Aureane-type sesquiterpene tetraketides as a novel class of immunomodulators with interleukin-17A inhibitory activity.

Interleukin (IL)-17A, a pro-inflammatory cytokine, is a fundamental function in the onset and advancement of multiple immune diseases. To uncover the primary compounds with IL-17A inhibitory activity, a large-scale screening of the library of traditional Chinese medicine constituents and microbial secondary metabolites was conducted using splenic cells from IL-17A-GFP reporter mice cultured under Th17-priming conditions. Our results indicated that some aureane-type sesquiterpene tetraketides isolated from a wetland mud-derived fungus, Myrothecium gramineum, showed remarkable IL-17A inhibitory activity. Nine new aureane-type sesquiterpene tetraketides, myrogramins A-I (1, 4-11), and two known ones (2 and 3) were isolated and identified from the strain. Compounds 1, 3, 4, 10, and 11 exhibited significant IL-17A inhibitory activity. Among them, compound 3, with a high fermentation yield dose-dependently inhibited the generation of IL-17A and suppressed glycolysis in splenic cells under Th17-priming conditions. Strikingly, compound 3 suppressed immunopathology in both IL-17A-mediated animal models of experimental autoimmune encephalomyelitis and pulmonary hypertension. Our results revealed that aureane-type sesquiterpene tetraketides are a novel class of immunomodulators with IL-17A inhibitory activity, and hold great promise applications in treating IL-17A-mediated immune diseases.

Ginsenoside Rb1 protects hippocampal neurons in depressed rats based on mitophagy-regulated astrocytic pyroptosis.

BACKGROUND: Astrocytes play a vital role in offering functional support for neurons, which are related to the pathogenic mechanism of depression. Ginsenoside Rb1 (GRb1) is demonstrated with antidepressant-like activities. PURPOSE: We aimed to investigate whether GRb1 can inhibit mitophagy-mediated astrocytic pyroptosis to protect neurons in depression. STUDY DESIGN: Model rats were subjected to chronic unpredictable mild stress (CUMS) for determining the in vivo antidepressant activity of GRb1. METHODS: The mitophagy-mediated antipyroptosis role of GRb1 was assessed in lipopolysaccharide (LPS) + ATP-stimulated astrocytes. The mechanism by which GRb1 protects synaptic plasticity was investigated using hippocampal neurons incubated in an astrocyte medium. The rat depressive-like behaviors were determined through sucrose preference, forced swimming, and the open-field tests. Escitalopram was used in the anti-depression control of GRb1. Cyclosporin A (CsA), a mitophagy inhibitor, and interleukin (IL)-1ß were used to reverse the role of GRb1 in mitophagy and pyroptosis, respectively. RESULTS: GRb1 inhibited LPS-induced inflammation and activation in the astrocytes and repressed nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. Also, GRb1 repressed LPS + ATP-promoted astrocytic pyroptosis. During GRb1 treatment, the activation of mitophagy with a decrease in ROS was observed in LPS + ATPs-stimulated astrocytes. CsA enhanced GRb1-decreased ROS and promoted astrocytic pyroptosis. The GRb1-treated astrocyte medium suppressed neuron death and increased neuron viability and synaptic density. Escitalopram and GRb1 improved the depressive-like behaviors of the rats. GRb1 activated mitophagy and inhibited astrocytic activation and pyroptosis in rats with depression. It also reduced impairments in synaptic structures and increased synaptic density in depressive-like rats. IL-1ß increased astrocytic pyroptosis and reversed GRb1-enhanced synaptic plasticity in the rats exposed to CUMS. There were no statistical changes in depressive-like behaviors between GRb1 and Escitalopram groups. CONCLUSION: GRb1 modulates mitophagy and the NF-κB pathway to inhibit astrocytic pyroptosis, thereby maintaining neurological homeostasis by repressing inflammation and enhancing synaptic plasticity.

The Effects of Tai Chi on the Executive Functions and Physical Fitness in Middle-Aged Adults with Depression: A Randomized Controlled Trial.

Objective: The present study examined the effects of Tai Chi exercise on the executive functions (EFs) and physical fitness of middle-aged adults with depression. Methods: A total of 39 middle-aged adults with depression (M age = 50.59, SD = 7.38) were randomly assigned to the Tai Chi group (n = 20) or the waiting-list control group (n = 19). The Tai Chi group engaged in two 90 min sessions of Tai Chi exercise per week for 12 weeks; the waiting-list control group was asked to maintain their usual daily routines for 12 weeks. Depression symptoms, EFs (i.e., inhibitory control, planning, working memory, and cognitive flexibility), and physical fitness (i.e., cardiovascular fitness, muscular strength, muscular endurance, power, and flexibility) were evaluated at the baseline (pretest), 6-week (mid-test), and 12-week (post-test) marks. Results: Both groups showed decreased depression symptoms over time. Compared with the control group, the Tai Chi group showed decreased reaction times for incongruent conditions in the Stroop test from pretest to mid- and post-test, and shorter reaction time for incongruent conditions in the Stroop test than the control group at post-test; the Tai Chi group performed significantly better than the control group in overall total move score of Tower of London (TOL). The Tai Chi group also showed increased total correct scores of TOL from pretest to mid- and post-test, and greater total correct scores of TOL than the control group at post-test. Additionally, results indicated that Tai Chi exercise comprehensively improved physical fitness from pretest to mid- and post-test. Greater performance in terms of cardiovascular fitness, muscular strength, and power was also found in the Tai Chi group at post-test than in the control group. Conclusions: These findings suggest that the 12-week Tai Chi exercise improved inhibitory control, planning and working memory aspects of executive functions, and physical fitness in middle-aged adults with depression.

Relationship between Mindfulness, Psychological Skills, and Mental Toughness in College Athletes.

Numerous studies have shown that dispositional mindfulness is positively associated with many mental abilities related to sports performance, including psychological skills and mental toughness. The purpose of this study was to explore the relationship between dispositional mindfulness, psychological skills, and mental toughness among different types of athletes. For this cross-sectional study, 101 college athletes were recruited. Their dispositional mindfulness, psychological skills, and mental toughness were measured by the Mindfulness Attention Awareness Scale (MAAS), Athletic Psychological Skills Inventory (APSI), and Traits of Mental Toughness Inventory for Sports Scale (TMTIS). Pearson's correlation was used to calculate how dispositional mindfulness is associated with psychological skills and mental toughness. The results revealed that dispositional mindfulness is positively associated with comprehensive APSI (r = 0.21-0.36, p < 0.05), TMTIS overall (r = 0.27, p < 0.01), positive effort (r = 0.26, p = 0.01), and pressure (r = 0.30, p < 0.01). These findings suggest a positive linkage between mindfulness and the two examined psychological characteristics related to sports performance. Other approaches to increase mindfulness may be considered in the future.

Effects of Chinese Mind-Body Exercises on Executive Function in Middle-Aged and Older Adults: A Systematic Review and Meta-Analysis.

Chinese mind-body exercises (CMBEs) are positively associated with executive function (EF), but their effects on EF, from synthesized evidence using systematic and meta-analytic reviews, have not been conducted. Therefore, the present systematic review with meta-analysis attempted to determine whether CMBEs affect EF and its sub-domains, as well as how exercise, sample, and study characteristics moderate the causal relationship between CMBEs and EF in middle-aged and older adults. Seven electronic databases were searched for relevant studies published from the inception of each database through June 2020 (PubMed, Web of Science, Embase, Cochrane Controlled Trials Register, Wanfang, China National Knowledge Infrastructure, and Weipu). Randomized controlled trials with at least one outcome measure of CMBEs on EF in adults of mean age ≥ 50 years with intact cognition or mild cognitive impairment (MCI) and with or without chronic diseases were included. A total of 29 studies (N = 2,934) ultimately were included in this study. The results indicated that CMBEs improved overall EF (Standardized Mean Differences = 0.28, 95% CI 0.12, 0.44), as well as its sub-domains of working memory and shifting. The beneficial effects of CMBEs on EF occurred regardless of type (Tai Chi, Qigong), frequency of group classes (≤2 time, 3-4 time, ≥5 times), session time (≤45 min, 46-60 min), total training time (≥150 to ≤300 min, >300 min), and length of the CMBEs (4-12 week, 13-26 week, and >26 week), in addition to that more frequent participation in both group classes and home practice sessions (≥5 times per week) resulted in more beneficial effects. The positive effects of CMBEs on EF were also demonstrated, regardless of participants mean age (50-65 years old, >65 years old), sex (only female, both), and cognitive statuses (normal, MCI, not mentioned), health status (with chronic disease, without chronic disease), as well as training mode (group class, group class plus home practice) and study language (English, Chinese). This review thus suggests that CMBEs can be used as an effective method with small to moderate and positive effects in enhancing EF, and that more frequent group classes and home practice sessions may increase these effects. However, certain limitations, including strictly design studies, limited ES (effect size) samples for specific variables, and possible biased publications, required paying particular attention to, for further exploring the effects of CMBEs on EF.

Chiral resolution, absolute configuration, and bioactivity of a new racemic asarone derivative from the rhizome of Acorus tatarinowii.

A new asarone-derived racemate (1) was isolated from the rhizome of Acorus tatarinowii. The structure of 1 was established by comprehensive spectroscopic analyses, and it was successfully resolved by chiral HPLC, demonstrating that it is racemic. The absolute configurations of 1a [(-)-acortatarone A] and 1b [(+)-acortatarone A] were determined using quantum chemical calculations. Compounds 1a and 1b were the first cases of asarone derivatives with the 5,7-dialkyl-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one core. The α-glucosidase inhibitory and acetylcholinesterase (AChE) inhibitory activities of 1 were evaluated, and it exhibited α-glucosidase inhibitory activity with potency close to that of the positive control (acarbose).

Squalene synthase as a target for Chagas disease therapeutics.

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.