 290 putative targets of curcuma molecules and 600 known therapeutic targets of OSMF, with 64 curcuma and OSMF common targets sorted out. In the PPI network, there were 63 nodes with 922 edges. The node indicates protein and the line indicates PPI relation. The most enriched GO term in the BP level is "gland development", followed by "cellular response to chemical stress", and then "response to oxygen levels", while the most enriched GO term in CC and MF is "membrane raft" and "cytokine receptor binding", respectively. We also found 131 KEGG pathways significantly enriched by curcuma and OSMF common targets. The binding energy of curcuma to ALB, TNF, TP53, IL6, and VEGFA was -9.5 kcal/mol, -3.9 kcal/mol, -3.5 kcal/mol, -3.6 kcal/mol, and -8.9 kcal/mol, respectively, which suggested ALB and VEGFA were regarded as main targets involving in the potential mechanism of curcuma against OSMF. Conclusion: The present study illustrated that the therapeutic effects of curcuma on OSMF were achieved by targeting ALB and VEGFA, which giving reference to further drug design and development for OSMF.

Curcumin alleviates aristolochic acid nephropathy based on SIRT1/Nrf2/HO-1 signaling pathway.

Aristolochic acid I (AA-I), presenting in a variety of natural medicinal plants, which could cause tubular epithelial cell injury. Curcumin (CUR), a polyphenolic substance isolated from turmeric, is a natural antioxidant. The aim of this experiment was to investigate whether CUR attenuated AA-I-induced renal injury in rats through the SIRT1/Nrf2/HO-1 signaling pathway. SD rats were treated with AA-I (10 mg/kg) or/and CUR (200 mg/kg) for 28 days to assess the protective effect of CUR on AA-I-induced renal injury in vivo. NRK-52E cells were treated with AA-I (40 µ M) or/and CUR (20 µ M) for 24 h in vitro. The intervention pathway of CUR against oxidative stress injury induced by AA-I was assessed by observing pathological changes, oxidative stress status, apoptosis and the expression of SIRT1/Nrf2/HO-1 signaling pathway-related factors. The results showed that AA-I exposure increased the contents of BUN, Cr, KIM-1, NGAL, ALT and AST in serum. It increased the content of MDA, decreased the activities of SOD, GST, GSH and the content of ATP in renal tissue. Pathological changes such as inflammatory cell infiltration and mitochondrial injury occurred in renal tissue. AA-I exposure resulted in a substantial rise in the levels of BAX, Ccaspase-9, Cleaved Caspase-9, Caspase-3, Cleaved Caspase-3 and a significant decrease in mRNA and protein expression levels of Bcl-2, SIRT1, Nrf2, NQO1, HO-1 and Keap1. However, these changes were reversed by CUR intervention. In summary, AA-I exposure caused mitochondrial dysfunction and triggered apoptosis through the oxidative stress pathway. However, CUR could reduce AA-I-induced renal injury by activating the SIRT1/Nrf2/HO-1 signaling pathway.

Promotion effect of angelica sinensis extract on angiogenesis of chicken preovulatory follicles in vitro.

Preovulatory follicles need a network of blood vessels to growth and maturation in hens (Gallus gallus). Angelica sinensis (Oliv.) (AS), a traditional Chinese herb, displays a novel pro-angiogenic activity. The molecular mechanisms underlying AS promoting preovulatory follicles angiogenesis are poorly understand. Several recent studies investigated the expression of vascular endothelial growth factor A (VEGF-A) in angiogenesis. In order to explore the promotion effect of AS extract on angiogenesis of chicken preovulatory follicles, we studied the effect of AS extract on follicle microvascular endothelial-like cells of chicken (FMEC) and granulosa cells (GC). The current study indicated that AS extract could promote the proliferation of FMECs and GCs. The assays of wounding healing, transwell invasion and tube formation showed that AS extract could enhance the invasion and migration ability of FMECs in vitro. The results of western blot and RT-PCR showed that AS extract promoted the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) in FMECs by activating the PI3K/AKT signaling pathway. The AS extract activated PI3K/AKT signaling pathway and up-regulated the expressions of hypoxia-inducible factor 1-α (HIF1-α) and VEGF-A in GCs. In addition, treatment of FMECs and GCs with LY294002 (a PI3K inhibitor) significantly down-regulated the phosphorylation of VEGFR2, VEGF-A, and HIF1-α. The mRNA expression levels of PI3K, AKT, VEGF-A, VEGFR2, and HIF1-α were consistent with protein expression levels. In conclusion, our research showed that AS extract can promote the follicle angiogenesis in hens in vitro, providing a basis for application of the traditional Chinese herb AS in poultry production.

Protective effects of maslinic acid on high fat diet-induced liver injury in mice.

AIMS: Due to the prevalence of high-fat diets and lack of exercise, diseases related to nutrient metabolism such as nonalcoholic fatty liver disease (NAFLD) have become one of the reasons causes endangering human liver health. Maslinic acid (MA) is a pentacyclic triterpenoid acid that is abundant in fruits such as hawthorn and jujube. In this study, we investigated the effect of MA on NAFLD to inform the development of dietary supplements for the treatment and prevention of NAFLD. MATERIALS AND METHODS: The NAFLD model was established by feeding mice a high-fat diet (HFD). HEPG2 cells were treated with oleic acid and used as a cell culture model. Testing kits, haematoxylin and eosin staining, oil red O staining, western blotting, and immunofluorescence were performed with in vivo and in vitro experiments. KEY FINDINGS: The current study revealed that MA significantly reduced liver weight, body weight and serum lipid levels, and protected against liver steatosis and injury induced by a HFD. MA increased the expression of Beclin1, ATG1, and Bcl-2 mRNA and protein while decreasing the expression of TNF-α and IL-1ß, caspase-3 and Bax mRNA and protein. Beclin1, and ATG1 were obviously increased, and the mRNA and protein expression of TNF-α and IL-1ß were obviously reduced, the mRNA and protein expression of Caspase-3 and Bax were obviously reduced, and the mRNA and protein expression of Bax were obviously increased by MA. SIGNIFICANCE: MA reduces the content of fat in the liver cells of NAFLD mice through lipophagy activitiy and reduces inflammation and apoptosis injury.

Effects of mental health interventions among people hospitalized with COVID-19 infection: A systematic review of randomized controlled trials.

OBJECTIVE: We evaluated the effects of mental health interventions among people hospitalized with COVID-19. METHODS: We conducted a systematic review and searched 9 databases (2 Chinese-language) from December 31, 2019 to June 28, 2021. Eligible randomized controlled trials assessed interventions among hospitalized COVID-19 patients that targeted mental health symptoms. Due to the poor quality of trials, we sought to verify accuracy of trial reports including results. RESULTS: We identified 47 randomized controlled trials from China (N = 42), Iran (N = 4) and Turkey (N = 1) of which 21 tested the efficacy of psychological interventions, 5 physical and breathing exercises, and 21 a combination of interventions. Trial information could only be verified for 3 trials of psychological interventions (cognitive behavioral, guided imagery, multicomponent online), and these were the only trials with low risk of bias on at least 4 of 7 domains. Results could not be pooled or interpreted with confidence due to the degree of poor reporting and trial quality, the frequency of what were deemed implausibly large effects, and heterogeneity. CONCLUSION: Trials of interventions to address mental health in hospitalized COVID-19 patients, collectively, are not of sufficient quality to inform practice. Health care providers should refer to existing expert recommendations and standard hospital-based practices. REGISTRATION: PROSPERO (CRD42020179703); registered on April 17, 2020.

Dracorhodin Perchlorate Regulates the Expression of Inflammatory Cytokines through the TLR4 Pathway and Improves Skin Wound Healing in Diabetic Rats.

Background: Dragon's blood is a natural medicine with hemostatic and blood-activating effects and is used to promote wound healing. Dracorhodin perchlorate (DP) is a stable form of dracarhod and is used as a substitute for cochinchinenin. DP promotes the proliferation of rat fibroblasts and promotes wound healing in rats. Methods: DP ointment (0.2 mg/mL) was applied to the skin wounds of nondiabetic and diabetic rats, and the skin of the wound was collected. Wound healing rate, H&E staining, Masson staining, TLR4 pathway, related inflammatory factors, nitric oxide synthase, and so forth were detected. Results: DP treatment alleviated the prolonged inflammatory cell infiltration time and the increase in the TLR4 pathway and inflammatory factors caused by diabetes. DP also promoted wound healing by increasing eNOS protein expression and NO content in the later stage of wound healing. Conclusion: DP promotes wound healing in diabetic rats by regulating the TLR4 pathway and related inflammatory factors. Therefore, adjuvant treatment of DP can be developed for diabetic wound healing.

Based on proteomics to explore the mechanism of mecobalamin promoting the repair of injured peripheral nerves.

Mecobalamin is commonly used in the adjuvant intervention of various peripheral nerve injuries. Actin cytoskeleton plays a role in the regeneration of myelin and axon. Therefore, the purpose of this study was to explore the possibility of mecobalamin regulating actin cytoskeleton in repairing nerve injury. In this study, a crush injury on the right sciatic nerve of two groups of rats (12 in each group) was established. The control group was only given normal saline (i.g.), and the intervention group was given mecobalamin 1 mg/kg (i.g.). The rats were sacrificed on 28th day and the injured nerves were collected for proteomics. The result shows that regulation of actin cytoskeleton pathway changed significantly. The expression of protein Vav1 was verified by Western blot and immunofluorescence. In the intervention group, the nerve fiber structure was complete, the axons were dense and symmetrical, and the myelin sheath was compact and uniform in thickness. The positive rate of myelin basic protein and ßⅢ-tubulin was higher than that in the control group. The findings of the study show that mecobalamin regulates the actin cytoskeleton in the repair of nerve damage and upregulates Vav1 in the regulation of actin cytoskeleton pathway.

An integrated multi-omics approach revealed the regulation of melatonin on age-dependent mitochondrial function impair and lipid dyshomeostasis in mice hippocampus.

Melatonin can improve mitochondrial dysfunction associated with the aging process by removing active oxygen, as well as inhibiting lipid peroxidation to maintain biofilm fluidity and resist free radical attack. However, there is poor understanding of the effect of melatonin on age-dependent mitochondrial function and lipid profile changes in brain. In this study, we investigated the energy metabolism of the whole body and brain of mice at 9 months, 13 months, and 25 months of continuous gastric administration of 3 mg/kg/d melatonin once per day morning for two months. In addition, we performed transcriptomic, proteomic and lipidomic analysis in the hippocampus of mice at different ages. Proteomics showed that melatonin regulated mitochondrial electron transport and leucine degradation in mouse hippocampus. Lipomics suggested that the long-chain unsaturated glycerol phospholipids in mouse hippocampus increased in an age-dependent manner, while ceramide and glycerol phospholipids decreased significantly in hippocampus of mouse chronically exposed to melatonin. The combined analysis of proteome and liposome demonstrated that Mpst, Ccsap, Hdhd5, Rpl5 and Flna were the key proteins of the network which involved in the regulation of numerous lipids. Furthermore, ultrastructure observation results illustrated that melatonin could improve the damaged mitochondrial and morphologies of 25-month-old mice hippocampus. In conclusion, we describe a mechanism that age-dependent up-regulation of long-chain unsaturated lipids is a driving risk factor for mitochondrial damage and this effect could be reversed by chronic supplement of low-dose melatonin.

Effects of COVID-19 Mental Health Interventions Among Children, Adolescents, and Adults Not Quarantined or Undergoing Treatment Due to COVID-19 Infection: A Systematic Review of Randomised Controlled Trials.

OBJECTIVES: Our objective was to assess the effects of mental health interventions for children, adolescents, and adults not quarantined or undergoing treatment due to COVID-19 infection. METHODS: We searched 9 databases (2 Chinese-language) from December 31, 2019, to March 22, 2021. We included randomised controlled trials of interventions to address COVID-19 mental health challenges among people not hospitalised or quarantined due to COVID-19 infection. We synthesized results descriptively due to substantial heterogeneity of populations and interventions and risk of bias concerns. RESULTS: We identified 9 eligible trials, including 3 well-conducted, well-reported trials that tested interventions designed specifically for COVID-19 mental health challenges, plus 6 other trials with high risk of bias and reporting concerns, all of which tested standard interventions (e.g., individual or group therapy, expressive writing, mindfulness recordings) minimally adapted or not specifically adapted for COVID-19. Among the 3 well-conducted and reported trials, 1 (N = 670) found that a self-guided, internet-based cognitive-behavioural intervention targeting dysfunctional COVID-19 worry significantly reduced COVID-19 anxiety (standardized mean difference [SMD] 0.74, 95% confidence interval [CI], 0.58 to 0.90) and depression symptoms (SMD 0.38, 95% CI, 0.22 to 0.55) in Swedish general population participants. A lay-delivered telephone intervention for homebound older adults in the United States (N = 240) and a peer-moderated education and support intervention for people with a rare autoimmune condition from 12 countries (N = 172) significantly improved anxiety (SMD 0.35, 95% CI, 0.09 to 0.60; SMD 0.31, 95% CI, 0.03 to 0.58) and depressive symptoms (SMD 0.31, 95% CI, 0.05 to 0.56; SMD 0.31, 95% CI, 0.07 to 0.55) 6-week post-intervention, but these were not significant immediately post-intervention. No trials in children or adolescents were identified. CONCLUSIONS: Interventions that adapt evidence-based strategies for feasible delivery may be effective to address mental health in COVID-19. More well-conducted trials, including for children and adolescents, are needed.

Rotenone induces hepatotoxicity in rats by activating the mitochondrial pathway of apoptosis.

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis.

TCQA, A Natural Caffeoylquinic Acid Derivative Attenuates H2O2-Induced Neuronal Apoptosis by Suppressing Phosphorylation of MAPKs Signaling Pathway.

1,3,5-Tri-O-caffeoyl quinic acid is a caffeoylquinic acid derivative isolated from the roots of Arctium lappa L. Our previous studies have revealed that the ethyl acetate extract of the roots of A. lappa L. and the caffeoylquinic acids contained in it possess antioxidant properties, especially 1,3,5-tri-O-caffeoyl quinic acid. The present study aimed to investigate the protective effects of 1,3,5-tri-O-caffeoyl quinic acid against hydrogen peroxide-induced oxidative stress and explore the underlying mechanism. We found that 1,3,5-tri-O-caffeoyl quinic acid prevented the decline of cell viability and excessive release of lactate dehydrogenase induced by hydrogen peroxide. In addition, Hoechst 33 342 staining and Annexin V-PI double staining showed that 1,3,5-tri-O-caffeoyl quinic acid inhibited hydrogen peroxide-induced neuronal cell apoptosis. 1,3,5-Tri-O-caffeoyl quinic acid reduced the excessive production of intracellular reactive oxygen species, decreased the malondialdehyde content, and improved the activity of superoxide dismutase. Furthermore, 1,3,5-tri-O-caffeoyl quinic acid restored the loss of mitochondrial membrane potential in SH-SY5Y cells induced by hydrogen peroxide. 1,3,5-Tri-O-caffeoyl quinic acid downregulated the overexpression of proapoptotic proteins, including Bax, cytochrome c, cleaved caspase-9, and cleaved caspase-3 as well as promoted the expression of the antiapoptotic protein Bcl-2. Moreover, the phosphorylation of mitogen-activated protein kinases induced by hydrogen peroxide was inhibited by 1,3,5-tri-O-caffeoyl quinic acid. Pretreatment with 1,3,5-tri-O-caffeoyl quinic acid also promoted the activation of phosphorylated Akt. Taken together, these findings suggest that 1,3,5-tri-O-caffeoyl quinic acid exerts protective effects against hydrogen peroxide-induced neuronal apoptosis. In addition, inhibition of the mitogen-activated protein kinase signaling pathway and the activation of Akt are implicated in the antioxidant activity of 1,3,5-tri-O-caffeoyl quinic acid, giving new insight in searching for a compound with antioxidant activity for the treatment of oxidative stress-associated neurological diseases.

Arctium lappa L. roots ameliorates cerebral ischemia through inhibiting neuronal apoptosis and suppressing AMPK/mTOR-mediated autophagy.

BACKGROUND: Arctium lappa L. roots are very popular cultivated vegetables, which possesses various pharmacological activities. Our previous studies have demonstrated that Arctium lappa L. roots exerted protective effects against H2O2, glutamate and N-methyl-D-aspartic acid (NMDA)-induced neuronal injury in vitro. However, whether Arctium lappa L. roots could prevent against cerebral ischemia and the underlying mechanism remain unclear. PURPOSE: The objective of the present study was to investigate the neuroprotective effects of ethyl acetate extract of Arctium lappa L. roots (EAL) and the active ingredient 4,5-O-dicaffeoyl-1-O-[4-malic acid methyl ester]-quinic acid (DCMQA) in EAL against cerebral ischemia and explore the underlying mechanism. STUDY DESIGN: The neuroprotective effects of EAL and DCMQA were investigated in rats with permanent middle cerebral artery occlusion (MCAO) and in oxygen glucose deprivation/reoxygenation (OGD/R)-stimulated SH-SY5Y cells, respectively. METHODS: The infarct volume, brain edema and neurological deficits were measured following MCAO. TUNEL and Nissl staining were performed to detect neuronal loss and apoptosis of neurons in rat brains. Cell survival was measured by MTT and LDH assay. In addition, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were determined by DCFH-DA and JC-1 fluorescent probe, respectively. Hoechst 33342 staining and Annexin V-FITC/PI double staining were performed to evaluate neuronal apoptosis. The expression levels of proteins were evaluated by western blot. RESULTS: EAL reduced brain infarct volume, ameliorated brain edema and improved neurological deficits in MCAO rats. In addition, EAL inhibited oxidative stress and inflammatory responses following MCAO. Besides, active compound DCMQA alleviated cytotoxicity as well as inhibited over-production of intracellular ROS and loss of MMP induced by OGD/R in SH-SY5Y cells. Moreover, EAL and DCMQA inhibited apoptosis by decreasing the expressions of pro-apoptotic proteins including bax, cytochrome c and cleaved caspase-3 while promoting the bcl-2 expression in MCAO rats and OGD/R-stimulated neurons, respectively. In addition, DCMQA suppressed the production of autophagosomes and down-regulated expression of Beclin 1 and LC3. Furthermore, inhibiting AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathway contributed to DCMQA-mediated suppression of autophagy induced by OGD/R. CONCLUSION: Our findings demonstrate that Arctium lappa L. roots protect against cerebral ischemia through inhibiting apoptosis and AMPK/mTOR-mediated autophagy in vitro and in vivo, providing a theoretical basis for the development of CQAs in Arctium lappa L. roots as neuroprotective drugs for the prevention and treatment of ischemic stroke.