Supplements for cognitive ability in patients with mild cognitive impairment or Alzheimer's disease: a protocol for systematic review and network meta-analysis of randomised controlled trials.

INTRODUCTION: Considering the increasing incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) worldwide, there is an urgent need to identify efficacious, safe and convenient treatments. Numerous investigations have been conducted on the use of supplements in this domain, with oral supplementation emerging as a viable therapeutic approach for AD or MCI. Nevertheless, given the multitude of available supplements, it becomes imperative to identify the optimal treatment regimen. METHODS AND ANALYSIS: Eight academic databases and three clinical trial registries will be searched from their inception to 1 June 2023. To identify randomised controlled trials investigating the effects of supplements on patients with AD or MCI, two independent reviewers (X-YZ and Y-QL) will extract relevant information from eligible articles, while the risk of bias in the included studies will be assessed using the Rob 2.0 tool developed by the Cochrane Collaboration. The primary outcome of interest is the overall cognitive function. Pair-wise meta-analysis will be conducted using RevMan V.5.3, while network meta-analysis will be carried out using Stata 17.0 and ADDIS 1.16.8. Heterogeneity test, data synthesis and subgroup analysis will be performed if necessary. The GRADE system will be employed to assess the quality of evidence. This study is scheduled to commence on 1 June 2023 and conclude on 1 October 2023. ETHICS AND DISSEMINATION: Ethics approval is not required for systematic review and network meta-analysis. The results will be submitted to a peer-reviewed journal or at a conference. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42023414700).

Research status and trends of physical activity on depression or anxiety: a bibliometric analysis.

Background: Anxiety and depression are prevalent mental disorders. As modern society continues to face mounting pressures, the incidence of anxiety and depression is on the rise. In recent years, there has been an increasing breadth of research exploring the relationship between anxiety, depression, and physical activity (PA). However, the current research progress and future development trends are unclear. The purpose of this study is to explore the research hotspots and development trends in this field, and to provide guidance for future studies and to provide some reference for clinicians. Methods: We searched the relevant literature of Web of Science Core Collection from the establishment of the database to August 15, 2023. CiteSpace, VOSviewer and Bibliometrix Packages based on the R language were used to analyze the number of publications, countries, institutions, journals, authors, references, and keywords. Results: A total of 1,591 studies were included in the analysis, and the research in the field of PA on anxiety or depression has consistently expanded. The USA (304 publications), Harvard University (93 publications), and the journal of affective disorders (97 publications) were the countries, institutions, and journals that published the highest number of articles, respectively. According to the keywords, students and pregnant women, adult neurogenesis, and Tai Chi were the groups of concern, physiological and pathological mechanisms, and the type of PA of interest, respectively. Conclusion: The study of PA on anxiety or depression is experiencing ongoing expansion. Clinicians can consider advising patients to take mind-body exercise to improve mood. In addition, future researchers can explore the mind-body exercise and its impact on anxiety or depression, PA and anxiety or depression in specific populations, and adult neurogenesis of various exercise in anxiety or depression.

Massage ameliorates lumbar disc herniation-related radicular pain in rats by suppressing TLR4/NLRP3 inflammasome signaling transduction.

BACKGROUND: Lumbar disc herniation (LDH) is a common spinal disease that can cause severe radicular pain. Massage, also known as Tuina in Chinese, has been indicated to exert an analgesic effect in patients with LDH. Nonetheless, the mechanism underlying this effect of massage on LDH remains unclarified. METHODS: Forty Sprague-Dawley rats were randomly divided into four groups. A rat LDH model was established by autologous nucleus pulpous (NP) implantation, followed by treatment with or without massage. A toll-like receptor 4 (TLR4) antagonist TAK-242 was administrated to rats for blocking TLR4. Behavioral tests were conducted to examine rat mechanical and thermal sensitivities. Western blotting was employed for determining TLR4 and NLRP3 inflammasome-associated protein levels in the spinal dorsal horn (SDH). Immunofluorescence staining was implemented for estimating the microglial marker Iba-1 expression in rat SDH tissue. RESULTS: NP implantation induced mechanical allodynia and thermal hyperalgesia in rat ipsilateral hindpaws and activated TLR4/NLRP3 inflammasome signaling transduction in the ipsilateral SDH. Massage therapy or TAK-242 administration relieved NP implantation-triggered pain behaviors in rats. Massage or TAK-242 hindered microglia activation and blocked TLR4/NLRP3 inflammasome activation in ipsilateral SDH of LDH rats. CONCLUSION: Massage ameliorates LDH-related radicular pain in rats by suppressing microglia activation and TLR4/NLRP3 inflammasome signaling transduction.

Cathodal bilateral transcranial direct-current stimulation regulates selenium to confer neuroprotection after rat cerebral ischaemia-reperfusion injury.

Non-invasive transcranial direct-current stimulation (tDCS) is a safe ischaemic stroke therapy. Cathodal bilateral tDCS (BtDCS) is a modified tDCS approach established by us recently. Because selenium (Se) plays a crucial role in cerebral ischaemic injury, we investigated whether cathodal BtDCS conferred neuroprotection via regulating Se-dependent signalling in rat cerebral ischaemia-reperfusion (I/R) injury. We first showed that the levels of Se and its transport protein selenoprotein P (SEPP1) were reduced in the rat cortical penumbra following I/R, whereas cathodal BtDCS prevented the reduction of Se and SEPP1. Interestingly, direct-current stimulation (DCS) increased SEPP1 level in cultured astrocytes subjected to oxygen-glucose deprivation reoxygenation (OGD/R) but had no effect on SEPP1 level in OGD/R-insulted neurons, indicating that DCS may increase Se in ischaemic neurons by enhancing the synthesis and secretion of SEPP1 in astrocytes. We then revealed that DCS reduced the number of injured mitochondria in OGD/R-insulted neurons cocultured with astrocytes. DCS and BtDCS prevented the reduction of the mitochondrial quality-control signalling, vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4), in OGD/R-insulted neurons cocultured with astrocytes and the ischaemic brain respectively. Under the same experimental conditions, downregulation of SEPP1 blocked DCS- and BtDCS-induced upregulation of VAMP2 and STX4. Finally, we demonstrated that cathodal BtDCS increased Se to reduce infract volume following I/R. Together, the present study uncovered a molecular mechanism by which cathodal BtDCS confers neuroprotection through increasing SEPP1 in astrocytes and subsequent upregulation of SEPP1/VAMP2/STX4 signalling in ischaemic neurons after rat cerebral I/R injury. KEY POINTS: Cathodal bilateral transcranial direct-current stimulation (BtDCS) prevents the reduction of selenium (Se) and selenoprotein P in the ischaemic penumbra. Se plays a crucial role in cerebral ischaemia injury. Direct-current stimulation reduces mitochondria injury and blocks the reduction of vesicle-associated membrane protein 2 (VAMP2) and syntaxin-4 (STX4) in oxygen-glucose deprivation reoxygenation-insulted neurons following coculturing with astrocytes. Cathodal BtDCS regulates Se/VAMP2/STX4 signalling to confer neuroprotection after ischaemia.

The effect of acupuncture on oxidative stress in animal models of vascular dementia: a systematic review and meta-analysis.

BACKGROUND: Growing evidence showed that acupuncture may improve cognitive function by reducing oxidative stress, key to the pathogenesis in vascular dementia (VaD), but this is yet to be systematically analysed. This study aimed to summarize and evaluate the effect of acupuncture on oxidative stress in animal models of VaD. METHOD: Eight databases including PubMed, Embase, Web of Science, Cochrane library, CNKI, Wan Fang, CBM, and VIP were searched since their establishment until April 2023, for studies that reported the effect of acupuncture on oxidative stress in VaD animal models. Relevant literature was screened, and information was extracted by two reviewers. The primary outcomes were the levels of oxidative stress indicators. The methodological quality was assessed via the SYRCLE Risk of Bias Tool. Statistical analyses were performed using the RevMan and Stata software. RESULTS: In total, 22 studies with 747 animals were included. The methodology of most studies had flaws or uncertainties. The meta-analysis indicated that, overall, acupuncture significantly reduced the expression of pro-oxidants including reactive oxygen species (standardized mean differences [SMDs] = -4.29, 95% confidence interval [CI]: -6.26, -2.31), malondialdehyde (SMD = -2.27, 95% CI: -3.07, -1.47), nitric oxide (SMD = -0.85, 95% CI: -1.50, -0.20), and nitric oxide synthase (SMD = -1.01, 95% CI: -1.69, -0.34) and enhanced the levels of anti-oxidants including super oxide dismutase (SMD = 2.80, 95% CI: 1.98, 3.61), glutathione peroxidase (SMD = 1.32, 95% CI: -0.11, 2.76), and catalase (SMD = 1.31, 95% CI: 0.05, 2.58) in VaD animal models. In subgroup analyses, acupuncture showed significant effects on most variables. Only partial modelling methods and treatment duration could interpret the heterogeneity of some outcomes. CONCLUSION: Acupuncture may inhibit oxidative stress to improve cognitive deficits in animal models of VaD. Nevertheless, the methodological quality is unsatisfactory. More high-quality research with a rigorous design and further experimental researches and clinical trials are needed to confirm these findings. SYSTEMATIC REVIEW REGISTRATION: This study was registered in PROSPERO (CRD42023411720).

Involvement of Plasma Melatonin in Medication-Overuse Headache: A Cross-Sectional Study.

OBJECTIVES: Patients with medication-overuse headache (MOH) are often complicated with anxiety, depression, and sleep disorders and are associated with dependence behavior and substance abuse. Melatonin has physiological properties including analgesia, regulation of circadian rhythms, soporific, and antidepressant and affects drug preference and addiction. This study aimed to investigate the role of melatonin in MOH compared with episodic migraine (EM) and healthy controls and to verify the relationship between plasma melatonin levels and psychiatric symptoms. METHODS: Thirty patients affected by MOH, 30 patients with EM, and 30 matched healthy controls were enrolled. All subjects completed a detailed headache questionnaire and scales including the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index, the Leeds Dependence Questionnaire. Melatonin levels in plasma samples were measured by enzyme immunoassay method. RESULTS: The levels of plasma melatonin were significantly different among 3 groups of subjects (MOH, 7.74 [5.40-9.89]; EM, 9.79 [8.23-10.62]; Control, 10.16 [8.60-17.57]; H = 13.433; P = 0.001). Significantly lower levels of melatonin were found in MOH patients compared with healthy controls ( P = 0.001). The level of plasma melatonin inversely correlated with the scores of HADS-Anxiety ( r = -0.318, P = 0.002), HADS-Depression ( r = -0.368, P < 0.001), Pittsburgh Sleep Quality Index ( r = -0.303, P = 0.004), and Leeds Dependence Questionnaire ( r = -0.312, P = 0.003). CONCLUSIONS: This study innovatively detects the plasma melatonin levels in MOH patients and explores the association between melatonin levels and psychiatric symptoms. Melatonin may be potential complementary therapy in the treatment of MOH considering its comprehensive role in multiple aspects of MOH.

Post-surgery interventions for hip fracture: a systematic review of randomized controlled trials.

BACKGROUND: Interventions provided after hip fracture surgery have been shown to reduce mortality and improve functional outcomes. While some systematic studies have evaluated the efficacy of post-surgery interventions, there lacks a systematically rigorous examination of all the post-surgery interventions which allows healthcare providers to easily identify post-operative interventions most pertinent to patient's recovery. OBJECTIVES: We aim to provide an overview of the available evidence on post-surgery interventions provided in the acute, subacute and community settings to improve outcomes for patients with hip fractures. METHODS: We performed a systematic literature review guided by the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA). We included articles that were (1) randomized controlled trials (RCTs), (2) involved post-surgery interventions that were conducted in the acute, subacute or community settings and (3) conducted among older patients above 65 years old with any type of non-pathological hip fracture that was surgically treated, and who were able to walk without assistance prior to the fracture. We excluded (1) non-English language articles, (2) abstract-only publications, (3) articles with only surgical interventions, (4) articles with interventions that commenced pre-surgery or immediately upon completion of surgery or blood transfusion, (5) animal studies. Due to the large number of RCTs identified, we only included "good quality" RCTs with Jadad score ≥ 3 for data extraction and synthesis. RESULTS: Our literature search has identified 109 good quality RCTs on post-surgery interventions for patients with fragility hip fractures. Among the 109 RCTs, 63% of the identified RCTs (n = 69) were related to rehabilitation or medication/nutrition supplementation, with the remaining RCTs focusing on osteoporosis management, optimization of clinical management, prevention of venous thromboembolism, fall prevention, multidisciplinary approaches, discharge support, management of post-operative anemia as well as group learning and motivational interviewing. For the interventions conducted in inpatient and outpatient settings investigating medication/nutrition supplementation, all reported improvement in outcomes (ranging from reduced postoperative complications, reduced length of hospital stay, improved functional recovery, reduced mortality rate, improved bone mineral density and reduced falls), except for a study investigating anabolic steroids. RCTs involving post-discharge osteoporosis care management generally reported improved osteoporosis management except for a RCT investigating multidisciplinary post-fracture clinic led by geriatrician with physiotherapist and occupational therapist. The trials investigating group learning and motivational interviewing also reported positive outcome respectively. The other interventions yielded mixed results. The interventions in this review had minor or no side effects reported. CONCLUSIONS: The identified RCTs regarding post-surgery interventions were heterogeneous in terms of type of interventions, settings and outcome measures. Combining interventions across inpatient and outpatient settings may be able to achieve better outcomes such as improved physical function recovery and improved nutritional status recovery. For example, nutritional supplementation could be made available for patients who have undergone hip fracture surgery in the inpatient settings, followed by post-discharge outpatient osteoporosis care management. The findings from this review can aid in clinical practice by allowing formulation of thematic program with combination of interventions as part of bundled care to improve outcome for patients who have undergone hip fracture surgery.

[Chemical constituents from leaves of Craibiodendron yunnanense].

The present study investigated the chemical constituents from the leaves of Craibiodendron yunnanense. The compounds were isolated and purified from the leaves of C. yunnanense by a combination of various chromatographic techniques including column chromatography over polyamide, silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were identified by extensive spectroscopic analyses including MS and NMR data. As a result, 10 compounds, including melionoside F(1), meliosmaionol D(2), naringenin(3), quercetin-3-O-α-L-arabinopyranoside(4), epicatechin(5), quercetin-3'-glucoside(6), corbulain Ib(7), loliolide(8), asiatic acid(9), and ursolic acid(10), were isolated. Compounds 1 and 2 were two new compounds, and compound 7 was isolated from this genus for the first time. All compounds showed no significant cytotoxic activity by MTT assay.

Influence of Vitamin D supplementation on reproductive outcomes of infertile patients: a systematic review and meta-analysis.

BACKGROUND: Low vitamin D status has been associated with an increased risk for infertility. Recent evidence regarding the efficacy of vitamin D supplementation in improving reproductive outcomes is inconsistent. Therefore, this systematic review was conducted to investigate whether vitamin D supplementation could improve the reproductive outcomes of infertile patients and evaluate how the parameters of vitamin D supplementation affected the clinical pregnancy rate. METHODS: We searched seven electronic databases (CNKI, Cqvip, Wanfang, PubMed, Medline, Embase, and Cochrane Library) up to March 2022. Randomized and cohort studies were collected to assess the reproductive outcomes difference between the intervention (vitamin D) vs. the control (placebo or none). Mantel-Haenszel random effects models were used. Effects were reported as odds ratio (OR) and their 95% confidence interval (CI). PROSPERO database registration number: CRD42022304018. RESULTS: Twelve eligible studies (n = 2352) were included: 9 randomized controlled trials (RCTs, n = 1677) and 3 cohort studies (n = 675). Pooled results indicated that infertile women treated with vitamin D had a significantly increased clinical pregnancy rate compared with the control group (OR: 1.70, 95% CI: 1.24-2.34; I2 = 63%, P = 0.001). However, the implantation, biochemical pregnancy, miscarriage, and multiple pregnancy rates had no significant difference (OR: 1.86, 95% CI: 1.00-3.47; I2 = 85%, P = 0.05; OR: 1.49; 0.98-2.26; I2 = 63%, P = 0.06; OR: 0.98, 95% CI: 0.63-1.53; I2 = 0%, P = 0.94 and OR: 3.64, 95% CI: 0.58-11.98; I2 = 68%, P = 0.21). The improvement of clinical pregnancy rate in the intervention group was influenced by the vitamin D level of patients, drug type, the total vitamin D dosage, the duration, administration frequency, and daily dosage of vitamin D supplementation. The infertile women (vitamin D level < 30 ng/mL) treated with the multicomponent drugs including vitamin D (10,000-50,000 IU or 50,000-500,000 IU), or got vitamin D 1000-10,000 IU daily, lasting for 30-60 days could achieve better pregnancy outcome. CONCLUSION: To the best of our knowledge, this is the first meta-analysis systematically investigated that moderate daily dosing of vitamin D supplementation could improve the clinical pregnancy rate of infertile women and reported the effects of vitamin D supplementation parameters on pregnancy outcomes. A larger sample size and high-quality RCTs are necessary to optimize the parameters of vitamin D supplementation to help more infertile patients benefit from this therapy.

Effects of breviscapine on cerebral ischemia-reperfusion injury and intestinal flora imbalance by regulating the TLR4/MyD88/NF-κB signaling pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: The plant Erigeron breviscapus (Vant.) Hand.-Mazz.,a Chinese herbal medicine with multiple pharmacological effects and clinical applications, has been traditionally used in the treatment of paralysis caused by stroke and joint pain from rheumatism by the Yi minority people of Southwest China for generations.However, its mechanism involves many factors and has not been fully clarified. AIM OF THE STUDY: Taking intestinal flora as the target, the protective effect of extract(breviscapine) of E. breviscapus on cerebral ischemia and its possible mechanism were discussed from the perspective of brain inflammatory pathway and intestinal CYP3A4, which depends on intestinal flora. MATERIALS AND METHODS: In this study, we first verified the binding ability between major active ingredient of Erigeron breviscapus and the core target TLR4 protein by molecular docking using Vina software.We established a rat model of cerebral ischemia-reperfusion injury in vivo.The neurological function of rats was scored by Bederson score table, the cerebral infarction volume was detected by TTC staining, and the serum NSE level was detected by ELASA. 16S rRNA sequencing was used to detect the intestinal flora of rats in each group.The expression levels of cerebral TLR4/MyD88/NF-κB and CYP3A4 mRNA and protein in different intestinal segments were detected by qRT-PCR and Western blot. RESULTS: Compared with the model group, the neurological injury score, infarct volume and serum NSE concentration of breviscapine low, medium and high dose groups and nimodipine groups decreased significantly. Meanwhile, breviscapine could significantly reduce the expression level of the TLR4/MyD88/NF-κB in brain tissue and CYP3A4 in different intestinal segments of rats with cerebral ischemia-reperfusion injury. In addition, breviscapine also significantly ameliorated intestinal flora dysbiosis of rats with cerebral ischemia-reperfusion injury. CONCLUSIONS: Breviscapine can protect rats from cerebral ischemia-reperfusion injury by regulating intestinal flora, inhibiting brain TLR4/MyD88/NF-κB inflammatory pathway and intestinal CYP3A4 expression.

Pharmacological properties and mechanisms of Notoginsenoside R1 in ischemia-reperfusion injury.

Panax notoginseng is an ancient Chinese medicinal plant that has great clinical value in regulating cardiovascular disease in China. As a single component of panax notoginosides, notoginsenoside R1 (NGR1) belongs to the panaxatriol group. Many reports have demonstrated that NGR1 exerts multiple pharmacological effects in ischemic stroke, myocardial infarction, acute renal injury, and intestinal injury. Here, we outline the available reports on the pharmacological effects of NGR1 in ischemia-reperfusion (I/R) injury. We also discuss the chemistry, composition and molecular mechanism underlying the anti-I/R injury effects of NGR1. NGR1 had significant effects on reducing cerebral infarct size and neurological deficits in cerebral I/R injury, ameliorating the impaired mitochondrial morphology in myocardial I/R injury, decreasing kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in renal I/R injury and attenuating jejunal mucosal epithelium injury in intestinal I/R injury. The various organ anti-I/R injury effects of NGR1 are mainly through the suppression of oxidative stress, apoptosis, inflammation, endoplasmic reticulum stress and promotion of angiogenesis and neurogenesis. These findings provide a reference basis for future research of NGR1 on I/R injury.

Disturbance of Fatty Acid Metabolism Promoted Vascular Endothelial Cell Senescence via Acetyl-CoA-Induced Protein Acetylation Modification.

Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated ß-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.

Astragaloside â £ alleviates ulcerative colitis by regulating the balance of Th17/Treg cells.

BACKGROUND: Restoring immune homeostasis by targeting the Th17/Treg response is a potentially valuable therapeutic strategy for ulcerative colitis (UC). Astragaloside IV (AS-Ⅳ) is a phytochemical naturally occurring in Astragalus membranaceus that has good anti-inflammatory, anti-oxidant and anti-stress properties. However, the effects of AS-IV on the homeostasis of Th17/Treg cells in colitis mice remains unknown. PURPOSE: To investigate the protective effects and potential immunomodulatory mechanisms of AS-IV on UC. METHODS: This study was constructed for DSS-induced acute colitis and recurrent colitis, with AS-IV administered prophylactically and therapeutically, respectively. The balance of Th17/Treg cells was analyzed by flow cytometry, their specific nuclear transcription factors were detected by RT-PCR as well as their secreted inflammatory cytokines were detected by ELISA and RT-PCR. Notch signaling-related proteins were detected by RT-PCR and Western blotting. Oxidative stress indicators were measured by biochemical technology. RESULTS: In this study, AS-IV treatment not only effectively prevented and alleviated the clinical symptoms of DSS-induced colitis mice, including weight loss, DAI soaring, colon length shortening and colon weight gain, but also significantly improved ulcer formation, inflammatory cell infiltration and index, and regulated the expression of inflammatory cytokines in colon tissues. Importantly, the efficacy of high-dose AS-IV (100 mg/kg/day) in mice with recurrent colitis in this study was comparable to that of 5-ASA. AS-IV early administration was able to reshape the homeostasis of Th17/Treg cells in mice with acute colitis; meanwhile, AS-IV inhibited Th17 cell responses and promoted Treg cell responses in mice with recurrent colitis. Moreover, AS-IV not only inhibited the activation of Notch signaling pathway in colitis mice, but also prevented and ameliorated DSS-induced oxidative stress injury. CONCLUSION: In conclusion, AS-IV effectively prevented and alleviated UC by reshaping Th17/Treg cell homeostasis and anti-oxidative stress.

Therapeutic targets of neuroprotection and neurorestoration in ischemic stroke: Applications for natural compounds from medicinal herbs.

Neuroprotective and neurorestorative therapy represent two major drug intervention strategies for ischemic stroke. Multiple factors such as excitotoxicity, inflammation, angiogenesis, and neurogenesis are the main pathological processes that underlie acute and chronic ischemic brain injury. Furthermore, their intimate interactions mediate blood-brain barrier permeability, increase neurovascular unit structural damage as well as a hemorrhagic transformation during ischemic stroke. We aimed to review the current understandings of the underlying mechanisms of neuroprotection and neurorestoration in ischemic stroke. Notably, traditional Chinese medicine (TCM) has notable advantages in the comprehensive treatment and overall regulation of multi-site and multi-target diseases. Therefore, we reviewed the recent advances in natural compounds from medicinal herbs that possess the bioactivities of simultaneously promoting neuroprotection (e.g., excitotoxicity, oxidative stress, apoptosis, inflammation, and autophagy) and neurorestoration (e.g., angiogenesis, neurogenesis, and axonal sprouting) following brain ischemia injury. These natural compounds were divided into glycosides (astragaloside IV, gastrodin, ginsenoside Rg1 and salidroside), flavonoids (baicalin, icariin, puerarin and breviscapine), phenols (resveratrol, curcumin and salvianolic acid B), and terpenes (ginkgolide B and catalpol). We found that all compounds exhibited anti-brain ischemia activities in vivo and in vitro experiments by promoting neuroprotection and, or neurorestoration. This review tracks and summarizes the progress of the past five years to explore the active compounds and the underlying molecular mechanisms of TCMs that produce pro-neuroprotection and pro-neurorestoration. Additionally, we provide another basis of reference supporting the advantages of TCMs, which could ultimately lead to the development of precise clinical medications for ischemic stroke treatment.

Exogenous melatonin positively regulates lignin biosynthesis in Camellia sinensis.

Melatonin (MT) is a bioactive molecule that can regulate various developmental processes. Changes in lignin content play important roles in plant growth and development. Herein, quantitative analysis and histochemical staining showed that lignin content significantly increased over time, and melatonin treatment triggered the lignification at 8 and 16 d in tea leaves. The POD activity participated in lignin formation had also been significantly improved. The effect of melatonin on the increase of lignin content was attenuation over time. Sequencing results based on transcriptome at 8 and 16 d showed that 5273 and 3019 differentially expressed genes (DEGs) were identified in CK1 vs. MT1 and CK2 vs. MT2, respectively. A total of 67 DEGs were annotated to lignin biosynthesis, and 38 and 9 genes were significantly up-regulated under melatonin treatment, respectively. Some transcription factor genes such as MYB were also identified among the two pairwise comparisons, which might relate to lignin metabolism. Melatonin increased the degree of lignification in tea leaves by modifying the enzyme genes expression involved in lignin synthesis pathway. These results provide a reference for further study on the molecular mechanism of the dynamic changes of lignin content induced by melatonin treatment in tea plants.

Moxibustion against Cyclophosphamide-Induced Premature Ovarian Failure in Rats through Inhibiting NLRP3-/Caspase-1-/GSDMD-Dependent Pyroptosis.

Premature ovarian failure (POF) is a clinical term used to describe a condition in which women present with amenorrhoea, hypergonadotropic hypogonadism, and infertility under 40 years old, which are mainly characterized by ovarian granulosa cell inflammation and death. Pyroptosis is a proinflammatory form of programmed cell death. However, the roles of pyroptosis in POF and moxibustion (Mox) on pyroptosis in POF have not been elucidated. The aim of the present study was to investigate the protective effect of moxibustion against cyclophosphamide- (CP-) induced POF and to determine the underlying mechanisms. The results indicated that Mox could decrease the follicle-stimulating hormone (FSH) and luteotropic hormone (LH) and increase estradiol (E2) in serum, which indicated that it could improve ovarian reserve capacity. Mox also ameliorated CP-induced ovarian injury accompanied by decreased levels of interleukin-1ß (IL-1ß), IL-18, and gasdermin D (GSDMD), which are key features of pyroptosis. Further investigation showed that Mox alleviated POF through NLRP3-mediated pyroptosis. On the one hand, Mox directly inhibited TXNIP/NLRP3/caspase-1 signaling-induced pyroptosis, and on the other hand, it indirectly decreased NLRP3, pro-IL-1ß, and pro-IL-18 through inhibiting TLR4/MyD88/NF-κB signaling. Our results show that Mox might be a new therapeutic strategy for the treatment of POF.

Efficacy and Mechanism of Qingre Lishi Prescription in Treating Children with Acute Bacterial Lower Urinary Tract Infection of Bladder Damp-heat Syndrome / 中国实验方剂学杂志

Objective:To observe the efficacy of Qingre Lishi prescription in treating children with acute bacterial lower urinary tract infection of bladder damp-heat syndrome， and to explore its mechanism of action. Method:Eighty children with acute bacterial lower urinary tract infection of late bladder damp-heat syndrome who were admitted to the Affiliated Hospital of Changchun University of Chinese Medicine were divided into control group and observation group， 40 cases in each group. Patients in control group were given Bazhengsan for oral treatment on basis of basic treatment， while patients in observation group were given Qingre Lishi prescription for oral administration plus external washing treatment. After two weeks of treatment， the clinical and etiological effect， traditional Chinese medicine （TCM） syndrome scores， antipyretic time and urinary negative time， adverse reactions， and urine pathogens （<italic>Escherichia coli， Enterococcus faecalis， Strange proteus， Klebsiella pneumoniae</italic>）， serum inflammatory factor indicators ［tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>）， interleukin-6 （IL-6）， interleukin-8 （IL-8）， calcium lowering PCT， white blood cell count （WBC） and serum C-reactive protein （CRP）］， immune function indicators ［T cell subsets （CD3⁺， CD4⁺， CD8⁺） and complement （C3， C4）］ were comapred between two groups. Result:The clinical efficacy of observation group was 92.50% （37/40）， which was significantly higher than 65.00% （26/40） in control group （<italic>χ²</italic>=9.038， <italic>P</italic><0.01）， the etiological efficacy of observation group was 87.50% （35/40）， which was significantly higher than 60.00% （24/40） in control group （<italic>χ²</italic>=7.813， <italic>P</italic><0.01）. After treatment， the scores of TCM syndromes of the two groups were significantly reduced （<italic>P</italic><0.05）. The scores of fever， frequent urination， urgent urination， painful urination， difficulty urinating and abdominal pain in two groups were significantly lower than those before treatment （<italic>P</italic><0.05）， and the TCM syndrome scores in observation group were lower than those in control group （<italic>P</italic><0.05）， the antipyretic time and urinary bacteria turning negative time of observation group were significantly lower than those in control group （<italic>P</italic><0.05）， the <italic>Escherichia coli， Enterococcus faecalis， Proteus mirabilis， Klebsiella pneumoniae</italic> pathogenic bacteria detected in both groups were both significantly lower than those before treatment （<italic>P</italic><0.05）. After treatment， the levels of inflammatory factors such as TNF-<italic>α</italic>， IL-6， IL-8， PCT， WBC and CRP in two groups were significantly lower than those before treatment （<italic>P</italic><0.05）， the immune function of the two groups was significantly improved， and the levels of CD3⁺， CD4⁺， C3， and C4 in observation group were higher than those in control group（<italic>P</italic><0.05）， and the CD8⁺ level was lower than that in control group （<italic>P</italic><0.05）. The incidence of adverse reactions had no significant difference between two groups. Conclusion:Qingre Lishi prescription has good clinical effect in treating children with acute bacterial lower urinary tract infection with bladder damp-heat syndrome. It can improve TCM syndromes and clinical symptoms. Its mechanism is related to inhibiting pathogenic bacteria， reducing inflammation， and improving immune function， and it has good security.

Continuous theta burst stimulation provides neuroprotection by accelerating local cerebral blood flow and inhibiting inflammation in a mouse model of acute ischemic stroke.

Acute ischemic stroke is a leading cause of disability with limited therapeutic options. Continuous theta burst stimulation (cTBS) has recently been shown to be a promising noninvasive therapeutic strategy for neuroprotection in ischemic stroke patients. Here, we investigated the protective effects of cTBS following acute infarction using a photothrombotic stroke (PTS) model in the right posterior parietal cortex (PPC) of C57BL/6 mice. Treatment with cTBS resulted in a reduction in the volume of the infarct region and significantly increased vascular diameter and blood flow velocity in peri-infarct region, as well as decreased the numbers of calcium binding adapter molecule 1 (Iba-1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes. Moreover, the number of CD16/32 positive microglia was decreased, whereas the number of CD206 positive microglia was increased. In addition, performance in a water maze task was significantly improved. These results indicated that cTBS protected against PPC infarct region, leading to an improvement in spatial cognitive function, possibly as a result of changes to cerebral microvascular function and inflammatory responses.

Emodin promotes fibroblast apoptosis and prevents epidural fibrosis through PERK pathway in rats.

BACKGROUND: Laminectomy is usually classed as a common orthopedic surgery, but postoperative epidural fibrosis often leads to less-than-desirable clinical outcomes. As demonstrated by prior studies, emodin (EMO) exerts an anti-fibrotic effect. Here, we carried out investigation into the inhibitory effect created by EMO application on epidural fibrosis after laminectomy in rats. METHODS: The paper conducts a series of experiment. In vitro, we observed the effect of EMO on fibroblasts by Cell Counting Kit-8 (CCK-8) assay. Apoptosis of fibroblasts induced by EMO was detected by western blot, TUNEL assay, and flow cytometry. The results revealed that EMO was capable of inducing fibroblast apoptosis, and the proteins of PERK pathway also changed accordingly. In vivo, the effect of EMO on epidural fibrosis in 12 male Sprague-Dawley rats was observed by histological staining. RESULTS: CCK-8 assay indicated that EMO was effective in reducing fibroblast viability in a time- and a dose-dependent manner. TUNEL assay and flow cytometry analysis have demonstrated that the apoptotic rate of fibroblasts increased as the EMO concentration rose. Western blot analysis proved that EMO promoted the relative expression of p-perk and p-eIF2α and that the expression of its downstream proteins CHOP and GRP78 was also enhanced. The expression of apoptotic protein Bax and cleaved PARP was upregulated, whereas the expression of anti-apoptotic protein Bcl-2 was downregulated. In addition, histological and immunohistochemical analysis demonstrated that EMO functioned to inhibit epidural fibrosis and increase GRP78 expression in fibrous tissue by promoting apoptosis of fibroblasts. CONCLUSIONS: EMO could have inhibitory effect on epidural fibrosis in a concentration-dependent manner. The potential mechanism might be through PERK signaling pathway to promote fibroblast apoptosis. It has a possibility to be taken as a novel method for the treatment of epidural fibrosis.

Efficacy and Safety of Toutongning Capsule in Patients with Migraine: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Objective: Toutongning (TTN) capsule, a Chinese patent medicine, is used as a prophylactic treatment for migraine. The present study was conducted as a postmarketing evaluation of the efficacy and safety of TTN capsule. Design: A randomized, double-blind, placebo-controlled trial. Location: Patients recruited from 14 medical centers in China from May 2014 to August 2015. Subjects: Patients between 18 and 65 years of age with a diagnosis of migraine. Interventions: The patients were randomly assigned to receive either TTN (1200 mg, three times daily) or a matched placebo (1:1) for 4 weeks. Outcome measures: The primary outcome measured was a minimum 50% reduction in the frequency of headaches from the 4-week baseline period to the last 4 weeks of the 12-week trial. Secondary outcomes included duration, days, and visual analog score of headache attack, interval between headache attacks, usage of acute analgesics, and score on the Headache Impact Test-6. In addition, all patients were evaluated for adverse events (AEs). Results: This study initially enrolled 400 patients; a total of 378 participants completed the experiment while fulfilling all study requirements. TTN had a superior effect compared with the placebo on both the primary and secondary outcome measures without any serious AEs or unexpected side effects. Conclusion: TTN can effectively prevent the occurrence of migraine headaches and is well-tolerated and safe. TTN may exhibit a persistent therapeutic effect even after cessation of use. Trial Registration number: ChiCTR-IPR-15007058.