Guava leaf extract attenuated muscle proteolysis in dexamethasone induced muscle atrophic mice via ubiquitin proteasome system, mTOR-autophagy, and apoptosis pathway.

Muscle atrophy is the waste or loss of muscle mass and is caused by physical inactivity, aging, or diseases such as diabetes, cancer, and heart failure. The number of patients suffering from musculoskeletal disorders is expected to increase in the future. However, intervention for muscle atrophy is limited, so research on treatment for muscle wasting is needed. This study hypothesized that guava leaf (Psidium guajava L. [GL]) would have ameliorative effects on muscle atrophy by regulation of protein degradation pathways in a dexamethasone (DEX)-induced muscle atrophy mice model. Muscle atrophy was induced by DEX injection for 28 days in 7 week-old-male ICR mice. Then, low-dose GL (LGL, 200 mg/kg) or high-dose GL (HGL, 500 mg/kg) extract (GLE) was supplemented by oral gavage for 21 days. Muscle strength, calf thickness, and body composition were analyzed. Histopathological changes in the gastrocnemius muscle were examined using hematoxylin and eosin staining, and molecular pathways related to muscle degradation were analyzed by western blots. GLE treatment regardless of dose increased muscle strength in mice with muscle atrophy accompanied by attenuating autophagy related pathway in the DEX-induced muscle atrophy mice. Moreover, a high dose of GLE treatment ameliorated ubiquitin proteasome system and apoptosis in the DEX-induced muscle atrophy mice. This study suggested that GLE could be helpful to improve muscle health and alleviate proteolysis by regulation of the ubiquitin-proteasome system, autophagy, and apoptosis, which are involved in muscle degradation. In conclusion, GLE could be a potential nutraceutical to prevent muscle atrophy.

Metabolomic Comparison of Guava (Psidium guajava L.) Leaf Extracts Fermented by Limosilactobacillus fermentum and Lactiplantibacillus plantarum and Their Antioxidant and Antiglycation Activities.

Probiotic fermentation of plant-based materials can lead to the generation of various bioactive substances via bacterial metabolites and the biotransformation of phenolic compounds. We compared the metabolic differences between fermentation by Limosilactobacillus fermentum KCTC15072BP (LFG) and fermentation by Lactiplantibacillus plantarum KGMB00831 (LPG) in guava leaf extract (0%, 0.5%, and 2% (w/v))-supplemented medium via non-targeted metabolite profiling. By performing multivariate statistical analysis and comparing the different guava leaf extract groups, 21 guava-derived and 30 bacterial metabolites were identified. The contents of guava-derived glucogallin, gallic acid, and sugar alcohols were significantly higher in LFG than they were in LPG. Similarly, significantly higher contents of guava-derived pyrogallol, vanillic acid, naringenin, phloretin, and aromatic amino acid catabolites were obtained with LPG than with LFG. LFG led to significantly higher antioxidant activities than LPG, while LPG led to significantly higher antiglycation activity than LFG. Interestingly, the fermentation-induced increase in the guava-leaf-extract-supplemented group was significantly higher than that in the control group. Thus, the increased bioactivity induced by guava fermentation with the Lactobacillaceae strain may be influenced by the synergistic effects between microbial metabolites and plant-derived compounds. Overall, examining the metabolic changes in plant-based food fermentation by differentiating the origin of metabolites provides a better understanding of food fermentation.

Solanum melongena extract supplementation protected skeletal muscle and brain damage by regulation of BDNF/PGC1α/irisin pathway via brain function-related myokines in high-fat diet induced obese mice.

In this study, we investigated the protective effects of SM on skeletal muscle and brain damage by regulation of BDNF/PGC1α/irisin pathway via brain function related myokines in high-fat diet-induced OB mice. OB was induced by high-fat diet for 6 weeks. SM extract (SME) was administered with 200 mg/kg BW (LSM) and 500 mg/kg BW (HSM) by oral gavage every day for 12 weeks. Behavior tests such as grip strength, Y-maze, and passive avoidance test were conducted to analyze muscle and cognitive function. Histopathological changes in skeletal muscle and brain were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to oxidative stress, inflammation, protein degradation, neuro-plasticity, and cell cycling were measured by western blot. SME regulated morphological changes (muscle cross-sectional area: 1.23%, 1.40%; density of neurons in hippocampus:1.74%, 1.73%) in T2DM mice. Importantly, SME supplementation significantly increased several muscle-derived myokines which might influence the expression of neuronal markers in OB mice (FGF21: 1.27%, 1.34%; PGC1α: 1.0%, 1.32%; IRISIN: 1.9%, 1.08%; BDNF: 1.35%, 1.23%). Accordingly, SME activated hippocampal neurotrophic factors including BDNF (1.0%, 1.2%) and its associated PGC1α/irisin pathway (PGC1α :1.1%, 1.1%; IRISIN:1.1%, 0.9%) significantly. This study demonstrated the possibliy that protective myokines increased by SME supplementation may contribute to neuro-protection in OB mice. Taken together, the current study suggests that SME can be used to prevent skeletal muscle and brain damage in OB by protecting against oxidative stress and inflammatin via modulation of the BDNF/PGC1α/irisin pathway in the therapeutic approach of obese patients.

A natural product YSK-A blocks SARS-CoV-2 propagation by targeting multiple host genes.

Natural products and herbal medicine have been widely used in drug discovery for treating infectious diseases. Recent outbreak of COVID-19 requires various therapeutic strategies. Here, we used YSK-A, a mixture of three herbal components Boswellia serrata, Commiphora myrrha, and propolis, to evaluate potential antiviral activity against SARS-CoV-2. We showed that YSK-A inhibited SARS-CoV-2 propagation with an IC50 values of 12.5 µg/ml and 15.42 µg/ml in Vero E6 and Calu-3 cells, respectively. Using transcriptome analysis, we further demonstrated that YSK-A modulated various host gene expressions in Calu-3 cells. Among these, we selected 9 antiviral- or immune-related host genes for further study. By siRNA-mediated knockdown experiment, we verified that MUC5AC, LIF, CEACAM1, and GDF15 host genes were involved in antiviral activity of YSK-A. Therefore, silencing of these genes nullified YSK-A-mediated inhibition of SARS-CoV-2 propagation. These data indicate that YSK-A displays an anti-SARS-CoV-2 activity by targeting multiple antiviral genes. Although the exact antiviral mechanism of each constituent has not been verified yet, our data indicate that YSK-A has an immunomodulatory effect on SARS-CoV-2 and thus it may represent a novel natural product-derived therapeutic agent for treating COVID-19.

SARS-CoV-2 exploits cellular RAD51 to promote viral propagation: implication of RAD51 inhibitor as a potential drug candidate against COVID-19.

IMPORTANCE: Viruses are constantly evolving to promote propagation in the host. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes host RAD51 for replication. Silencing of RAD51 impaired SARS-CoV-2 propagation. Viral RNA colocalized with RAD51 in the cytoplasm of SARS-CoV-2-infected cells, suggesting that both viral RNA and RAD51 may form a replication complex. We, therefore, evaluated RAD51 inhibitors as possible therapeutic agents against SARS-CoV-2. Indeed, RAD51 inhibitors exerted antiviral activities against not only Wuhan but also variants of SARS-CoV-2. Molecular docking model shows that RAD51 inhibitors impede SARS-CoV-2 propagation by interfering with dimerization of RAD51. These data suggest that RAD51 may represent a novel host-based drug target for coronavirus disease 2019 treatment.

Polygalic acid inhibits african swine fever virus polymerase activity: findings from machine learning and in vitro testing.

African swine fever virus (ASFV), an extremely contagious virus with high mortality rates, causes severe hemorrhagic viral disease in both domestic and wild pigs. Fortunately, ASFV cannot be transmitted from pigs to humans. However, ongoing ASFV outbreaks could have severe economic consequences for global food security. Although ASFV was discovered several years ago, no vaccines or treatments are commercially available yet; therefore, the identification of new anti-ASFV drugs is urgently warranted. Using molecular docking and machine learning, we have previously identified pentagastrin, cangrelor, and fostamatinib as potential antiviral drugs against ASFV. Here, using machine learning combined with docking simulations, we identified natural products with a high affinity for AsfvPolX proteins. We selected five natural products (NPs) that are located close in chemical space to the six known natural flavonoids that possess anti-ASFV activity. Polygalic acid markedly reduced AsfvPolX polymerase activity in a dose-dependent manner. We propose an efficient protocol for identifying NPs as potential antiviral drugs by identifying chemical spaces containing high-affinity binders against ASFV in NP databases.

Annona muricate Extract Supplementation Contributes to Improve Aberrant Multi-Organ Energy Metabolism via Muscle-Brain Connectivity in Diabetic Mice.

Type 2 diabetes mellitus (T2DM) is related with the incidence of sarcopenia and cognitive impairment that reduces quality of life in the elderly. Recent evidence has demonstrated that sarcopenia is associated with cognitive dysfunction, and muscle-derived endocrine factors might contribute to cognitive function by the skeletal muscle-brain endocrine loop. This study investigated the beneficial effects of Annona muricata (AM, graviola) on multi-organ energy metabolism with muscle-brain connectivity via brain function-related myokines in mice. Body composition, fasting blood glucose level, insulin, HbA1c%, histopathological changes, and the protein levels of insulin-signaling, energy metabolism, neuroprotection, inflammation, and protein-degradation pathways were measured. AM extract (AME) treatment selectively enhanced insulin signaling in the skeletal muscle and hippocampus of T2DM mice. Furthermore, AME treatment effectively increased muscle-derived fibroblast growth factor 21 (FGF21), cathepsin-B (CTSB), irisin, brain-derived neurotrophic factor (BDNF), and liver-derived FGF21 that contribute to whole-body energy homeostasis. In particular, AME increased the levels of circulating myokines (FGF21, BDNF, irisin, and CTSB), and these were accordance with the hippocampal neurotrophic factors (BDNF and CTSB) in T2DM mice. In conclusion, we suggest that AME would be a potential nutraceutical for improving the energy metabolism associated with muscle-brain connectivity via brain function-related myokines in T2DM.

Effect of diabetes-specific oral nutritional supplements with allulose on weight and glycemic profiles in overweight or obese type 2 diabetic patients.

BACKGROUND/OBJECTIVES: Diabetes-specific oral nutritional supplements (ONS) have anti-hyperglycemic effects, while D-allulose exerts anti-diabetic and anti-obesity effects. In this study, we investigated the efficacy and safety of diabetes-specific ONS, including allulose, on glycemic and weight changes in overweight or obese patients with type 2 diabetes mellitus (T2DM). SUBJECTS/METHODS: A single-arm, historical-control pilot clinical trial was conducted on 26 overweight or obese patients with T2DM (age range: 30-70 yrs). The participants were administered 2 packs of diabetes-specific ONS, including allulose (200 kcal/200 mL), every morning for 8 weeks. The glycemic profiles, obesity-related parameters, and lipid profiles were assessed to evaluate the efficacy of ONS. RESULTS: After 8 weeks, fasting blood glucose (FBG) level significantly decreased from 139.00 ± 29.66 mg/dL to 126.08 ± 32.00 mg/dL (P = 0.007) and glycosylated hemoglobin (HbA1c) improved (7.23 ± 0.82% vs. 7.03 ± 0.69%, P = 0.041). Moreover, the fasting insulin (δ: -1.81 ± 3.61 µU/mL, P = 0.017) and homeostasis model assessment for insulin resistance (HOMA-IR) (δ: -0.87 ± 1.57, P = 0.009) levels decreased at 8 weeks, and body weight significantly decreased from 67.20 ± 8.29 kg to 66.43 ± 8.12 kg (P = 0.008). Body mass index (BMI) also decreased in accordance with this (from 25.59 ± 1.82 kg/m2 to 25.30 ± 1.86 kg/m2, P = 0.009), as did waist circumference (δ: -1.31 ± 2.04 cm, P = 0.003). CONCLUSIONS: The consumption of diabetes-specific ONS with allulose in overweight or obese patients with T2DM improved glycemic profiles, such as FBG, HbA1c, and HOMA-IR, and reduced body weight and BMI.

Amuvatinib Blocks SARS-CoV-2 Infection at the Entry Step of the Viral Life Cycle.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 propagation is mediated by the protein interaction between viral proteins and host cells. Tyrosine kinase has been implicated in viral replication, and hence, it has become a target for developing antiviral drugs. We have previously reported that receptor tyrosine kinase inhibitor blocks the replication of hepatitis C virus (HCV). In the present study, we investigated two receptor tyrosine kinase-specific inhibitors, amuvatinib and imatinib, for their potential antiviral efficacies against SARS-CoV-2. Treatment with either amuvatinib or imatinib displays an effective inhibitory activity against SARS-CoV-2 propagation without an obvious cytopathic effect in Vero E6 cells. Notably, amuvatinib exerts a stronger antiviral activity than imatinib against SARS-CoV-2 infection. Amuvatinib blocks SARS-CoV-2 infection with a 50% effective concentration (EC50) value ranging from ~0.36 to 0.45 µM in Vero E6 cells. We further demonstrate that amuvatinib inhibits SARS-CoV-2 propagation in human lung Calu-3 cells. Using pseudoparticle infection assay, we verify that amuvatinib blocks SARS-CoV-2 at the entry step of the viral life cycle. More specifically, amuvatinib inhibits SARS-CoV-2 infection at the binding-attachment step. Moreover, amuvatinib exhibits highly efficient antiviral activity against emerging SARS-CoV-2 variants. Importantly, we demonstrate that amuvatinib inhibits SARS-CoV-2 infection by blocking ACE2 cleavage. Taken together, our data suggest that amuvatinib may provide a potential therapeutic agent for the treatment of COVID-19. IMPORTANCE Tyrosine kinase has been implicated in viral replication and has become an antiviral drug target. Here, we chose two well-known receptor tyrosine kinase inhibitors, amuvatinib and imatinib, and evaluated their drug potencies against SARS-CoV-2. Surprisingly, amuvatinib displays a stronger antiviral activity than imatinib against SARS-CoV-2. Amuvatinib blocks SARS-CoV-2 infection by inhibiting ACE2 cleavage and the subsequent soluble ACE2 receptor. All these data suggest that amuvatinib may be a potential therapeutic agent in SARS-CoV-2 prevention for those experiencing vaccine breakthroughs.

Two Faces of Catechol-O-Methyltransferase Inhibitor on One-Carbon Metabolism in Parkinson's Disease: A Meta-Analysis.

Levodopa (L-dopa) and catechol-O-methyltransferase (COMT) inhibition are widely used therapeutics in Parkinson's disease (PD). Despite their therapeutic effects, it was raised that nutrients involved in one-carbon metabolism can be deteriorated by PD therapies. The aim of this meta-analysis was to investigate the impact of L-dopa and COMT inhibitors on levels of homocysteine (Hcy), vitamin B12 and folate in patients with PD. A total of 35 case-control studies from 14 different countries were selected through PubMed, MEDLINE and Google Scholar and were meta-analyzed. In the L-dopa group, the Hcy level was higher compared to the PD without L-dopa group (SMD: 5.11 µmol/L, 95% CI: 3.56 to 6.66). Moreover, vitamin B12 and folate levels in the L-dopa group were lower compared to the healthy control (SMD: -62.67 pg/mL, 95% CI: -86.53 to -38.81; SMD: -0.89 ng/mL, 95% CI: -1.44 to -0.33, respectively). The COMT inhibitor group showed lower levels of Hcy (SMD: -3.78 µmol/L, 95% CI: -5.27 to -2.29) and vitamin B12 (SMD: -51.01 pg/mL, 95% CI: -91.45 to -10.57), but higher folate levels (SMD: 1.78 ng/mL, 95% CI: -0.59 to 4.15) compared to the L-dopa group. COMT inhibitors may ameliorate L-dopa-induced hyper-homocysteine and folate deficiency but exacerbate vitamin B12 deficiency.

Lespedeza bicolor extract supplementation reduced hyperglycemia-induced skeletal muscle damage by regulation of AMPK/SIRT/PGC1α-related energy metabolism in type 2 diabetic mice.

Lespedeza bicolor (LB) is known to have antidiabetic activities; however, the underlying molecular mechanisms of LB in hyperglycemia-induced skeletal muscle damage is unclear. Inflammation and oxidative stress caused by type 2 diabetes mellitus (T2DM) not only contributes to insulin resistance, but also promotes muscle atrophy via decreased muscle protein synthesis and increased protein degradation, leading to frailty and sarcopenia. In this study, we hypothesized that LB extract (LBE) supplementatin has an ameliorative effect on hyperglycemia-induced skeletal muscle damage by activation of 5' adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)/proliferator-activated receptor γ coactivator 1α (PGC1α)-associated energy metabolism in mice with T2DM. Diabetes was induced by a high-fat diet with a 2-time streptozotoxin injection (30 mg/kg body weight) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose level ≥140 mg/dL), the mice were administered with LBE at a low dose (100 mg/kg/d) or high dose (250 mg/kg/d) by gavage for 12 weeks. LBE supplementation ameliorated glucose tolerance and hemoglobin A1c (%) in mice with T2DM. Moreover, LBE supplementation upregulated protein levels of insulin receptor subunit-1 and Akt accompanied by increased translocation of glucose transporter 4 in mice with T2DM. Furthermore, LBE increased mitochondrial biogenesis by activating SIRT1, SIRT3, SIRT4, and peroxisome PGC1α in diabetic skeletal muscle. Meanwhile, LBE supplementation reduced oxidative stress and inflammation in mice with T2DM. Taken together, the current study suggested that LBE could be a potential therapeutic to prevent skeletal muscle damage by regulation AMPK/SIRT/PGC1α-related energy metabolism in T2DM.

Effects of Whey Peptide Supplementation on Sarcopenic Obesity in High-Fat Diet-Fed Mice.

The incidence of sarcopenic obesity gradually increased in parallel with the aged population. This research examined the effects of whey peptide (WP) supplementation with/without resistant exercise (RE) on sarcopenic obesity. Male 8-month-old C57BL/6J mice were fed a control diet (10 kcal% fat) or a high-fat diet (60 kcal% fat) for 8 weeks. High-fat diet-fed mice were randomly divided into four groups: obesity control group (OB), RE (RE only), WP (WP only), and WPE (RE and WP). WP supplementation (1500 mg/day/kg B.W.) gavage and RE (ladder climbing, five times weekly, 8−10 repetitions, 10−20% B.W. load) were conducted for an additional 8 weeks. Protein and mRNA levels of markers related to energy, protein, and lipid metabolism were analyzed in skeletal muscle and adipose tissue by one-way analysis of variance (ANOVA). WP supplementation regardless of RE significantly suppressed the increasing fat mass (p = 0.016) and decreasing lean mass (p = 0.014) and alleviated abnormal morphological changes in skeletal muscle and adipose tissue (p < 0.001). In adipose tissue, WP supplementation regardless of RE ameliorated dysregulated energy metabolism and contributed to the reduction in adipocyte differentiation (PPAR-γ (p = 0.017), C/EBPα (p = 0.034)). In skeletal muscle, WP supplementation regardless of RE alleviated energy metabolism dysregulation and resulted in down-regulated protein degradation (Atrogin-1 (p = 0.003), MuRF1 (p = 0.006)) and apoptosis (Bax) (p = 0.004). Taken together, the current study elucidated that WP supplementation regardless of RE has potential anti-obesity and anti-sarcopenic effects in sarcopenic obesity.

Potential Effects of Resistant Exercise on Cognitive and Muscle Functions Mediated by Myokines in Sarcopenic Obese Mice.

Recently, it has been demonstrated that in sarcopenic obesity (SO), physical activity could improve cognitive functions. Moreover, previous studies suggested that muscle contraction could influence cognitive function via myokines. This study investigated the potential effects of resistant exercise on cognitive and muscle functions in SO. SO was induced by a high-fat diet treatment for 8 weeks in 8-month-old male C57BL/6J mice. Then, resistant exercise (ladder climbing) for 8 weeks was performed. Muscle and cognitive function tests and morphological analysis were conducted. The protein levels of myokines were investigated in muscle, plasma, and the hippocampus in sarcopenic obese mice. Muscle and cognitive functions were significantly elevated in the obesity-exercise group (EX) compared to the obesity-control group (OB). Interestingly, muscle function was positively correlated with cognitive function. Abnormal morphological changes in the hippocampus were ameliorated in EX compared to OB, but not in the muscle. Protein levels of cognitive function-related myokines and energy metabolism-related markers in EX were significantly elevated in both muscle and hippocampus compared to those in OB. Interestingly, the protein level of brain-derived neurotrophic factor (BDNF) in EX was simultaneously increased in all tissues including muscle, plasma, and hippocampus compared to that in OB. In conclusion, modulation of muscle-derived cognitive function-related myokines in various pathological conditions via a resistant exercise could be a possible way of relieving muscle and cognitive dysfunction.

Identification of a potent NAFLD drug candidate for controlling T2DM-mediated inflammation and secondary damage in vitro and in vivo.

Accumulation of glucose/sugar results in the formation of reactive di-carbonyl compounds such as MGO and GO that interact with several amino acids and proteins to form toxic advanced glycation end products (AGEs). Induction of AGEs breakdown can control symptoms and severity in T2DM and other related complications like NAFLD where AGEs are the key players. Therefore, an AGE cross-link breaker has been suggested for preventing the onset/progression of NAFLD. In this study, we reported novel synthetic naphthalene-2-acyl thiazolium derivatives (KHAGs). Among synthesized KHAG derivatives, we observed that a novel KHAG-04, a 1,4-dimethoxynaphthalen-2-acyl thiazolium salt which is an analog of alagebrium, dramatically cleaves MGO/GO-AGE cross-links, and it also inhibited inflammation by lowering the level of nitric oxide production and IL-1ß and TNF-α secretion in LPS and/or MGO-AGE-activated macrophage. Moreover, it also reduced FFA and MGO-AGE-induced lipogenesis in Hep-G2 cells. In mice, KHAG-04 significantly reduced the level of glyoxal in the liver, which was induced by DMC. Furthermore, KHAG-04 treatment significantly reduced blood glucose levels, lipid accumulation, and inflammation in the NAFLD/T2DM animal model. Novel KHAG-04-mediated induction of AGEs breakdown could be the possible reason for its anti-inflammatory, antihyperglycemic, and anti-lipidemic effects in cells and NAFLD in the T2DM animal model, respectively. Further research might explore the pharmacological efficacy and usefulness and consider the ability of this compound in the treatment strategy against various models of NAFLD in T2DM where MGO/GO-AGEs play a key role in the pathogenesis.

The Potential Role of Myokines/Hepatokines in the Progression of Neuronal Damage in Streptozotocin and High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice.

BACKGROUND: Diabetes is highly prevalent, and the number of patients with diabetic sarcopenia and cognitive impairment has grown, leading to decreased quality of life. Although the exact mechanisms between sarcopenia and cognitive impairment have not been elucidated, it is speculated that muscle and liver-derived mediators might contribute to brain function. This study examined the molecular mechanisms associated with muscle-brain interaction accompanied by insulin resistance (IR) caused by aberrant energy metabolism via myokines/hepatokines in type 2 diabetes mellitus (T2DM) mice. METHODS: T2DM was induced by a high-fat diet and streptozotocin injection. Behavior tests were conducted to analyze grip strength and cognitive function. Histopathological changes in skeletal muscle and brain tissue were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to energy metabolism via myokines/hepatokines were measured by western blot. RESULTS: T2DM caused peripheral and central IR. Furthermore, T2DM led to aberrant energy metabolism through the reduced fibroblast growth factor 21 dependent AMP-activated kinase (AMPK)/surtuin1/proliferator-activated receptor γ coactivator-1α pathway in T2DM. Subsequently, reduced circulating myokines/hepatokines were in accordance with their levels with hippocampal neuronal markers in T2DM mice. Accordingly, skeletal muscle (muscle strength: 2.83 ± 0.39 vs. 2.187 ± 0.51, p = 0.004) and brain function (PAT: 38.5 ± 57.91 vs. 11.556 ± 12.03, p = 0.02) impairment and morphological changes (muscle cross-sectional area: 872.43 ± 242.87 vs. 743.68 ± 169.31, p = 0.01; density of neurons in hippocampus: 145 ± 15.13 vs. 77 ± 35.51, p = 0.05; density of neurons in cortex: 138.333 ± 6.66 vs. 78 ± 17.35, p = 0.05) were shown in T2DM mice. In addition, the working ability demonstrated by Y-maze was positively correlated with % lean mass (p = 0.046, R = 0.3426). CONCLUSIONS: T2DM led to aberrant energy in skeletal muscle and brain via myokines/hepatokines. This study suggested that myokines and hepatokines might have potential roles in skeletal muscle and central metabolic functions which can mediate cognitive function in T2DM mice.

Quamoclit angulata extract supplementation attenuates hepatic damage via regulation of AMPK/SIRT associated hepatic lipid metabolism in streptozotocin and high fat diet-induced T2DM mice.

Quamoclit angulata (QA) is a species of the Convolvulaceae family and has a regulatory effect on glucose homeostasis. However, the effects of QA on hyperglycemia-induced hepatic damage has not been elucidated. We hypothesized that QA extract (QAE) would alleviate hepatic damage through regulation of hepatic lipid accumulation in type 2 diabetes mellitus (T2DM). T2DM was induced by streptozotocin-high-fat diet in C57BL6 male mice for 8 weeks. The diabetic mice were supplemented with QAE at low dose (5 mg/kg) or high dose (HQ, 10 mg/kg) by oral gavage every day for 12 weeks. Histopathological changes in hepatic tissue were examined using hematoxylin and eosin staining, and the protein levels of biomarkers related to AMP-activation kinase (AMPK)/sirtuin-1 (SIRT1)-associated lipid metabolism were measured using Western blotting. QAE supplementation ameliorated plasma insulin and glycated hemoglobin in diabetic mice. Furthermore, QAE decreased hepatic lipid accumulation demonstrated by hepatic triglyceride and cholesterol levels. QAE supplementation induced hepatic AMPK, which activates SIRT1 accompanied by reduced lipogenesis in the HQ group. These changes were partially explained by the amelioration of advanced glycation end product, hepatic oxidative stress, inflammation, and fibrosis in diabetic mice. Altogether, QAE would be a potential nutraceutical to prevent hepatic damage by regulation of AMPK/SIRT1-associated lipid metabolism through oxidative stress, inflammation, and fibrosis in T2DM.

Can Low-Dose of Dietary Vitamin E Supplementation Reduce Exercise-Induced Muscle Damage and Oxidative Stress? A Meta-Analysis of Randomized Controlled Trials.

Vitamin E plays an important role in attenuating muscle damage caused by oxidative stress and inflammation. Despites of beneficial effects from antioxidant supplementation, effects of antioxidants on exercise-induced muscle damage are still unclear. The aim of this meta-analysis was to investigate the effects of dietary vitamin E supplementation on exercise-induced muscle damage, oxidative stress, and inflammation in randomized controlled trials (RCTs). The literature search was conducted through PubMed, Medline, Science Direct, Scopus, SPORTDiscuss, EBSCO, Google Scholar database up to February 2022. A total of 44 RCTs were selected, quality was assessed according to the Cochrane collaboration risk of bias tool (CCRBT), and they were analyzed by Revman 5.3. Dietary vitamin E supplementation had a protective effect on muscle damage represented by creatine kinase (CK; SMD -1.00, 95% CI: -1.95, -0.06) and lactate dehydrogenase (SMD -1.80, 95% CI: -3.21, -0.39). Muscle damage was more reduced when CK was measured immediately after exercise (SMD -1.89, 95% CI: -3.39, -0.39) and subjects were athletes (SMD -5.15, 95% CI: -9.92, -0.39). Especially vitamin E supplementation lower than 500 IU had more beneficial effects on exercise-induced muscle damage as measured by CK (SMD -1.94, 95% CI: -2.99, -0.89). In conclusion, dietary vitamin E supplementation lower than 500 IU could prevent exercise-induced muscle damage and had greater impact on athletes.

Non-invasive administration of AAV to target lung parenchymal cells and develop SARS-CoV-2-susceptible mice.

Adeno-associated virus (AAV)-mediated gene delivery holds great promise for gene therapy. However, the non-invasive delivery of AAV for lung tissues has not been adequately established. Here, we revealed that the intratracheal administration of an appropriate amount of AAV2/8 predominantly targets lung tissue. AAV-mediated gene delivery that we used in this study induced the expression of the desired protein in lung parenchymal cells, including alveolar type II cells. We harnessed the technique to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-susceptible mice. Three kinds of immune function-relevant gene knockout (KO) mice were transduced with AAV encoding human angiotensin-converting enzyme 2 (hACE2) and then injected with SARS-CoV-2. Among these mice, type I interferon receptor (IFNAR) KO mice showed increased viral titer in the lungs compared to that in the other KO mice. Moreover, nucleocapsid protein of SARS-CoV-2 and multiple lesions in the trachea and lung were observed in AAV-hACE2-transduced, SARS-CoV-2-infected IFNAR KO mice, indicating the involvement of type I interferon signaling in the protection of SARS-CoV-2. In this study, we demonstrate the ease and rapidness of the intratracheal administration of AAV for targeting lung tissue in mice, and this can be used to study diverse pulmonary diseases.

Hepatitis C Virus Nonstructural 5A Protein Interacts with Telomere Length Regulation Protein: Implications for Telomere Shortening in Patients Infected with HCV.

Hepatitis C virus (HCV) is a major cause of chronic liver disease and is highly dependent on cellular proteins for viral propagation. Using protein microarray analysis, we identified 90 cellular proteins as HCV nonstructural 5A (NS5A) interacting partners, and selected telomere length regulation protein (TEN1) for further study. TEN1 forms a heterotrimeric complex with CTC and STN1, which is essential for telomere protection and maintenance. Telomere length decreases in patients with active HCV, chronic liver disease, and hepatocellular carcinoma. However, the molecular mechanism of telomere length shortening in HCV-associated disease is largely unknown. In the present study, protein interactions between NS5A and TEN1 were confirmed by immunoprecipitation assays. Silencing of TEN1 reduced both viral RNA and protein expression levels of HCV, while ectopic expression of the siRNA-resistant TEN1 recovered the viral protein level, suggesting that TEN1 was specifically required for HCV propagation. Importantly, we found that TEN1 is re-localized from the nucleus to the cytoplasm in HCV-infected cells. These data suggest that HCV exploits TEN1 to promote viral propagation and that telomere protection is compromised in HCV-infected cells. Overall, our findings provide mechanistic insight into the telomere shortening in HCV-infected cells.

Identification of African Swine Fever Virus Inhibitors through High Performance Virtual Screening Using Machine Learning.

African swine fever virus (ASFV) is a highly contagious virus that causes severe hemorrhagic viral disease resulting in high mortality in domestic and wild pigs, until few antiviral agents can inhibit ASFV infections. Thus, new anti-ASFV drugs need to be urgently identified. Recently, we identified pentagastrin as a potential antiviral drug against ASFVs using molecular docking and machine learning models. However, the scoring functions are easily influenced by properties of protein pockets, resulting in a scoring bias. Here, we employed the 5'-P binding pocket of AsfvPolX as a potential binding site to identify antiviral drugs and classified 13 AsfvPolX structures into three classes based on pocket parameters calculated by the SiteMap module. We then applied principal component analysis to eliminate this scoring bias, which was effective in making the SP Glide score more balanced between 13 AsfvPolX structures in the dataset. As a result, we identified cangrelor and fostamatinib as potential antiviral drugs against ASFVs. Furthermore, the classification of the pocket properties of AsfvPolX protein can provide an alternative approach to identify novel antiviral drugs by optimizing the scoring function of the docking programs. Here, we report a machine learning-based novel approach to generate high binding affinity compounds that are individually matched to the available classification of the pocket properties of AsfvPolX protein.