Sodium houttuyfonate against cardiac fibrosis attenuates isoproterenol-induced heart failure by binding to MMP2 and p38.

BACKGROUND: Heart failure (HF), caused by stress cardiomyopathy, is a major cause of mortality. Cardiac fibrosis is an essential structural remodeling associated with HF; therefore, preventing cardiac fibrosis is crucial to decelerating the progression of HF. Sodium houttuyfonate (SH), an extract of Houttuynia cordata, has a potent therapeutic effect on hypoxic cardiomyocytes in a myocardial infarction model. PURPOSE: To investigate the preventative and therapeutic effects of SH during isoproterenol (ISO)-induced HF and explore the pharmacological mechanism of SH in alleviating HF. METHODS: We analyzed the overlapping target genes between SH and cardiac fibrosis or HF using a network pharmacology analytical method. We verified the suppressive effect of SH on ISO-induced proliferation and activation of cardiac fibroblasts by immunohistochemical staining and histological analysis in an isoproterenol-induced HF mouse model. Additionally, we investigated the effect of SH by evaluating fibrosis and cardiac remodeling markers. To further decipher the pharmacological mechanism of SH against cardiac fibrosis and HF, we performed a molecular docking analysis between SH and hub common target genes. RESULTS: There were 20 overlapping target genes between SH and cardiac fibrosis and 32 overlapping target genes between SH and HF. The 16 common target genes of SH against cardiac fibrosis and HF included MMP2 (matrix metalloproteinase 2), and p38. SH significantly inhibited the ISO- or TGF-ß-induced expression of Col1α (collagen 1), α-SMA (smooth muscle actin), MMP2, TIMP2 (tissue inhibitor of metalloproteinase 2), TGF-ß (transforming growth factor), and Smad2 phosphorylation. Moreover, both ISO- and TGF-ß-induced p38 phosphorylation was inhibited. Molecular docking analysis showed that SH forms a stable complex with MMP2 and p38. CONCLUSIONS: In addition to protecting cardiomyocytes, SH directly inhibits cardiac fibroblast activation and proliferation by binding to MMP2 and p38, subsequently delaying cardiac fibrosis and HF progression. Our prevention- and intervention-based approaches in this study showed that SH inhibited the development of stress cardiomyopathy-mediated cardiac fibrosis and HF when SH was administered before or after the initiation of cardiac stress.

Mitochondrial regulation of acute extrafollicular B-cell responses to COVID-19 severity.

BACKGROUND: Patients with COVID-19 display a broad spectrum of manifestations from asymptomatic to life-threatening disease with dysregulated immune responses. Mechanisms underlying the detrimental immune responses and disease severity remain elusive. METHODS: We investigated a total of 137 APs infected with SARS-CoV-2. Patients were divided into mild and severe patient groups based on their requirement of oxygen supplementation. All blood samples from APs were collected within three weeks after symptom onset. Freshly isolated PBMCs were investigated for B cell subsets, their homing potential, activation state, mitochondrial functionality and proliferative response. Plasma samples were tested for cytokine concentration, and titer of Nabs, RBD-, S1-, SSA/Ro- and dsDNA-specific IgG. RESULTS: While critically ill patients displayed predominantly extrafollicular B cell activation with elevated inflammation, mild patients counteracted the disease through the timely induction of mitochondrial dysfunction in B cells within the first week post symptom onset. Rapidly increased mitochondrial dysfunction, which was caused by infection-induced excessive intracellular calcium accumulation, suppressed excessive extrafollicular responses, leading to increased neutralizing potency index and decreased inflammatory cytokine production. Patients who received prior COVID-19 vaccines before infection displayed significantly decreased extrafollicular B cell responses and mild disease. CONCLUSION: Our results reveal an immune mechanism that controls SARS-CoV-2-induced detrimental B cell responses and COVID-19 severity, which may have implications for viral pathogenesis, therapeutic interventions and vaccine development.

5-Demethylnobiletin: Insights into its pharmacological activity, mechanisms, pharmacokinetics and toxicity.

BACKGROUND: 5-Demethylnobiletin (5DN) is a polymethoxyflavone (PMF) primarily found in citrus fruits. It has various health-promoting properties and hence has attracted significant attention from scholars worldwide. PURPOSE: This review is the first to systematically summarize the recent research progress of 5DN, including its pharmacological activity, mechanism of action, pharmacokinetics, and toxicological effects. In addition, the pharmacological mechanism of action of 5DN has been discussed from a molecular biological perspective, and data from in vivo and in vitro animal studies have been compiled to provide a more thorough understanding of 5DN as a potential lead drug. METHODS: Data were extracted from SciFinder, PubMed, ScienceDirect and China National Knowledge Infrastructure (CNKI) from database inception to January 2022. RESULTS: 5DN has broad pharmacological activities. It exerts anti-inflammatory effects, promotes apoptosis and autophagy, and induces melanogenesis mainly by regulating the JAK2/STAT3, caspase-dependent apoptosis, ROS-AKT/mTOR, MAPK and PKA-CREB signaling pathways. 5DN can be used for treating diseases such as cancer, inflammation-related diseases, rheumatoid arthritis, and neurodegenerative diseases. To date, there have been only a few toxicological studies on 5DN, and both in vitro and in vivo on 5DN have not revealed significant toxic side effects. Pharmacokinetic studies have revealed that the metabolites of 5DN are mainly 5,3'-didemethylnobiletin (M1); 5,4'-didemethylnobiletin (M2) and 5,3',4'-tridemethylnobiletin (M3), in either, glucuronide-conjugated or monomeric form. The pharmacokinetic products of 5DN, especially M1, possess better activity than 5DN for the treatment of cancer. CONCLUSION: The anticancer effects of 5DN and its metabolites warrant further investigation as potential drug candidates, especially through in vivo studies. In addition, the therapeutic effects of 5DN in neurodegenerative diseases should be examined in more experimental models, and the absorption and metabolism of 5DN should be further investigated in vivo.

Meta-Analysis on the Chinese Herbal Formula Xiaoer-Feike Granules as a Complementary Therapy for Children With Acute Lower Respiratory Infections.

BACKGROUND: Over the past five years the Chinese herbal formula (CHF) medicine, Xiaoer-Feike granules (XFG), has become a widely used adjuvant therapy for acute lower respiratory infections (ALRI). Considering the rapid popularization and application of XFG, and the lack of systematic evidence evaluating its effectiveness and safety in treating ALRI, it is necessary to conduct a meta-analysis to determine its benefits for patients. METHODS: This study systematically identified randomized controlled trials (RCTs) of XFG treatments for ALRI through July 2019 using four English-databases (PubMed, Cochrane Library, Ovid, and Web of Science) and four Chinese-databases (Sino-med database, China National Knowledge Infrastructure (CNKI), VIP database, and the WANFANG database). We then performed a quality assessment and data analysis with Review Manager 5.3.5 and Stata 15.1. RESULTS: Twenty-one RCTs involving 3425 patients were randomly divided into an XFG group and a conventional medicine (CM) group. The results showed that the clinical efficacy rate (CER) of the XFG group was significantly higher than that of the CM group (RR=1.17, 95% CI =1.13-1.22, P< 0.00001). In comparison with the CM group, the XFG group had strikingly shortened: resolution time of cough (RTC) (MD = -1.92; 95% CI =-2.33, -1.51, P<0.00001); resolution time of rale (RTR) (MD = -1.68; 95% CI =-2.27, -1.10, P<0.00001); resolution time of fever (RTF) (MD = -1.46; 95% CI =-1.92, -1.00, P<0.00001); resolution time of inflammatory lesions (RTIL) (MD = -2.43, 95% CI =-2.94, -1.93, P< 0.00001); and hospital stays (HS) (MD = -2.26, 95% CI =-3.03, -1.49, P< 0.00001). At the cellular and molecular level, the CD4, CD8, CD4/CD8, IL-6, TNF-α, and CRP levels were significantly improved when CM was complemented with XFG. In addition, no significant difference was observed between the XFG and CM groups in terms of the adverse events (AE) (RR =0.97, 95% CI= 0.61-1.54, P= 0.89). CONCLUSIONS: The findings of this meta-analysis support the use of XFG in the treatment of ALRI. However, these results should be treated with caution due to the significant heterogeneity and publication bias of existing data. Further well-designed and high-quality RCTs are needed to interrogate the efficacy and safety of XFG.

Acute EPA-induced learning and memory impairment in mice is prevented by DHA.

Eicosapentaenoic acid (EPA), an omega-3 fatty acid, has been widely used to prevent cardiovascular disease (CVD) and treat brain diseases alone or in combination with docosahexaenoic acid (DHA). However, the impact of EPA and DHA supplementation on normal cognitive function and the molecular targets of EPA and DHA are still unknown. We show that acute administration of EPA impairs learning and memory and hippocampal LTP in adult and prepubescent mice. Similar deficits are duplicated by endogenously elevating EPA in the hippocampus in the transgenic fat-1 mouse. Furthermore, the damaging effects of EPA are mediated through enhancing GABAergic transmission via the 5-HT6R. Interestingly, DHA can prevent EPA-induced impairments at a ratio of EPA to DHA similar to that in marine fish oil via the 5-HT2CR. We conclude that EPA exhibits an unexpected detrimental impact on cognitive functions, suggesting that caution must be exercised in omega-3 fatty acid supplementation and the combination of EPA and DHA at a natural ratio is critical for learning and memory and synaptic plasticity.

SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition.

Acetaminophen (APAP) is the leading cause of drug-induced acute liver failure. Sphingosine-1-phosphate (S1P), whose formation is catalyzed by sphingosine kinase (SPHK)-1 or -2, is a bioactive lipid implicated in human health and disease. Here, we show that APAP-treated sphK1-deficient (sphK1-/-) mice exhibited markedly less liver damage and reduced inflammation compared with the wild-type mice. SPHK1 deficiency alleviated APAP-induced endoplasmic reticulum (ER) stress by affecting the phosphorylation of inositol-requiring enzyme 1α (IRE1α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α), levels of activating transcription factor 4 (ATF4), and activation of activating transcription factor 6 (ATF6). SPHK1 deficiency also inhibited mitochondrial permeability transition (MPT), as evidenced by the impaired phosphorylation of JNK, apoptosis signal-regulated kinase 1 (ASK1), and glycogen synthase kinase 3ß (GSK3ß). In addition, SPHK1 deficiency reduced the levels of histone deacetylase and promoted the acetylation of p65 and STAT1, thereby impairing the transcription of inflammatory genes. Supplementation with exogenous S1P significantly reversed the activation of the PERK-eIF2α-ATF4 pathway and ATF6 during ER stress as well as the activation of GSK3ß, ASK1, and JNK during MPT. Both FTY720, a functional S1P receptor antagonist, and PF543, an SPHK1 inhibitor, significantly ameliorated APAP-induced liver injury and improved animal survival. Our study reveals a critical role for SPHK1 in mediating APAP-induced hepatotoxicity by promoting ER stress and MPT.

Meta-Analysis on the Efficacy and Safety of Traditional Chinese Medicine as Adjuvant Therapy for Refractory Androgenetic Alopecia.

OBJECTIVE: Traditional Chinese medicine (TCM) therapies have been widely used for the treatment of androgenetic alopecia (AGA) for thousands of years. We conducted a meta-analysis to evaluate the curative efficacy and safety of TCM for treating AGA. METHODS: Randomized controlled trials (RCTs) of TCM for the treatment of AGA through March 2019 were systematically identified in 4 English databases, namely, PubMed, Cochrane Library, EMBASE, and Web of Science, and 4 Chinese databases, namely, Sino-Med, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WanFang. Quality assessment and data analysis were performed by Review Manager 5.3.5, and Stata 15.1 was used to cope with publication bias. RESULTS: 30 RCTs involving 2615 patients were randomly divided into a TCM group and a conventional medicine (CM) group. The results showed that the total efficacy rate (TER) of the TCM group was significantly higher than that of the control group (OR = 3.34, 95% CI = 2.75-4.05, P < 0.00001). The total symptom score (TSS) of the TCM group was markedly reduced when compared with the CM group (SMD = -0.86; 95% CI = -1.19, -0.53; P < 0.00001). The microelement levels (Fe2+, Zn2+, and Cu2+) in hair were significantly improved when complemented with TCM therapy. In addition, no significant differences were observed between the two groups in terms of adverse events (OR = 0.55, 95% CI = 0.29-1.05, P=0.07). CONCLUSIONS: In view of the effectiveness and safety of TCM, the present meta-analysis suggests that TCM could be recommended as an effective and safe adjuvant therapy for the treatment of AGA by improving the TER, symptoms, serum testosterone levels, and microelement levels. However, long-term and higher-quality RCTs are needed to overcome the limitations of the selected studies and more precisely interrogate the efficacy and safety of TCM.

Meta-Analysis on the Efficacy and Safety of Hyperbaric Oxygen as Adjunctive Therapy for Vascular Dementia.

Background: Vascular dementia (VD) is a common type of disease in the elderly. Numerous clinical trials have suggested that hyperbaric oxygen is an effective and safe complementary therapy for aging-related disorders. However, there is no reliable systematic evidence regarding hyperbaric oxygen therapy (HBOT) for the treatment of VD. Therefore, we performed a meta-analysis to evaluate the clinical efficacy and safety of HBOT in treating VD. Methods: We methodically retrieved the clinical studies from eight databases (PubMed, Cochrane Library, Embase, Web of Science, Sino-Med, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WanFang) from their inception to November 2018. RevMan 5.3.5 was used for quality assessment and data analysis. Stata 15.1 was employed for publication bias detection and sensitivity analysis. Results: Twenty-five randomized clinical trials (RCTs) involving 1,954 patients met our inclusion criteria. These articles researched the HBOT + oxiracetam + conventional therapy (CT) vs. oxiracetam + CT (n = 13), HBOT + butylphthalide +CT vs. butylphthalide + CT (n = 5), HBOT + donepezil + CT vs. donepezil + CT (n = 4), HBOT + nicergoline + CT vs. nicergoline + CT (n = 2) and HBOT + CT vs. CT (n = 1). The results indicated that additional HBOT strikingly improved the Mini-Mental State Examination (MMSE) (MD = 4.00; 95% CI = 3.28-4.73; P < 0.00001), activities of daily living (ADL) (MD = -5.91; 95% CI = -6.45, -5.36; P < 0.00001) and ADL by Barthel index (BADL) (MD = 13.86; 95% CI = 5.63-22.10; P = 0.001) and increased the total efficacy rate (TEF) (OR = 4.84, 95% CI = 3.19-7.33, P < 0.00001). The adverse events rates were not statistically significant between the HBOT and CT groups (OR = 0.85, 95% CI = 0.26-2.78, P = 0.79). Conclusion: In view of the effectiveness and safety of HBOT, the present meta-analysis suggested that HBOT can be recommended as an effective and safe complementary therapy for the treatment of VD. Protocol Registration: PROSPERO (ID: CRD42019117178). Available online at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42019117178.

Can leisure activities slow dementia progression in nursing home residents? A cluster-randomized controlled trial.

BACKGROUND: To examine the effects of complex cognitive (mahjong) and physical (Tai Chi) activities on dementia severity in nursing home residents with dementia. METHODS: Cluster-randomized open-label controlled design. 110 residents were randomized by nursing home into three conditions: mahjong, Tai Chi, and simple handicrafts (control). Activities were conducted three times a week for 12 weeks. Clinical Dementia Rating (CDR) was taken at 0 (baseline), 3 (post-treatment), 6, and 9 months. The outcome measure was CDR sum-of-box, which is a composite measure of both cognitive and functional deterioration in dementia. RESULTS: Intent-to-treat analyses were performed using multilevel regression models. Apolipoprotein E ε4 allele and education were included as covariates. Neither treatments had effects on the cognitive and functional components of the CDR, but mahjong had a significant interaction with time on the CDR sum-of-box total, suggesting a slower rate of global deterioration in the mahjong group as compared with the control group. CONCLUSIONS: Mahjong led to a gradual improvement in global functioning and a slightly slower rate of dementia progression over time. The effect was generalized and was not specific to cognition or daily functioning.

Development of a screening assay to evaluate the potential of drugs to cause immune-mediated hypersensitivity reactions.

Evidence suggests that bio-activation of drugs to generate chemically reactive metabolites (RM) that act as haptens to form immunogenic protein conjugates may be an important cause of immune-mediated drug hypersensitivity reactions (IDHR). Although many drugs that form RMs raise concerns about producing IDHR, standard non-clinical testing methods are rarely able to identify compounds with the potential to produce IDHR in humans. The objective of this study was to develop a predictive assay for IDHR that involves: (1) the use of an in vitro drug-metabolizing system to generate the RM that is captured by GSH, (2) conjugating the RM-GSH conjugate to mouse serum albumin (MSA) by using a chemical cross-linker, (3) immunization of mice with RM-GSH-MSA adducts, and (4) ex vivo challenge with RM-GSH-MSA adduct and measurement of lymphocyte proliferation to determine if the RM is immunogenic. The predictivity of the assay was evaluated by using drugs that produce RM and have been strongly, weakly, or not associated with IDHRs in the clinic. While this method requires additional validation with more drugs, the results demonstrate the feasibility of identifying drugs strongly associated with IDHR and the utility of the assay for rank ordering drugs with respect to their potential to cause IDHR.

Mental and physical activities delay cognitive decline in older persons with dementia.

OBJECTIVES: To examine the effects of cognitive stimulation (mahjong) and physical exercise (tai chi [TC]) on cognitive performance in persons with dementia. DESIGN: Cluster-randomized open-label controlled design. SETTING: Nursing homes. PARTICIPANTS: One hundred ten residents, most of whom were cholinesterase-inhibitor naive. Inclusion criteria were Mini-Mental State Examination (MMSE) = 10-24 and suffering from at least very mild dementia (Clinical Dementia Rating ≥ 0.5). Exclusion criteria were being bedbound, audio/visual impairment, regular activity participation before study, or contraindications for physical or group activities. INTERVENTIONS: Homes were randomized into three conditions (mahjong, TC, and simple handicrafts [control]). Activities were conducted three times weekly for 12 weeks. MEASUREMENTS: Primary outcome was MMSE. Secondary outcomes were immediate/delayed recall, categorical fluency, and digit span. Various biological risk factors, including apolipoprotein E ε4 allele, were included as covariates. Measures were collected at 0 (baseline), 3 (posttreatment), 6, and 9 months. RESULTS: Intent-to-treat analyses were performed using mixed-effects regression. Mahjong's effect varied by time for MMSE, delayed recall, and forward digit span. TC had similar effects but not for delayed recall. The typical pattern was that control participants deteriorated while mahjong and TC participants maintained their abilities over time, leading to enlarged treatment effects as time progressed. By 9 months, mahjong and TC differed from control by 4.5 points (95% confidence interval: 2.0-6.9; d = 0.48) and 3.7 points (95% confidence interval: 1.4-6.0; d = 0.40), respectively, on MMSE. No treatment effects were observed for immediate recall and backward digit span. CONCLUSIONS: Mahjong and TC can preserve functioning or delay decline in certain cognitive domains, even in those with significant cognitive impairment.

A facile synthesis of (+/-)-heliannuol-D.

A facile synthesis of (+/-)-heliannuol-D 1, which serves as an allelopathic chemical in nature and a potential lead compound in the search for new herbicides, has been achieved in a linear 11 steps, together with its epimer. The synthesis commenced with 4-methoxy-3-methyl-acetophenone, through the Baeyer-Villiger reaction, lithiation and addition, epoxidation and intramolecular cyclization to give (+/-)-heliannuol-D (1) and its epimer (la) in 32.6% overall yield. Our synthetic approach is cost-effective; this will be helpful in applying this kind of compound for the development of a new generation of agrochemicals.

[The location of Ciliao (BL 32) acupoint by three-dimensional reconstruction of computed tomography in women].

OBJECTIVE: To determine the location of Ciliao (BL 32) by the help of three-dimensional (3-D) surface reconstruction of computed tomography (CT) so as to provide a reference for clinical application. METHODS: A total of 106 female volunteer subjects were enrolled in the present study. A CT scanner was used to scan the subjects' pelvis, and the collected image data was processed by Dextroscope workstation. The distances and angels of Ciliao(BL 32) in the 3-D space were measured. RESULTS: A linear correlation existed between the inter-iliac distance (L 1) and sacro-foremen distance (L 2, with the regression equation being Y = 20.219 + 0.25X), and between the sacro-iliac distance and sacral foremen-iliac distance (with the regression equation being Y = -14.007 + 0.446X), which were used to determine the location of BL 32. A linear correlation also existed between the body weight and the needling depth (with the regression equation being Y = -18.893 + 0.988X). So, the suitably inserted straight depth of acupuncture needle could be determined according to the woman's body weight. The oblique angle of the 2nd sacral foremen was (30.08 +/- 4.26), and the depth of the 2nd sacral foramen was (20.13 +/- 2.11) mm. CONCLUSION: In accordance with the results obtained from CT 3-D reconstruction, oblique needling of an acupuncture needle for Ciliao (BL 32) is highly recommended.

[Studies on the flavones in of Chrozophora sabulosa].

OBJECTIVE: To study the flavone constituents in Chrozophora sabulosa (Xinjiang origin). METHOD: The compounds were extracted with 95% ethyl alcohol, isolated by various column chromatography and identified by spectroscopic methods. RESULT: Seven flavanoids were isolated and identified as quercetin (I), kaempferol (II), apigenin (III), chrysoerid (IV), isoquercitrin (V), chrysoerin-7-O-beta-D-glucoside (VI) and quercetin-3-O-alpha-D-arabinfuranoside (VII). CONCLUSION: All of these seven compounds were obtained from this genus for the first time.

Studies on the flavones in of Chrozophora sabulosa / 中国中药杂志

<p><b>OBJECTIVE</b>To study the flavone constituents in Chrozophora sabulosa (Xinjiang origin).</p><p><b>METHOD</b>The compounds were extracted with 95% ethyl alcohol, isolated by various column chromatography and identified by spectroscopic methods.</p><p><b>RESULT</b>Seven flavanoids were isolated and identified as quercetin (I), kaempferol (II), apigenin (III), chrysoerid (IV), isoquercitrin (V), chrysoerin-7-O-beta-D-glucoside (VI) and quercetin-3-O-alpha-D-arabinfuranoside (VII).</p><p><b>CONCLUSION</b>All of these seven compounds were obtained from this genus for the first time.</p>