Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine.

Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.

Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Cav channels.

Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Cav channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Cav1.1 and Cav1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Cav channels.

Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands.

Mutations in the PKD2 gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment.

The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2.

Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes. The latter encodes polycystin-2 (PC2, also known as TRPP2), a member of the transient receptor potential ion channel family. Despite most pathogenic mutations in PKD2 being truncation variants, there are also many point mutations, which cause small changes in protein sequences but dramatic changes in the in vivo function of PC2. How these mutations affect PC2 ion channel function is largely unknown. In this study, we systematically tested the effects of 31 point mutations on the ion channel activity of a gain-of-function PC2 mutant, PC2_F604P, expressed in Xenopus oocytes. The results show that all mutations in the transmembrane domains and channel pore region, and most mutations in the extracellular tetragonal opening for polycystins domain, are critical for PC2_F604P channel function. In contrast, the other mutations in the tetragonal opening for polycystins domain and most mutations in the C-terminal tail cause mild or no effects on channel function as assessed in Xenopus oocytes. To understand the mechanism of these effects, we have discussed possible conformational consequences of these mutations based on the cryo-EM structures of PC2. The results help gain insight into the structure and function of the PC2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.

Interaction, Surface Activity, and Application of Mixed Systems of Alcohol Ether Sulfate Anionic Surfactants with Multiple Ethylene Oxide Groups and Gemini Quaternary Ammonium Surfactant.

The surface activities and application properties for the mixtures of cationic surfactants tetramethylene-1,4-bis[N,N-bis(hydroxypropyl)-hexa/decyloxypropylammonium] bromide (GC10-P) and tetramethylene-1,4-bis[N,N-bis(hydroxyethyl)-hexa/decyloxypropylammonium] bromide (GC10-E) and anionic surfactant isomeric sodium fatty alcohol ether sulfates (iso-AE9S) were investigated using both the tensiometry and the conductometry. The interaction parameters and thermodynamic micellization parameters of GC10-P/iso-AE9S and GC10-E/iso-AE9S mixtures were evaluated by Clint-Rubingh and Motomura theoretical models. When the mole fraction of α1 for GC10-P/iso-AE9S mixed system was 0.2, the critical micelle concentration (CMC) reached a minimum of 1.61 × 10-4 mol/L, and the minimum critical micelle concentration of the GC10-E/iso-AE9S mixed system is 2.67 × 10-5 mol/L at α1 = 0.6. The CMC value of the mixed system is 1-2 orders of magnitude lower than that of any single component. The results indicate that the synergistic effects of the investigated mixed systems (evaluated by ßm) are in order of GC10-P/iso-AE9S < GC10-E/iso-AE9S, with maximum ßm values of -17.98 and -9.78, respectively. The change in zeta potential indicates that the poly(ethylene oxide) chain has weakened the charge density of the hydrophilic headgroup of the anionic surfactant. The interfacial tension at the oil-water interface in the mixed system of anionic/cationic surfactants is lower than that of any single component, exhibiting a higher interfacial activity. The mixed system exhibits a decreased contact angle and superior wetting ability over any single component, and it also enhances foam performance, emulsification performance, and degreasing performance.

Anisotropic Magnetic Polymeric Particles with a Controllable Structure via Seeded Emulsion Polymerization.

Magnetic polymer composites have been widely utilized in potential applications in material science, such as reduction of dyes, immunodiagnostics, biomedicals, and magnetically controllable photonic crystals owing to large surface areas, fast separation, and recyclable performance. In this work, anisotropic magnetic particles were prepared by seeded emulsion polymerization, with morphologies of "Fe3O4-shell", "hemisphere-like", "raspberry-like", "multiple lobes-like", and "sandwich-like". Poly(styrene/divinylbenzene/mono-2-(methacryloxy)ethyl succinate)@ Fe3O4 (P(St/DVB/MMES)@Fe3O4) were the seed microspheres, and P(St/DVB/MMES)@Fe3O4@polymer particles are achieved by seeded emulsion polymerizations. The morphology of the particles depends on polymerization conditions (monomer ratios and surfactant), particle properties, and so on. Then, the minimum surface free energy change principles were used to predict the equilibrium morphologies of the magnetic polymer composites. Through theory, the model gives the correct tendency and good agreement with the equilibrium morphology which was in tandem with TEM results. Lastly, after in situ surface deposition of Ag nanoparticles, magnetic composite particles with sandwich-like morphology were applied for the catalytic degradation of 4-nitrophenol (4-NP) reacting with NaBH4. The apparent rate coefficient is 0.0069 s-1, and it can keep mainly about 80% efficiency in catalysis after five cycles.

Polymer Microspheres Copolymerized with Deep Red Fluorescent Molecules as a Label for Lateral Flow Immunochromatography.

The development of fluorescently labeled microspheres is a critical aspect of advancing the technology of lateral flow immunochromatography (LFIA) for biological detection. Nevertheless, potential interference posed by the background fluorescence originating from the nitrocellulose (NC) membrane would significantly impact the sensitivity and accuracy of microsphere-based detection in LFIA. In this work, an attempt was made to extend the π-conjugated system and asymmetric structure of rhodamine fluorophore, resulting in the synthesis of dye molecules (RB2) incorporating double bonds, which can reach an absolute photoluminescence quantum yield (PLQY) of 30.01% in EtOH. Subsequently, carboxyl group functionalized fluorescent microspheres were prepared in a two-step copolymerization via soap-free emulsion polymerization. The obtained microspheres were characterized by scanning electron microscopy, transmission electron microscopy, DLS, Fourier transform infrared spectroscopy, ultraviolet spectrophotometry, and fluorescence spectrophotometry. The results showed that RB2 was successfully copolymerized into the microspheres, and the resulting microspheres had good dispersion and stability with high red fluorescence intensity (λabs ∼ 610 nm, λem ∼ 660 nm). Utilizing these microspheres, the resulting lateral flow immunoassay was successfully found to detect SARS-CoV-2 N protein with a detection limit of 2.5 pg/mL and the linear concentration spanning from 2.5 pg/mL to 10 ng/mL. The results confirm the effectiveness of the synthetic fluorescent microspheres as the label for LFIA.

Insights into treatment-specific prognostic somatic mutations in NSCLC from the AACR NSCLC GENIE BPC cohort analysis.

BACKGROUND: Treatment of non-small lung cancer (NSCLC) has evolved in recent years, benefiting from advances in immunotherapy and targeted therapy. However, limited biomarkers exist to assist clinicians and patients in selecting the most effective, personalized treatment strategies. Targeted next-generation sequencing-based genomic profiling has become routine in cancer treatment and generated crucial clinicogenomic data over the last decade. This has made the development of mutational biomarkers for drug response possible. METHODS: To investigate the association between a patient's responses to a specific somatic mutation treatment, we analyzed the NSCLC GENIE BPC cohort, which includes 2,004 tumor samples from 1,846 patients. RESULTS: We identified somatic mutation signatures associated with response to immunotherapy and chemotherapy, including carboplatin-, cisplatin-, pemetrexed- or docetaxel-based chemotherapy. The prediction power of the chemotherapy-associated signature was significantly affected by epidermal growth factor receptor (EGFR) mutation status. Therefore, we developed an EGFR wild-type-specific mutation signature for chemotherapy selection. CONCLUSION: Our treatment-specific gene signatures will assist clinicians and patients in selecting from multiple treatment options.

Quality of systematic reviews with meta-analyses of resveratrol: A methodological systematic review.

Recently, several meta-analyses (MAs) have focused on the health effects of resveratrol. However, the methodological and reporting quality of these MAs has not yet been fully evaluated so far. Therefore, the present study evaluated the quality of these MAs through a methodological systematic review. Systematic searches were conducted in PubMed, Embase, Web of Science, and Cochrane Library from inception until May 20, 2022, and PubMed was used to update the search until September 6, 2023. The methodological and reporting quality of the selected MAs was evaluated using AMSTAR-2 and PRISMA 2009. Fifty-one MAs published during 2013-2023 were included. In each review, the number of primary studies ranged from 3 to 37, and the number of participants ranged from 50 to 2114. Among the first-listed primary outcomes, only 23 (45.10%) were "positive." As for the methodological quality, most MAs (44, 86.27%) on resveratrol were rated critically low. Inadequate reporting of the included MAs mainly involved items 2 ("Structured summary"), 5 ("Protocol and registration"), 8 ("Search"), 9 ("Study selection"), 10 ("Data collection process"), 12 ("Risk of bias in individual studies"), and 24 ("Summary of evidence") based on the PRISMA 2009. Additionally, journal's impact factor, number of authors, and funding support were positively associated with the overall methodological quality but were not statistically significant (p > 0.05). Future MAs on resveratrol require better design, implementation, and reporting by following the Cochrane Handbook, AMSTAR-2, and PRISMA.

[Economic evaluation of Annao Pills combined with antihypertensive drugs in treatment of primary hypertension: a study based on decision tree model].

The purpose of this study was to evaluate the economics of Annao Pills combined with antihypertensive drugs in the treatment of primary hypertension in the Chinese medical setting. TreeAge pro 2018 was used for cost-effect analysis and sensitivity analysis of the two treatment regimens. The intervention time of the simulation model was 2 weeks. The cost parameters were derived from Yaozhi.com, and the effect parameters were based on Meta-analysis of randomized controlled trial(RCT) involving Annao Pills. The experimental group was treated with Annao Pills combined with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets), and the control group was treated with anti-hypertensive drugs(nifedipine controlled-release tablets + losartan potassium tablets). The basic analysis showed that the incremental cost-effect ratio(ICER) of the two groups was 2 678.67 yuan, which was less than 7.26% of the per capita disposable income in 2022. That is, compared with anti-hypertensive drugs alone, Annao Pills combined with antihypertensive drugs cost 2 678.67 yuan more for each additional patient with primary hypertension. The results of sensitivity analysis verified the robustness of the basic analysis results. The probability sensitivity results showed that when the patient's personal willingness to pay the price was higher than 2 650 yuan, the probability of the regimen in the experimental group was higher, which was consistent with the results of the basic analysis. In conclusion, when the price was higher than 2 650 yuan, Annao Pills combined with anti-hypertensive drugs was more economical than anti-hypertensive drugs alone in terms of improving the response rate of the patients with primary hypertension.

[Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines].

Due to the lack of specialized guidance, the post-marketing research on clinical effectiveness of Chinese patent medicines demonstrates varied quality and lacks high-quality evidence, failing to meet the demands of policy-making, clinical decision-making, and industrial decision-making. To address this issue, this project gathered experts in clinical medicine, clinical pharmacy, evidence-based medicine, drug epidemiology, medical ethics, and policy and regulation in China. They referred to the model of international post-marketing research on medicines and developed Guidelines for post-marketing research on clinical effectiveness of Chinese patent medicines under the framework of relevant laws and regulations and technical guidance documents in China. The guidelines were developed with consideration to the characteristics of Chinese patent medicines, China's national conditions, and all the stakeholders including marketing authorization holders, clinical researchers, drug administration, and users. The development of the guidelines followed the requirements for developing group standards set by the China Association of Chinese Medicine. The guidelines fully implement the concept of full life-cycle research, emphasizing the combination of traditional Chinese medicine(TCM) theory, human use experience, and clinical trials and pay attention to the compliance, scientificity, and ethics of research. The guidelines clarify the topic selection and decision-making path of the post-marketing research on effectiveness of Chinese patent medicines through six steps: determining research purpose, analyzing drug characteristics, evaluating research basis, proposing clinical orientation, clarifying research purpose, and implementing classified research. The general principles of research design and implementation were clarified from eight aspects: research type, research objects, sample size, efficacy indicators, bias, missing data, evidence level, and practicality. It focuses on the research on the TCM syndrome-based efficacy evaluation, clinical value-oriented mechanism of action, and the effectiveness of Chinese patent medicines with different routes of administration. The guidelines provide a universal methodological basis for the post-marketing research on clinical effectiveness of Chinese patent medicines.

[Guidelines for economic evaluation of post-marketing Chinese patent medicine].

With the premise of drug safety and effectiveness, pharmacoeconomic evaluation can provide optimal solutions for diversified decision-making application scenarios from different research perspectives while maximizing the rational utilization of existing healthcare resources. Chinese patent medicine is an essential component of pharmaceutical utilization in China and a significant part of healthcare expenditure in China. However, the economic evaluation of post-marketing Chinese patent medicine is lacking. These evaluations often lack standardization, exhibit varying quality, and are unable to effectively support healthcare decisions, indicating a need for improvement in overall quality. Given this situation, this project has gathered leading experts from China and has strictly adhered to the requirements of the group standards set by the China Association of Traditional Chinese Medicine in developing Guidelines for economic evaluation of post-marketing Chinese patent medicine, aiming to provide methodological guidance for the post-market pharmacoeconomic evaluation of Chinese patent medicine, enhancing the standardization of pharmacoeconomic evaluations of Chinese patent medicine and the scientific validity of research results, and thereby elevating the overall quality of pharmacoeconomic evaluations for post-marketing Chinese patent medicine. The guidelines adhere to the framework provided by relevant laws and regulations in China and technical guidance documents. It is based on guidance from traditional Chinese medicine(TCM) theories, focusing on the unique characteristics of TCM. It covers various aspects of pharmacoeconomic evaluation, including fundamental principles, research topic selection, research question definition, study design type selection, cost identification and measurement, health outcomes, and evaluation methods. The guidelines offer methodological recommendations and decision guidance to address common issues and challenges in the pharmacoeconomic evaluation of post-marketing Chinese patent medicine.

HDAC Inhibitor SAHA Alleviates Pyroptosis by up-regulating miR-340 to Inhibit NEK7 Signaling in Subarachnoid Hemorrhage.

BACKGROUND: Subarachnoid hemorrhage (SAH) is a cerebral hemorrhagic disease with a high disability and fatality rate. Cell pyroptosis is involved in the brain injury following SAH. Here, we explored the effect of HDAC inhibitor SAHA against cell pyroptosis after SAH. METHODS: The rat SAH model was established by endovascular perforation and the rat microglia were treated with 25 µm oxyhemoglobin (OxyHb) for 24 h to mimic SAH model in vitro. Neurological score and brain edema were assessed in rat SAH model. TUNEL staining detected apoptosis. qRT-PCR and western blotting were employed to detect expression levels of miR-340, NEK7 and inflammatory cytokines. ELISA assay determined the secretion of IL-1ß and IL-18 in rat serum and cell supernatant. A lactate dehydrogenase (LDH) kit measured the LDH activity in rat primary microglia. Microglia pyroptosis was detected by flow cytometry. RIP and dual luciferase reporter assays confirmed the binding relationship between miR-340 and NEK7. RESULTS: SAHA alleviated neurological dysfunction, inflammatory injury and microglia pyroptosis in SAH rats. SAHA suppressed LDH release, inflammatory factor expression and pyroptosis in microglia treated with OxyHb. Meanwhile, SAHA increased miR-340 expression and inhibited NEK7 level in vivo and in vitro SAH models. Further, miR-340 directly targeted NEK7 to inhibit the NLRP3 signaling pathway. Knockdown of miR-340 or overexpression of NEK7 reversed the suppressive effects of SAHA on microglia inflammation and pyroptosis. Additionally, knockdown of NEK7 impaired microglia inflammation and pyroptosis induced by miR-340 inhibitor. CONCLUSION: HDAC inhibitor SAHA ameliorates microglia pyroptosis in SAH through triggering miR-340 expression to suppress NEK7 signaling. This novel mechanism provides promise for SAHA in SAH treatment.

Rational design of a turn-on near-infrared fluorescence probe for the highly sensitive and selective monitoring of carboxylesterase 2 in living systems.

In vivo selective fluorescence imaging of carboxylesterase 2 (CES2) remains a great challenge because existing fluorescence probes can potentially suffer from interference by other hydrolases. In addition, some fluorescent probes that have been separately reported for measuring CES2 activity in vitro are affected by autofluorescence and absorption of the biological matrix due to their limited emission wavelength or short Stokes shift. Herein, based on the substrate preference and catalytic performance of CES2, a novel and NIR fluorescent probe was developed, in which a hemi-cyanine dye ester derivative was used as the basic fluorescent group. In the presence of CES2, the probe was hydrolyzed to expose the fluorophore CZX-OH (λabs ∼ 675 nm, λem ∼ 850 nm), which led to a notable red-shift in the fluorescence (∼175 nm) spectrum. Confocal imaging of cells and live mice demonstrated that the fluorescent signal of this probe was related to the real activities of CES2 in cancer cells. All these results will powerfully promote the screening of CES2 regulators and the analysis of CES2-related physiological and pathological processes.

Sources of information on surgical options for patients undergoing antireflux surgery: a single-center questionnaire-based survey.

BACKGROUND: To explore the sources of information on antireflux surgery for patients undergoing this surgery in China. METHODS: Patients who underwent antireflux surgery in the Gastroesophageal Reflux Center of the Zhejiang Provincial People's Hospital from January 2016 to June 2021 were selected as survey subjects, and a questionnaire survey was conducted by telephone. RESULTS: A total of 358 questionnaires were distributed, and 320 valid questionnaires were recovered, yielding a 89.4% completion rate. Among patients' sources of information about antireflux surgery, the media was the primary source (33.8%) followed by recommendations from relatives or friends (27.8%), referrals from physicians (23.4%) and other sources (15.0%). Patients of different ages and educational levels have different sources for obtaining information about the procedure. Most of the information on surgery for patients aged 20 to 49 years was derived from recommendations from friends or relatives, whereas most of the information on surgery for patients aged 50 to 80 years was obtained from the media. Most of the information on surgery for patients with a primary school education or less was derived from physicians' recommendations, whereas most of the information for patients with a junior secondary school education or higher was obtained from the media. The recommendation of patients for surgery varied among the different departments (X2 = 36.011, p < 0.001), and a two-to-two comparison found that the recommended rates for cardiology and gastroenterology differed from the rates of other groups (p < 0.001, Table 2). CONCLUSIONS: The results of this investigation show that a large number of patients who underwent antireflux surgery learned about the operation through the media and recommendations from relatives or friends rather than physicians at the hospital. Notably, physicians specializing in GERD need to increase their knowledge of the disease and surgical treatment options to provide correct medical information to patients and to conduct media campaigns.

A study of simulation training in laparoscopic bilioenteric anastomosis on a 3D-printed dry lab model.

BACKGROUND: There are few studies on simulation training in laparoscopic bilioenteric anastomosis. There is also a lack of mature and reliable training models for bilioenteric anastomosis. In this study, we aimed to assess a feasible training model for bilioenteric anastomosis. Surgeons can improve their surgical ability by performing laparoscopic bilioenteric anastomosis on this model through repeated training. METHOD: The original articles related to simulation training in surgical anastomosis were identified from January 2000 to November 2021 in the Clarivate Analytics Web of Science Core Collection database. We conducted a bibliometric analysis based on the country of these publications and the type of anastomosis. A 3D-printed bilioenteric anastomosis model was applied in this study. Baseline data of 15 surgeons (5 surgeons of Attendings, 5 surgeons of Fellows, and 5 surgeons of Residents) were collected. The bilioenteric anastomosis data, including the operation time and operation score, were recorded and analyzed. A study of the learning curve was also performed for further assessment. RESULT: Surgeons at different levels of experience exhibited different levels of performance in conducting laparoscopic bilioenteric anastomosis on this model. Experienced surgeons completed their first training session in a shorter time and obtained a higher surgical score. In turn, repeated training significantly shortened the time of laparoscopic bilioenteric anastomosis for each trainer and improved the surgical score. Surgeons with different levels of experience needed different numbers of cases to reach the stable period of the learning curve. Experienced surgeons were able to reach a proficient level through fewer training cases. CONCLUSION: A suitable biliary-enteric anastomosis model can help surgeons conduct simulation training and provide experience and skill accumulation for future real operations. Our training model performed well in this study and can effectively accomplish this goal.

Development and evaluation of a portable and soft 3D-printed cast for laparoscopic choledochojejunostomy model in surgical training.

BACKGROUND: Laparoscopic choledochojejunostomy (LCJ) is an essential basic skill for biliary surgeons. Therefore, we established a convenient and effective LCJ 3D printing model to evaluate whether the model could simulate the actual operation situation and determine its effectiveness and validity in surgical training. METHODS: A 3D printing dry laboratory model was established to simulate LCJ. The face and content validity of the model were evaluated by six experienced biliary surgeons based on 5-point Likert scale questionnaires. A total of 15 surgeons with different levels of experience performed LCJ on the model and evaluated the structural validity of the model using the objective structured assessment of technical skills (OSATS). Simultaneously, the operation time of each surgery was also recorded. A study was also performed to further evaluate the learning curve of residents. RESULTS: The operating space score of the model was 4.83 ± 0.41 points. The impression score of bile duct and intestinal canal was 4.33 ± 0.52 and 4.17 ± 0.41 points, respectively. The tactile sensation score of bile duct suture and intestinal canal suture was 4.00 ± 0.63 and 3.83 ± 0.41points, respectively. The OSATS score for model operation in the attending group was 29.20 ± 0.45 points, which was significantly higher than that in the fellow group (26.80 ± 1.10, P = 0.007) and the resident group (19.80 ± 1.30, P < 0.001). In addition, there was a statistical difference in operation time among surgeons of different experience levels (P < 0.05). Residents could significantly improve the surgical score and shorten the time of LCJ through repeated training. CONCLUSIONS: The 3D printing LCJ model can simulate the real operation scenes and distinguish surgeons with different levels of experience. The model is expected to be one of the training methods for biliary tract surgery in the future.

Efficacy and safety of berberine for premature ventricular contractions: a meta-analysis and systematic review of randomized controlled trials.

CONTEXT: Berberine is a potential drug that can effectively treat cardiovascular diseases, including premature ventricular contractions (PVCs). OBJECTIVE: This study was conducted to assess the efficacy and safety of berberine for PVCs. METHODS: The literature was searched using PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang, and Chinese Biomedical Literature Database (CBM) for randomized controlled trials (RCTs) from inception to October 1, 2022. The risk of bias was assessed using the Revised Cochrane risk-of-bias tool for randomized trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to assess the quality of evidence. RESULTS: Ten RCTs with 896 participants were included in the meta-analysis. The results showed that compared to antiarrhythmic drugs (AD), berberine (BE) combined with AD had a higher effective rate (RR = 1.26; 95% CI:1.12, 1.42; p = 0.0001) with no significant incidence of adverse reactions (RR = 0.93; 95% CI:0.33, 2.57; p = 0.88), and BE alone had no significant difference in effective rate (RR = 0.91; 95% CI:0.77, 1.07; p = 0.23), and a lower incidence of adverse reactions (RR = 0.38; 95% CI:0.15, 0.97; p = 0.04) and recurrence rate (RR = 0.40; 95% CI:0.18, 0.88; p = 0.02). CONCLUSIONS: The results suggest that BE is an effective and safe adjunctive method for PVCs. In addition, BE is recommended for patients with PVCs who had severe adverse reactions after administrating AD as an alternative therapy.

[Clinical comprehensive evaluation of Xiangju Capsules in treatment of rhinosinusitis].

The articles involving Xiangju Capsules were retrieved, and qualitative research and quantitative research methods were combined to evaluate the evidence of the safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine( "6+1" dimensions) of this drug. Multi-criteria decision analysis(MCDA) model and CSC v2.0 software were used to comprehensively evaluate the clinical value of Xiangju Capsules in the treatment of rhinosinusitis and clarify the precise clinical positioning. The dimensions are graded A, B, C, or D. Multi-source safety evidence showed that the main adverse reactions were gastrointestinal reactions, rash, itching, dizziness, and headache. Based on the available studies, the risk is controllable and the safety is grade A. Meta-analysis showed that Xiangju Capsules + conventional western medicine could recover the Lund-Kennedy score, Lund-Mackay score, and CT score, relieve headache, nasal congestion, olfactory disturbance, and facial pain, with the effectiveness is grade B. The incremental cost-effectiveness ratio of Xiangju Capsules + conventional western medicine compared with conventional western medicine alone in the treatment of chronic rhinosinusitis was 263.71 yuan, about 0.82% of the per capita disposable income. The results of sensitivity analysis showed that the research results were relatively robust. Based on the assumption that the per capita disposable income in 2020 will be the threshold of patients' willingness to pay, it is more economical to use Xiangju Capsules + conventional western medicine. The drug belongs to grade A of the national medical insurance, with an average daily cost of 3.06 yuan, and the economy is grade B. This formula is modified from classic formulas and characteristic empirical formulas, be capable of improving immunity and preventing repeated attacks. It can be used for acute and chronic rhinitis-rhinosinusitis. It had a wide range of applicability, especially for the patients with head and face tenderness. Service innovation was reflected in the measures to guarantee supply, capacity, scalability, and coverage of grass-roots sales channels. The industrial innovation was improved through the management of medicinal resources, pharmaceutical industry, production technology, quality control, scientific research and development, and this formula won three national invention patents. Comprehensively, the innovation of Xiangju Capsules is grade B. According to the survey of 188 medical practitioners and 196 patients in 20 provinces, municipalities, and autonomous regions of China, the drug was characterized by easy preparation and administration, individualized medication, simple technology and management, convenient use, storage, and transport, and controllable adverse reactions, with the suitability is grade B. Xiangju Capsules showed the cost of 45.9 and 275.4 yuan for treatment of acute and chronic rhinitis-rhinosinusitis, respectively, being well affordable. It was sold in 35 000 medical institutions in China. The dosage form was suitable for transportation, storage, and grass-root application. With rich, sustainable, and available medicinal resources, the accessibility of Xiangju Capsules is grade A. This drug can be used for both acute and chronic rhinitis-rhinosinusitis, clearing heat and expelling pus, and strengthening the exterior to prevent relapse. After this drug was available on the market, over 4 000 cases were studied, with rich experience in human use accumulated, and characteristics of traditional Chinese medicine is grade B. Overall, the clinical value of Xiangju Capsules is class B. It is suggested that Xiangju Capsules should be used in accordance with the relevant policies of basic clinical drug administration to play its role.

The Notch signalling pathway and miRNA regulation play important roles in the differentiation of Schwann cells from adipose-derived stem cells.

An exploration of the underlying mechanisms is necessary to improve nerve myelin-forming cell Schwann cell (SC) differentiation from adipose-derived stem cells (ADSCs). Primary rat ADSCs were isolated and characterised for cell surface markers using flow cytometry analysis. After treatment with a mixture of glial growth factors, ADSCs were induced to differentiate and subsequently identified by immunofluorescence staining and western blotting. A miRNA microarray analysis was performed to explore the genes and signalling pathways regulating ADSC differentiation into SCs. ELISAs were conducted to measure the expression of neurotrophic factors and changes in the level of nerve cell adhesion factor. Dual luciferase reporter assays and RIP assays were performed to explore the potential mechanism of miR-21-5p in ADSC differentiation. The isolated ADSCs were positive for CD29 and CD44 but negative for CD49. After induction with specific cytokines, the differentiated ADSCs presented a spindle-like morphology similar to SCs and expressed S100. RNA-sequencing analyses revealed that 9821 mRNAs of protein-coding genes and 175 miRNAs were differentially expressed in differentiated SC-like cells compared to primary cultures of ADSCs. KEGG and Gene Ontology analyses revealed that the involvement of the Notch signalling pathway and miRNA negative regulation may be associated with the differentiation of ADSCs into SCs. Treatment with a Notch inhibitor promoted the differentiation of ADSCs. Furthermore, mechanistic studies showed that Jag1 bound to miR-21-5p and upregulated its target gene Jag1, thus affecting ADSC differentiation. These results revealed the mechanism underlying the important roles of miRNAs and the Notch signalling pathway in the differentiation of SCs from ADSCs, enabling potential therapeutic applications of ADSCs in peripheral nerve regeneration in the future.