Constituents, pharmacological activities, pharmacokinetic studies, clinical applications, and safety profile on the classical prescription Kaixinsan.

Kaixinsan (KXS) is a noteworthy classical prescription, which consists of four Chinese medicinal herbs, namely Polygalae Radix, Ginseng Radix et Rhizoma, Poria, and Acori Tatarinowii Rhizoma. KXS was initially documented in the Chinese ancient book Beiji Qianjin Yaofang written by Sun Simiao of the Tang Dynasty in 652 A.D. As a traditional Chinese medicine (TCM) prescription, it functions to nourish the heart and replenish Qi, calm the heart tranquilize the mind, and excrete dampness. Originally used to treat amnesia, it is now also effective in memory decline and applied to depression. Although there remains an abundance of literature investigating KXS from multiple aspects, few reviews summarize the features and research, which impedes better exploration and exploitation of KXS. This article intends to comprehensively analyze and summarize up-to-date information concerning the chemical constituents, pharmacology, pharmacokinetics, clinical applications, and safety of KXS based on the scientific literature, as well as to examine possible scientific gaps in current research and tackle issues in the next step. The chemical constituents of KXS primarily consist of saponins, xanthones, oligosaccharide esters, triterpenoids, volatile oils, and flavonoids. Of these, saponins are the predominant active ingredients, and increasing evidence has indicated that they exert therapeutic properties against mental disease. Pharmacokinetic research has illustrated that the crucial exposed substances in rat plasma after KXS administration are ginsenoside Re (GRe), ginsenoside Rb1 (GRb1), and polygalaxanthone III (POL). This article provides additional descriptions of the safety. In this review, current issues are highlighted to guide further comprehensive research of KXS and other classical prescriptions.

Molecular Mechanism by Which TRPC6 Regulates Calcium Signaling and Neuroinflammation in the Onset and Development of Ischemic Stroke: A Review.

Cerebral infarction, also known as ischemic stroke, is caused by various regional blood supply disorders in the brain tissue, leading to ischemic hypoxic lesions and necrosis of the brain tissue and then the corresponding clinical manifestations of neurological loss, which has high mortality and disability. This study comprehensively reviews the potential molecular mechanisms of TRPC6 in neuroprotection in cerebral infarction and provides a summary of TRPC6 as a targeted drug or prognostic biomarker for cerebral infarction patients. We will screen and synthesize evidence about the molecular mechanisms of TRPC6 in cerebral infarction from the current literature to obtain comprehensive knowledge on this topic. In the pathogenesis, neuroinflammation and intracellular calcium accumulation play an important role in the onset and development of cerebral infarction. Transient receptor potential cation channel subfamily C6 (TRPC6) is the main component of calcium store-operated calcium channels. It plays a central role in ischemic cerebrovascular disease by mediating the calcium ion signaling pathway. In this review, evidence on the neuroprotective effects of TRPC6 has been shown, including inhibiting neuroinflammation and inhibiting nerve cell apoptosis, thereby alleviating nerve injury. However, at the same time, TRPC6 promotes inflammation in other organs. Generally, although an increasing number of researches support the protective role of TRPC6 in cerebral infarction, there is still evidence showing that overexpression of TRPC6 increases inflammatory tissue damage in other organs. Therefore, clarifying the molecular mechanism of TRPC6 will help develop targeted drugs or prognostic biomarkers for cerebral infarction to promote and predict neurological function recovery. More evidence to elucidate the molecular mechanism of TRPC6 in cerebral infarction is needed. Enriching TRPC6 in neuroinflammation areas and modifying its cell specificity might be the orientation of drug development that increases the effect of stroke treatment and reduces the impact on other organs. In conclusion, in cerebral infarction, TRPC6 has been proven to alleviate neuroinflammation and inhibit nerve cell apoptosis. However, at the same time, TRPC6 may promote inflammation in other organs. Therefore, the targeting potential of TRPC6 in cerebral infarction needs to be further explored.

Effect of governor vessel moxibustion (GVM) therapy with mild to moderate psoriasis: A randomized clinical trial.

BACKGROUND: It was hypothesized that governor vessel moxibustion (GVM) therapy may improve the course of mild to moderate psoriasis (PS) in patients. METHODS: A randomized, controlled clinical trial lasting 40 days was conducted at the Shaanxi Provincial Hospital of Chinese Medicine. Investigators were blinded to patient groupings. Individuals with mild to moderate PS ranging in age from 18 to 70 years were enrolled. GVM therapy was administered one every 10 days for 40 days with 1.5 hours on the governor meridian in the GVM therapy group. The PS area and severity index (PASI) and dermatological life quality index (DLQI) scores were monitored before and after treatment. RESULTS: There was a significant reduction in the mean PASI score in the GVM therapy group of 0.76 points (2.37 [2.61]; SE, 0.39) after 40 days of treatment compared with the control group (3.12 [2.12], SE, 0.32) (P < .01). There were also significantly greater changes in the DLQI scores of the GVM therapy group (4.23 [2.25]; SE, 0.34) compared with those in the control group (8.91 [3.85]; SE, 0.59) (P < .001). CONCLUSION: GVM therapy effectively reduced both PASI and DLQI scores in patients with mild to moderate PS.

Mechanism determination on the interactive effects between host immunity and gut microbiome to resist consecutive hydrogen sulfide inhalation of laying hens.

The study aims to investigate the underlying mechanism of the interactions between intestinal microbiota and host immunity-related parameters in response to H2S inhalation of layer hens. A total of 180 healthy 300-day-old Lohmann pink hens with similar body weight were randomly allotted into the control (CON) and the hydrogen sulfide (H2S) treatments for an 8-wk-long feeding procedure. Productive performances, antioxidant capacities, immunity-related parameters, blood metabolites, and cecal microbiota were measured to determine the physiological and gastrointestinal responses to H2S treatment. Results showed that feed intake, egg production, eggshell strength, Haugh unit, and relative yolk weight significantly declined under H2S treatment compared with CON (P < 0.05). Antioxidant and immunity-related parameters showed that glutathione peroxidase, IL-4, and TNF-α contents significantly decreased, whereas contents of IL-1ß, IL-2, and IL-6 significantly increased after H2S treatment (P < 0.05). Further metabolic results showed H2S treatment upregulated 2-mercaptobenzothiazole, D-glucopyranuronic acid, deoxyuridine, cholic acid, and mimosine, etc., which mainly enriched into the pyrimidine metabolism, beta-alanine metabolism, valine, leucine, and isoleucine biosynthesis, and pantothenate and CoA biosynthesis pathways. Meanwhile, aceturic acid, 9-oxodecenoic acid, palmitoleic acid, lauric acid, linoleic acid, oleic acid, and valeric acid mainly contributed to the downregulated metabolites, and enriched into the biosynthesis of unsaturated fatty acids, amino sugar and nucleotide sugar metabolism, tryptophan metabolism and linoleic metabolism. Moreover, H2S treatment significantly proliferated the relative abundances of Faecalibacterium, Ruminococcaceae, and Streptococcus, while decreased Prevotella, Lactobacillus, Bifidobacterium, Clostridium, and Campylobacter (P < 0.05). The altered bacteria were functionally enriched in the carbohydrate metabolism, amino acid metabolism, and metabolism of cofactors and vitamins pathways. H2S treatment also significantly downregulated the expression of ZO-1, Claudin 4, and Claudin 7 (P < 0.05). In summary, intestinal microbial communities altered significantly to make proper adaptations in interacting with the host immune systems through the immunity-related metabolites secretion, and epithelial tight-junction-related genes expressions, purposely to regulate the productive performance under hydrogen sulfide inhalation.

Pharmacokinetics, absorption and transport mechanism for ginseng polysaccharides.

BACKGROUND: Ginseng polysaccharide (GP) is one of the most abundant components in Panax ginseng. However, the absorption pathways and mechanisms of GPs have not been investigated systematically due to the challenges of their detection. METHODS: The fluorescein isothiocyanate derivative (FITC) was employed to label GP and ginseng acidic polysaccharide (GAP) to obtain target samples. HPLC-MS/MS assay was used to determine the pharmacokinetics of GP and GAP in rats. The Caco-2 cell model was used to investigate the uptake and transport mechanisms of GP and GAP in rats. RESULTS: Our results demonstrated that the absorption of GAP was more than that of GP in rats after gavage administration, while there was no significant difference between both after intravenous administration. In addition, we found that GAP and GP were more distributed in the kidney, liver and genitalia, suggesting that GAP and GP are highly targeted to the liver, kidney and genitalia. Importantly, we explored the uptake mechanism of GAP and GP. GAP and GP are endocytosed into the cell via lattice proteins or niche proteins. Both are transported lysosomally mediated to the endoplasmic reticulum (ER) and then enter the nucleus through the ER, thus completing the process of intracellular uptake and transportation. CONCLUSION: Our results confirm that the uptake of GPs by small intestinal epithelial cells is primarily mediated via lattice proteins and the cytosolic cellar. The discovery of important pharmacokinetic properties and the uncovering of the absorption mechanism provide a research rationale for the research of GP formulation and clinical promotion.

A review on the plant resources of important medicinal licorice.

ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrizae Radix et Rhizoma has various effects, including tonifying the spleen and qi, clearing heat and toxic substances, eliminating phlegm, relieving cough and pain, and harmonizing the effects of other medicines. It is widely used in the pharmaceutical and food industries. AIMS OF THE STUDY: This review systematically collates the identification of Glycyrrhiza Linn. species with medicinal value and their distributions. The morphological and genetic characteristics, distribution, quantity of reserves in China, suitable environment, and area of suitable habitat of important medicinal species were reviewed. The effects of the natural environment and cultivation management (water and nutrients) on the growth and quality of licorice were reviewed. The aim is to make people have a systematic understanding of the status of medicinal plant resources of the G. Linn., and understand the natural and human factors that affect its quality, so as to provide help for the collection of resources of the important medicinal licorice and the human control of its quality in the future. MATERIALS AND METHODS: We conducted extensive searches of the primary literature, master's and doctoral theses, and pharmacopeias of many countries using PubMed, Geenmedical, CNKI, Web of Science, SCI-hub and other databases. The keywords used in searches included "classification of Glycyrrhiza," "medicinal Glycyrrhiza," "distribution of Glycyrrhiza," and "suitable environment for Glycyrrhiza" The results of research conducted by our research group on the morphological and genetic characteristics, natural distribution, and effects of artificial regulation on the growth and quality of licorice were summarized. RESULTS: There are approximately 29 species of G. Linn. worldwide, including 15 species with medicinal value. These species occur on all continents except Antarctica across 41 countries. Only one licorice is recorded in Indian pharmacopoia,two species are recorded in US and Japanese pharmacopoeias,and three species are recorded in most national pharmacopoeias: G. glabra Linn., G. uralensis Fisch. and G. inflata Batalin. These three medicinal licorice species are mainly distributed in Eurasia, especially Central Asia. The main morphological differences between these three medicinal licorice species are in the leaves, inflorescences, pods, and seeds, and they can be distinguished by ITS and psbA-trnH sequences. The reserves of wild licorice in China have decreased annually to 1.04 million(t) in 2010. The cultivation area of G. uralensis Fisch in China is currently approximately 26,900 hm2. Soil conditions have a substantial effect on the yield and quality of G. uralensis Fisch, especially water and nutrients. Appropriate irrigation and fertilization measures can enhance the quality of G. uralensis Fisch. CONCLUSIONS: G. Linn. species and their natural distributions were summarized. The morphology, genetic characteristics, suitable environment, and area of suitable habitat of three medicinal licorice species collected in major countries were described. The main environmental conditions and cultivation measures affecting their growth and medicinal quality were determined. This article provides a comprehensive review on G. Linn. medicinal plant resources to enhance the future use of these resources.

Role of Danggui Buxue Decoction for the prevention and treatment of cardiovascular and pulmonary diseases. / å½“å½’è¡¥è¡€æ±¤é˜²æ²»å¿ƒè‚ºç–¾ç— çš„ä½œç”¨.

Cardiovascular and pulmonary diseases have become the major disease endangering people's physical and mental health because of its high morbidity and mortality. Danggui Buxue Decoction, a noteworthy classical prescription, is composed of astragali radix and angelicae sinensis radix at a ratio of 5꞉1. It is a prescription for tonifying both vital energy and blood and has the effect of dredging collaterals. Its main active components, such as polysaccharides, saponins, flavonoids and volatile oils, have good effects on antioxidation, inflammation regulation, immune regulation and promotion of blood circulation. Danggui Buxue Decoction can improve myocardial ischemia-reperfusion injury and heart failure, relieve the symptoms of diabetic cardiomyopathy, inhibit pulmonary fibrosis, protect lung injury and fight against lung cancer and other cardiopulmonary diseases. Preclinical studies have showed that this prescription can inhibit inflammation and oxidative stress, regulate autophagy and enhance immune function through multi-target pathways. Reviewing the main effective components, pharmacological action and mechanism, and clinical application of Danggui Buxue Decoction are helpful to provide comprehensive information for the clinical application of Danggui Buxue Decoction in prevention and treatment of cardiovascular and pulmonary diseases.

Research progress in the prevention and treatment of insomnia with classical prescriptions. / ç»å ¸åæ–¹é˜²æ²»å¤±çœ çš„ç ”ç©¶è¿›å±•.

Insomnia is a common disease and its impact on human health cannot be ignored. At present, there are 3 main clinical treatments for insomnia, including traditional Chinese medicine treatment, sedative hypnotic drug therapy, and cognitive behavioral therapy. Traditional Chinese medicine (TCM) treatment for insomnia is widely used due to its advantages of low side effects, good efficacy, and no drug dependence. This paper summarizes the pathogenesis of insomnia in the theories of traditional Chinese and Western medicine. Modern medical research generally believes that sleep-wake disorder is the main pathological mechanism of insomnia, involving many factors such as monoamine neurotransmitter disorder, cytokine imbalance and intestinal flora imbalance. TCM mainly divides the pathogenesis of insomnia into 9 kinds of syndrome types: Liver depression transforming into fire, hyperactivity of fire due to yin deficiency, phlegm-heat attacking internally, disharmony between heart and kidney, deficiency of both heart and spleen, qi deficiency of both heart and gallbaldder, stomach qi disharmony, exuberance of heart fire, and internal blockade of static blood. According to these 9 kinds of pathogenesis of insomnia, the corresponding classical prescriptions such as Longdanxiegan decoction, Suanzaoren decoction, Huanglian-Wendan decoction, Jiaotai pill and Guipi decoction were analyzed and summarized. There is evidence that traditional Chinese medicine could treat insomnia mainly by increasing the level of 5-hydroxytryptamine, reducing the levels of dopamine, noradrenaline, tumor necrosis factor α, and interlukin-6, decreasing the ratio of glutamic acid to γ-aminobutyric acid, and inhibiting the hypothalamic-pituitary-adrenal axis.

Protective effect of heme chloride on hypoxia-induced tissue injury in mice. / æ°¯åŒ–è¡€çº¢ç´ å¯¹ç¼ºæ°§å¯¼è‡´å°é¼ ç»„ç»‡æŸä¼¤çš„ä¿æŠ¤ä½œç”¨.

OBJECTIVES: Heme chloride (Hemin) is an in vitro purified form of natural heme and an important raw material for anti-anemia and antitumor drugs. This study aims to analyze the protective effect of Hemin on tissue damage in low-pressure oxygen chamber simulated plateau hypoxic mice, and explore its role in anti-plateau hypoxia. METHODS: Thirty male BALB/c mice were randomly divided into a blank group, a positive drug group (acetazolomide, 200 mg/kg), a Hemin low-dose group (15 mg/kg), a Hemin medium-dose group (30 mg/kg), and a Hemin high-dose group (60 mg/kg) with intraperitoneal injection. The anti-hypoxic activity of Hemin was explored by atmospheric closed hypoxia experiment and the optimal dose was screened. Thirty-six male BALB/c mice were randomly divided into a blank group, a hypoxia group, a positive drug group, and a Hemin high-dose group. The plasma inflammatory factor levels and oxidative stress indicators malondialdehyde (MDA), glutataione (GSH), and superoxide dismutase (SOD) levels of myocardium, brain, lung, and liver tissues were measured in different groups with hypoxia for 24 h. The degree of histopathological damage of mice was observed with HE staining. The degree of protection of Hemin against tissue hypoxia injury was detected with the hypoxia probe piperidazole. RESULTS: Compared with the blank group, the survival time of mice in the positive drug group, the Hemin medium-dose group, and high-dose group was significantly extended (all P<0.05), with the highest prolongation rate in the Hemin high-dose group. Compared with the hypoxia group, mice in the Hemin high-dose group showed a significant increase in SOD level and GSH content of brain tissue, and a significant decrease in MDA content of lung tissue (all P<0.05). The results of HE staining and hypoxia probe showed that Hemin had a significant protective effect on the damage of liver, heart, brain and lung tissues of mice with hypoxia, and the most obvious effect on that of the brain tissue. CONCLUSIONS: Hemin has an effect of improvement on oxidative stress and inflammatory response caused by hypoxia, and has obvious protective effect on tissue damage caused by hypoxia.

The exploration of the potential mechanism of oxymatrine-mediated antipruritic effect based on network pharmacology and weighted gene co-expression network analysis.

The treatment of chronic itch is considered to be a challenge for its non-histamine dependence and the search for alternative medicine is still striving. The pathology of the chronic itch is closely related to immune system regulation and inflammatory response. Oxymatrine (OMT) is a traditional Chinese medicine ingredient extracted from the roots of Sophora flavescens Aiton with significant antitumor, analgesic, and anti-inflammatory effects. However, the underlying mechanism of OMT on chronic itch is obscure, which limits clinical application. Hence, this study is aimed to clarify the pruritus alleviation mechanism of OMT by combining network pharmacology analysis, weighted gene co-expression analysis (WGCNA), and molecular docking. We screened 125 common targets of OMT regulating inflammation and pruritus with pharmacology technology, the GO enrichment function analysis and KEGG signaling pathway analysis to demonstrate the close relation to the signaling pathways regulating inflammation such as MAPK signaling pathway and PI3K-AKT signaling pathway. We adopted the most relevant templates for pruritus diseases, combined with network pharmacology to preliminarily screen out 3 OMT functions and regulatory targets, exerting a good connection and correlation with the target at the screened disease targets. Further experiments were conducted to explore the potential mechanism of OMT using the LPS-induced RAW264.7 cell inflammation model. The results showed that pretreatment with different concentrations of OMT (25 µM, 50 µM, and 100 µM) for 24 h, inhibited expression of IL-6, iNOS TLR4 and TGFR-1 as well as apoptosis of Raw264.7 cells induced by LPS. Moreover, OMT effectively inhibited LPS-induced MAPK pathway activation and the expression of related sites MAP2K1, MAPK8 MAP2K4, and MAPKAP-K2 in RAW 264.7 cells. The OMT also reduced the phosphorylation of p-38, associated with site in the activation of MAPK signaling pathway. These results could contribute to a better understanding of the mechanisms underlying how OMT alleviates inflammation to treat chronic pruritic diseases and provide a potential drug for the treatment of chronic itch.

Influence of crosslinking density on the mechanical and thermal properties of plant oil-based epoxy resin.

Plant oil-based epoxy resins are of great interest due to their ecological and economic necessity. Previous studies suggested that the crosslinking density had a considerable influence on the mechanical and thermal properties of plant oil-based epoxy resins. However, so far, the relationship between the crosslinking density and the thermo-mechanical properties of plant oil-based epoxy resins is not clear. To address this issue, model tung oil-based epoxy resins with different crosslinking densities were fabricated to investigate the influence of crosslinking density on the mechanical and thermal properties of tung oil-based epoxy resins. Results show that the tensile strength, Young's modulus, and glass transition temperature are linearly increased with increasing crosslinking density. The elongation at break and tensile toughness show nonlinear downward trends as the crosslinking density increases. The elongation at break decreases gently at first, then dramatically, and finally slowly as the crosslinking density increases. The tensile toughness declines sharply at first and then slowly with increasing crosslinking density. The relationship between the thermostability and the crosslinking density is complex, because the thermostability is determined by both the molecular structure of the curing system and the crosslinking density. These results provide some information for designing plant oil-based epoxy resins according to the requirements of their applications.

Pharmacodynamic of cilostazol for anti-altitude hypoxia. / 西洛他唑抗高原缺氧的药效学评价.

OBJECTIVES: The plateau environment is characterized by low oxygen partial pressure, leading to the reduction of oxygen carrying capacity in alveoli and the reduction of available oxygen in tissues, and thus causing tissue damage. Cilostazol is a phosphodiesterase III inhibitor that has been reported to increase the oxygen release of hemoglobin (Hb) in tissues. This study aims to explore the anti-hypoxic activity of cilostazol and its anti-hypoxic effect. METHODS: A total of 40 male BALB/C mice were randomly divided into a low-dose cilostazol (6.5 mg/kg) group, a medium-dose (13 mg/kg) group, a high-dose (26 mg/kg) group, and a control group. The atmospheric airtight hypoxia experiment was used to investigate the anti-hypoxic activity of cilostazol and to screen the optimal dosage. Twenty-four male Wistar rats were randomly divided into a normoxia control group, a hypoxia model group, an acetazolamide (22.33 mg/kg) group, and a cilostazol (9 mg/kg) group. After 3 days of hypoxia in the 4 010 m high altitude, blood from the abdominal aorta was collected to determine blood gas indicators, the levels of IL-6 and TNF-α in plasma were determined by enzyme-linked immunosorbent assay, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutataione (GSH) were measured. The degree of pathological damage for rat tissues was observed with HE staining. RESULTS: Compared with the control group, the survival time of mice in the low, medium, and high dose group of cilostazol was significantly prolonged, and the survival time of mice in the medium dose group was the longest, with an extension rate at 29.34%, so the medium dose was the best dose. Compared with the hypoxia model group, the P50 (oxygen partial pressure at Hb oxygen saturation of 50%) value of rats in the cilostazol group was significantly increased by 1.03%; Hb and Hct were significantly reduced by 8.46% and 8.43%, and the levels of IL-6 and TNF-α in plasma were reduced by 50.65% and 30.77%. The MDA contents in heart, brain, lung, liver, and kidney tissues were reduced by 37.12%, 29.55%, 25.00%, 39.34%, and 21.47%, respectively. The SOD activities were increased by 94.93%, 9.14%, 9.42%, 13.29%, and 20.80%, respectively. The GSH contents were increased by 95.24%, 28.62%, 28.57%, 20.80%, and 44.00%, respectively. The results of HE staining showed that compared with the hypoxia model group, cilostazol significantly improved the damage of heart, lung, and kidney tissues in rats after hypoxia. CONCLUSIONS: Cilostazol can significantly improve the oxidative stress and inflammatory reaction caused by rapid altitude hypoxia, and it has a significant protective effect on tissue damage caused by hypoxia, suggesting that it has obvious anti-hypoxic activity.

Overexpression of Soybean GmWRI1a Stably Increases the Seed Oil Content in Soybean.

WRINKLED1 (WRI1), an APETALA2/ethylene-responsive-element-binding protein (AP2/EREBP) subfamily transcription factor, plays a crucial role in the transcriptional regulation of plant fatty acid biosynthesis. In this study, GmWRI1a was overexpressed in the soybean cultivar 'Dongnong 50' using Agrobacterium-mediated transformation to generate three transgenic lines with high seed oil contents. PCR and Southern blotting analysis showed that the T-DNA was inserted into the genome at precise insertion sites and was stably inherited by the progeny. Expression analysis using qRT-PCR and Western blotting indicated that GmWRI1a and bar driven by the CaMV 35S promoter were significantly upregulated in the transgenic plants at different developmental stages. Transcriptome sequencing results showed there were obvious differences in gene expression between transgenic line and transgenic receptor during seed developmental stages. KEGG analysis found that the differentially expressed genes mainly annotated to metabolic pathways, such as carbohydrated metabolism and lipid metabolism. A 2-year single-location field trial revealed that three transgenic lines overexpressing GmWRI1a (GmWRI1a-OE) showed a stable increase in seed oil content of 4.97-10.35%. Importantly, no significant effect on protein content and yield was observed. Overexpression of GmWRI1a changed the fatty acid composition by increasing the linoleic acid (C18:2) content and decreasing the palmitic acid (C16:0) content in the seed. The three GmWRI1a-OE lines showed no significant changes in agronomic traits. The results demonstrated that the three GmWRI1a overexpression lines exhibited consistent increases in seed oil content compared with that of the wild type and did not significantly affect the seed yield and agronomic traits. The genetic engineering of GmWRI1a will be an effective strategy for the improvement of seed oil content and value in soybean.

Effects of salidroside on exercise tolerance of mice under high altitude hypoxia environment.

OBJECTIVE: To investigate the effect of salidroside on the exercise tolerance of mice under high altitude hypoxia environment. METHODS: C57BL/6J healthy male mice were randomly divided into normoxia control group, model control group, Rhodiola rosea capsule group and salidroside low-dose (5 mg/kg), medium-dose (10 mg/kg) and high-dose (20 mg/kg) groups, with 15 mice in each group. After 3 days, all groups (except the normoxia control group) entered a plateau with an altitude of 4010 m. After 1 day of hypoxia exposure, the exhausted swimming test was performed to determine the exhaustive time of mice; the pathological changes of liver and muscle tissue were observed with hematoxylin and eosin staining. The levels of malondialdehyde (MDA), hydrogen peroxide (H 2O 2), glutathione (GSH), total superoxide dismutase (T-SOD), glycogen, lactate and ATPase were measured and compared among groups. RESULTS: Compared with the normoxia control group, the exhaustive swimming time of the model control group was shortened ( P<0.05), the liver tissue and muscle tissue were pathologically damaged, the level of oxidative stress was significantly increased, the levels of sodium potassium ATPase and calcium magnesium ATPase were significantly increased. Compared with the model control group, the exhaustive swimming time of the mice in the Rhodiola rosea capsule group and salidroside groups was significantly prolonged ( P<0.05). The oxidative stress injury was alleviated, the contents of MDA, H 2O 2 and lactic acid in liver and muscle tissues decreased, the contents of GSH, liver glycogen and muscle glycogen increased, and the activities of T-SOD and ATPase increased (all P<0.05). CONCLUSION: Salidroside has significant anti-fatigue activity, and its anti-fatigue effect is related to the reduction of oxidative stress damage, the reduction of the accumulation of undesirable metabolites and the increase in the reserve of energy substances.

Screening of activators of 2,3-diphosphoglycerate mutase from traditional Chinese herb medicines.

OBJECTIVE: To screen activators of 2,3-diphosphoglycerate (BPG) mutase (BPGM) from Chinese herb medicines, so as to improve the hypoxia tolerance of erythrocytes. METHODS: BPGM was used as the receptor and Chinese medicine ingredients database was used as the ligand in the study. After Lipinski rule of five screening, LibDock and CDOCKER docking were used for virtual screening. The effect of the screened compounds on the affinity of BPGM in erythrocytes was verified. Finally, the erythrocytes were incubated in vitro to establish the erythrocyte hypoxia model, and the effect of the compound on the activity of BPGM in the erythrocyte hypoxia model was verified. RESULTS: Ten compounds with highest binding affinity to BPGM were selected by LibDock and CDOCKER, and the cytoplasm protein was incubated with the ten compounds. Compared with blank control group, methyl rosmarinate group, dihydrocurcumin high dose group, octahydrocurcumin medium dose group and coniferyl ferulate high dose group were able to further activate the BPGM, significantly increase the levels of 2, 3-BPG in normal erythrocytes (all P<0.05); while the low dose of tetrahydrocurcumin, high dose and low dose of aurantiamide, hexahydrocurcumin and medium dose of N- (p-coumaroyl) serotonin had a tendency to increase the contents of 2,3-BPG in normal erythrocytes (all P>0.05). In the hypoxic red blood cells, the medium dose methyl rosmarinate, medium dose octahydrocurcumin, high dose hexahydrocurcumin and medium dose N-(p-coumaroyl) serotonin could significantly increase the contents of 2,3-BPG (all P<0.05). CONCLUSION: The methyl rosmarinate, octahydrocurcumin, hexahydrocurcumin and N-(p-coumaroyl) serotonin could activate BPGM and increase the contents of 2,3-BPG in hypoxic erythrocytes.

Fish oil supplementation alters emotion-generated corticolimbic functional connectivity in depressed adolescents at high-risk for bipolar I disorder: A 12-week placebo-controlled fMRI trial.

OBJECTIVE: To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. METHODS: Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. RESULTS: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY-ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale-Revised and Clinical Global Impression-Severity Scale scores. CONCLUSIONS: In depressed high-risk youth FO supplementation alters emotion-generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings.

A preliminary study of the effects of mindfulness-based cognitive therapy on structural brain networks in mood-dysregulated youth with a familial risk for bipolar disorder.

BACKGROUND: Mindfulness-based cognitive therapy for children (MBCT-C), as a psychotherapeutic intervention, has been shown to be effective for treating mood dysregulation (MD). While previous neuroimaging studies of MD have reported both pre-treatment structural and functional alterations, the effects of MBCT-C on brain morphological network organisation has not been investigated. METHODS: We investigated brain morphological network organisation in 10 mood-dysregulated youth with familial risk for bipolar disorder and 15 matched healthy comparison youth (HC). Effects of 12 weeks of MBCT-C were examined in the mood-dysregulated youth. Topological properties of brain networks used for analyses were constructed based on morphological similarities in regional grey matter using a graph-theory approach using MRI data. RESULTS: At baseline, compared with the HC group, the mood-dysregulated group exhibited increased global efficiency (Eglob ), decreased path length (Lp ), and abnormal nodal properties, mainly in the limbic system. Right temporal pole alterations at baseline predicted change in Child and Adolescent Mindfulness Measure scores after treatment. The mood-dysregulated group showed significant decreases in both the Eglob and Lp metrics after MBCT-C, suggesting an improved capacity for optimal information processing. Changes in Lp were correlated with changes in Emotion Regulation Checklist scores. Our results show significant topological alterations in the mood-dysregulated group as compared to controls at baseline. After MBCT-C, disrupted topological properties in the mood-dysregulated group were significantly reduced. CONCLUSION: MBCT-C may facilitate clinically meaningful changes in the brain structural network in mood-dysregulated individuals.

Emotion-Related Network Reorganization Following Fish Oil Supplementation in Depressed Bipolar Offspring: An fMRI Graph-Based Connectome Analysis.

INTRODUCTION: Mood disorders are associated with fronto-limbic structural and functional abnormalities and deficits in omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging evidence also suggests that n-3 PUFA, which are enriched in fish oil, promote cortical plasticity and connectivity. The present study performed a graph-based connectome analysis to investigate the role of n-3 PUFA in emotion-related network organization in medication-free depressed adolescent bipolar offspring. METHODS: At baseline patients (n = 53) were compared with healthy controls (n = 53), and patients were then randomized to 12-week double-blind treatment with placebo or fish oil. At baseline and endpoint, erythrocyte EPA+DHA levels were measured and fMRI scans (4 Tesla) were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Graph-based analysis was used to characterize topological properties of large-scale brain network organization. RESULTS: Compared with healthy controls, patients exhibited lower erythrocyte EPA+DHA levels (p = 0.0001), lower network clustering coefficients (p = 0.029), global efficiency (p = 0.042), and lower node centrality and connectivity strengths in frontal-limbic regions (p<0.05). Compared with placebo, 12-week fish oil supplementation increased erythrocyte EPA+DHA levels (p<0.001), network clustering coefficient (p = 0.005), global (p = 0.047) and local (p = 0.023) efficiency, and node centralities mainly in temporal regions (p<0.05). LIMITATIONS: The duration of fish oil supplementation was relatively short and the sample size was relatively small. CONCLUSIONS: These findings provide preliminary evidence that abnormalities in emotion-related network organization observed in depressed high-risk youth may be amenable to modification through fish oil supplementation.

Network-level functional topological changes after mindfulness-based cognitive therapy in mood dysregulated adolescents at familial risk for bipolar disorder: a pilot study.

BACKGROUND: Given that psychopharmacological approaches routinely used to treat mood-related problems may result in adverse outcomes in mood dysregulated adolescents at familial risk for bipolar disorder (BD), Mindfulness-Based Cognitive Therapy for Children (MBCT-C) provides an alternative effective and safe option. However, little is known about the brain mechanisms of beneficial outcomes from this intervention. Herein, we aimed to investigate the network-level neurofunctional effects of MBCT-C in mood dysregulated adolescents. METHODS: Ten mood dysregulated adolescents at familial risk for BD underwent a 12-week MBCT-C intervention. Resting-state functional magnetic resonance imaging (fMRI) was performed prior to and following MBCT-C. Topological metrics of three intrinsic functional networks (default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON)) were investigated respectively using graph theory analysis. RESULTS: Following MBCT-C, mood dysregulated adolescents showed increased global efficiency and decreased characteristic path length within both CON and FPN. Enhanced functional connectivity strength of frontal and limbic areas were identified within the DMN and CON. Moreover, change in characteristic path length within the CON was suggested to be significantly related to change in the Emotion Regulation Checklist score. CONCLUSIONS: 12-week MBCT-C treatment in mood dysregulated adolescents at familial risk for BD yield network-level neurofunctional effects within the FPN and CON, suggesting enhanced functional integration of the dual-network. Decreased characteristic path length of the CON may be associated with the improvement of emotion regulation following mindfulness training. However, current findings derived from small sample size should be interpreted with caution. Future randomized controlled trials including larger samples are critical to validate our findings.

Electroacupuncture Inhibits Neuronal Autophagy and Apoptosis via the PI3K/AKT Pathway Following Ischemic Stroke.

Electroacupuncture (EA) is a safe and effective therapy for ischemic stroke in both clinical and laboratory settings. However, the underlying mechanism behind EA treatment for stroke remains unclear. Here, we aimed to evaluate whether EA treatment at the acupoints of Zusanli (ST36) and Quchi (LI11) exerted a neuroprotective effect on ischemic stroke rats by modulating autophagy and apoptosis via the PI3K/AKT/mTOR signaling pathway. EA was performed at 24 h following brain ischemia/reperfusion (I/R) for 30 min per day for 3 days. Our results indicated that EA treatment significantly decreased neurological deficits and cerebral infarct volume in ischemic stroke rats. Also, EA intervention markedly reduced neuronal apoptosis by suppressing the activation of cleaved caspase-3 (CCAS3) at 72 h following I/R, as shown by a Western blot analysis. Furthermore, EA treatment after ischemic stroke suppressed the ischemia activated expression level of LC3II/I and Atg7 and increased the ischemia inhibited expression level of PI3K, phosphorylation of mTOR, phosphorylation of AKT, P62 and LAMP1, hence mediating the autophagy level of the neurocyte, which was reversed by the PI3K inhibitor Dactolisib. In summary, our results indicate that the protective effects of EA treatment at points of Quchi (LI11) and Zusanli (ST36) in rats following cerebral I/R injury was associated with the inhibition of neuronal apoptosis and autophagy via activating the PI3K/AKT/mTOR signaling pathway.