The first selective VAP-1 inhibitor in China, TT-01025-CL: safety, tolerability, pharmacokinetics, and pharmacodynamics of single- and multiple-ascending doses.

Introduction: TT-01025-CL is an oral, irreversible small molecule that potently inhibits vascular adhesion protein-1 (VAP-1) for the treatment of inflammation associated with non-alcoholic steatohepatitis (NASH). The objectives of this study were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of TT-01025-CL, a VAP-1 inhibitor, in healthy Chinese volunteers. Methods: Double-blind, placebo-controlled, dose-escalation studies were conducted in subjects randomized to receive oral once-daily TT-01025-CL (ranges: 10-300 mg [single dose]; 20-100 mg for 7 days [multiple doses]) or placebo under fasting conditions. Safety and tolerability were monitored throughout the study. Pharmacokinetic (PK) parameters were determined using non-compartment analysis. The activity of semicarbazide-sensitive amine oxidase (SSAO)-specific amine oxidase and the accumulation of methylamine in plasma were evaluated as pharmacodynamic (PD) biomarkers. Results: A total of 36 (single-dose group) and 24 (multiple-dose group) subjects were enrolled in the study. No serious adverse events (AEs) were reported, and no subject discontinued due to an AE. All treatment-emergent adverse events (TEAEs) were mild and moderate in intensity. No dose-dependent increase in the intensity or frequency of events was observed. TT-01025-CL was rapidly absorbed after administration. In the single-ascending dose (SAD) study, median Tmax ranged from 0.5 to 2 h and mean t1/2z ranged from 2.09 to 4.39 h. PK was linear in the range of 100-300 mg. The mean Emax of methylamine ranged from 19.167 to 124.970 ng/mL, with mean TEmax ranging from 13.5 to 28.0 h. The complete inhibition (>90%) of SSAO activity was observed at 0.25-0.5 h post-dose and was maintained 48-168 h post-dose. In the multiple-ascending dose (MAD) study, a steady state was reached by day 5 in the 40 mg and 100 mg dose groups. Negligible accumulation was observed after repeated dosing. PK was linear in the range of 20-100 mg. Plasma methylamine appeared to plateau at doses of 20 mg and above, with mean Emax ranging from 124.142 to 156.070 ng/mL and mean TEmax ranging from 14.2 to 22.0 h on day 7. SSAO activity in plasma was persistently inhibited throughout the treatment period. No evident change in methylamine and SSAO activity was observed in the placebo groups. Conclusion: TT-01025-CL was safe and well-tolerated at a single dose of up to 300 mg and multiple doses of up to 100 mg once daily for 7 consecutive days. Absorption and elimination occurred rapidly in healthy volunteers. Linearity in plasma exposure was observed. TT-01025-CL inhibited SSAO activity rapidly and persistently in humans. The profile of TT-01025-CL demonstrates its suitability for further clinical development.

Long-term Follow-up of photodynamic therapy of cervical intraepithelial neoplasia grade 2 (CIN2).

BACKGROUND: To determine the long-term efficacy and safety of 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) for treating cervical intraepithelial neoplasia grade 2 (CIN2) as well as the suitability of ALA-PDT in treating of cervical lesions divided into cervical transformation zone type 3. METHODS: We included 81 patients diagnosed with CIN2 at the Department of Gynecology of the Affiliated Hospital of Qingdao University with data collected between January 2019 and January 2021 following ALA-PDT. Furthermore, we analyzed the superiority of ALA-PDT in fertility preservation among women of childbearing age based on follow-up data from 11 patients with fertility requirements. RESULTS: Our findings confirmed the long-term efficacy of ALA-PDT for CIN2 treatment, with an overall efficacy of 95.83% (23/24) at follow-up of 25-36 months. Moreover, the cervical transformation zone type 3 improvement and human papillomavirus (HPV)-negative efficacy were 69.2% (18/26) and 82.4% (14/17), respectively. ALA-PDT is recommended for consenting patients with cervical transformation zone type 3. Additionally, women without primary infertility could experience natural pregnancy and full-term birth of more than one baby following ALA-PDT for CIN2 treatment, with a satisfaction rate of ≈100%. CONCLUSIONS: ALA-PDT is recommendable for treating high-grade squamous intraepithelial lesions, especially in patients with fertility requirements.

Shexiang tongxin dropping pill alleviates myocardial injury induced by coronary microembolization by down-regulating APOC1 to inhibit STAT3 signaling pathway.

AIM: This study determines to validate the mechanism of Shexiang Tongxin dropping pill (STDP) in attenuating coronary microembolization (CME) induced myocardial injury. METHODS: CME rat models were established and underwent corresponding treating. Gene chip analysis was performed in rat myocardial tissues for GO and KEGG enrichment analysis. The differentially expressed genes were detected by qRT-PCR. H&E staining and ELISA were used for pathological analysis and detection of troponin (cTnI) and Creatine Kinase Isoenzyme (CK-MB). Lipopolysaccharide (LPS) treated primary cardiomyocytes were used to mimic inflammatory in vitro models. Cell viability and apoptosis of cardiomyocytes were determined by MTT and flow cytometry. The expressions of inflammatory cytokines, apoptotic proteins and proteins related to the STAT3 signal pathway were detected by western blot. APOC1 mRNA expression was detected by qRT-PCR. Immunofluorescence (IF) was used for subcellular localization of p-STAT3 and the binding of APOC1 with STAT3 was verified using Co-IP. RESULTS: STDP can attenuate myocardial injury in CME rat models, and lead to decreased expression of APOC1 and suppressed STAT3 signal pathway. In vitro models found STDP can suppress the cell viability and cell apoptosis of primary cardiomyocytes, in addition to suppressing the secretions of IL-6, IL-1ß and TNF-α, while the protective effect of STDP can be reversed by overexpression of APOC1. Co-IP found that APOC1 can bind STAT3 directly. APOC1 can increase p-STAT3 expression in the nucleus to activate the STAT3 signal pathway. CONCLUSIONS: STDP can suppress APOC1 and STAT3 signal pathway to inhibit inflammation and cell apoptosis of cardiomyocytes. APOC1 may be one of the key regulatory factors in CME-induced myocardial injury.

TRIM27-Induced Protective Autophagy: A Novel Therapeutic Approach for Pneumonia.

BACKGROUND: Pneumonia is a prevalent respiratory ailment involving complex physiological and pathological mechanisms. The tripartite motif containing 27 (TRIM27) plays a crucial role in regulating inflammation mechanisms. Therefore, the purpose of this study is to further explore the therapeutic potential of TRIM27 in pneumonia, based on its regulatory mechanisms in inflammation and autophagy. METHODS: This study established a mouse pneumonia animal model through lipopolysaccharide (LPS) administration, designating it as the LPS model group. Subsequently, adenovirus-mediated TRIM27 overexpression was implemented in the animals of the LPS model group, creating the TRIM27 treatment group. After a 7-day treatment period, lung tissues from the mice were collected. Various techniques, including immunohistochemistry, quantitative reverse transcription PCR (RT-qPCR), western blot, enzyme-linked immunosorbent assay (ELISA), and electron microscopy were utilized to analyze the impact of TRIM27 overexpression on inflammatory factors, oxidative stress, autophagy, and inflammatory processes in pulmonary tissues. Finally, an in vitro LPS cell model was established, and the effects of TRIM27 overexpression and autophagy inhibition on inflammatory cytokines and autophagosomes in LPS-induced inflammatory cells were examined through RT-qPCR and immunofluorescence techniques. RESULTS: The research findings demonstrate a significant reduction in the elevated levels of interleukin-6 (IL-6), IL-1ß, and Tumor necrosis factor-alpha (TNF-α) induced by LPS with TRIM27 overexpression (p < 0.01). Conversely, the autophagy inhibitor 3-Methyladenine (3-MA) diminished the effects induced by TRIM27 overexpression. Moreover, TRIM27 overexpression enhanced the expression of Microtubule-associated protein 1A/1B light chain 3 (LC3) II/I and Beclin-1 proteins in mice subjected to LPS stimulation (p < 0.01), while reducing the expression of the p62 protein (p < 0.01). The addition of 3-MA, however, decreased Beclin-1 expression and inhibited autophagy (p < 0.01). Additionally, TRIM27 overexpression decreased the expression of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), cleaved caspase-1, IL-1ß, and Gasdermin D N-terminal fragment (GSDMD-N) proteins in LPS-stimulated mice (p < 0.05). TRIM27 overexpression also decreased the levels of malondialdehyde (MDA), Activating Transcription Factor 6 (ATF6), and C/EBP-homologous protein (CHOP), while increasing the levels of superoxide dismutase (SOD) and glutathione (GSH) in mice exposed to LPS (p < 0.01). CONCLUSION: The induction of TRIM27 overexpression emerges as a potential and effective pneumonia treatment. The underlying mechanism may involve inducing protective autophagy, thereby reducing oxidative stress and cell pyroptosis.

The effect of food on the pharmacokinetics of Sutetinib maleate capsule, an irreversible EGFR tyrosine kinase inhibitor, in healthy Chinese subjects.

Sutetinib is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and showed favorable efficacy and safety in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring nondrug-resistant rare EGFR mutations. To evaluate the potential food effect, eighteen healthy Chinese subjects were enrolled in a single-centre, randomized, open-label, two-sequence, two-period crossover study. Sutetinib was administered as a single oral 100 mg under fasting or fed conditions, and pharmacokinetic sampling was performed following each dose and analysed by a validated liquid chromatography/mass spectrometry method. Safety and tolerability were also evaluated. Food intake slightly decreased maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUC0 - inf) of sutetinib (geometric least-squares mean [GLSM] ratio, 80.94% and 86.11%; 90% confidence interval [CI], 68.43-95.72 and 75.88-97.73) and its active metabolite sutetinib N-Oxide (GLSM ratio, 75.58% and 84.00%; 90% CI, 65.69-86.95 and 75.42-93.56), respectively. In addition, the time to maximum plasma concentration (Tmax) of both sutetinib and its metabolite has been prolonged by 2 h under fed conditions. A total of 31 adverse events (AEs) occurred during the study, with no serious adverse events (SAE) reported, and no obvious difference was observed between the fasting and fed groups. Our results demonstrated that a high-fat and high-calorie diet caused a significant delay in drug absorption and a marginal reduction in drug exposure. Sutetinib was generally well tolerated in healthy Chinese subjects. (This trial was registered at http://www.chinadrugtrials.org.cn . The registration No. is CTR20201933, and the date of registration is 2020-10-16).

YAP1/TAZ Mediates Rumen Epithelial Cell Proliferation but Not Short-Chain Fatty Acid Metabolism In Vitro.

Promoting rumen development is closely related to the health and efficient growth of ruminants. The transcriptional co-activators Yes1-associated protein (YAP1) and WW domain-containing transcription regulator protein 1 (TAZ) are key regulators of the mammalian epithelium. In the present study, we assessed the impact of YAP1/TAZ on rumen epithelial (RE) cell proliferation using their activator GA-017 (GA) and inhibitor verteporfin (VP). We also investigated whether YAP1/TAZ-dependent alteration was involved in the RE developmental process induced by sodium butyrate (SB). The results indicated that GA promoted RE cell proliferation, while VP disrupted RE cell proliferation. The Hippo, Wnt, and calcium signaling pathways were altered following the regulation of YAP1/TAZ. Upon YAP1/TAZ activation, the expression of CCN1/2 increased. However, when YAP1/TAZ was inhibited, the expression of BIRC3 decreased. In the SB-treated cells, YAP1/TAZ-induced changes were not observed. SB increased the expressions of differentiated cell marker genes and genes involved in short-chain fatty acid (SCFA) metabolism, while YAP1/TAZ did not. Thus, YAP1/TAZ could be potential targets for regulating RE cell proliferation but not for SCFA metabolism. SB could not affect YAP1/TAZ. These findings broaden our understanding of the role of YAP1/TAZ and their regulators in RE development.

Microbiological impact of long-term wine grape cultivation on soil organic carbon in desert ecosystems: a study on rhizosphere and bulk sandy soils.

The improvement of nutrients in soil is essential for using deserts and decertified ecosystems and promoting sustainable agriculture. Grapevines are suitable crops for desert soils as they can adapt to harsh environments and effectively impact soil nutrients; however, the mechanisms underlying this remain unclear. This study explored the impact of the different duration(3, 6, and 10 years) of grape cultivation on soil organic carbon, physicochemical properties, enzyme activities, microbial communities, and carbon cycle pathways in both rhizosphere and bulk soils. Partial least squares path modeling was used to further reveal how these factors contributed to soil nutrient improvement. Our findings indicate that after long-term grape cultivation six years, soil organic carbon, total nitrogen, total phosphorus, microbial biomass carbon and nitrogen, and enzyme activities has significantly increased in both rhizosphere and bulk soils but microbial diversity decreased in bulk soil. According to the microbial community assembly analysis, we found that stochastic processes, particularly homogenizing dispersal, were dominant in both soils. Bacteria are more sensitive to environmental changes than fungi. In the bulk soil, long-term grape cultivation leads to a reduction in ecological niches and an increase in salinity, resulting in a decrease in soil microbial diversity. Soil enzymes play an important role in increasing soil organic matter in bulk soil by decomposing plant litters, while fungi play an important role in increasing soil organic matter in the rhizosphere, possibly by decomposing fine roots and producing mycelia. Our findings enhance understanding of the mechanisms of soil organic carbon improvement under long-term grape cultivation and suggest that grapes are suitable crops for restoring desert ecosystems.

MoOx Synaptic Memristor with Programmable Multilevel Conductance for Reliable Neuromorphic Hardware.

Memristor holds great potential for enabling next-generation neuromorphic computing hardware. Controlling the interfacial characteristics of the device is critical for seamlessly integrating and replicating the synaptic dynamic behaviors; however, it is commonly overlooked. Herein, we report the straightforward oxidation of a Mo electrode in air to design MoOx memristors that exhibit nonvolatile ultrafast switching (0.6-0.8 mV/decade, <1 mV/decade) with a high on/off ratio (>104), a long durability (>104 s), a low power consumption (17.9 µW), excellent device-to-device uniformity, ingeniously synaptic behavior, and finely programmable multilevel analog switching. The analyzed physical mechanism of the observed resistive switching behavior might be the conductive filaments formed by the oxygen vacancies. Intriguingly, upon organization into memristor-based crossbar arrays, in addition to simulated multipattern memorization, edge detection on random images can be implemented well by parallel processing of pixels using a 3 × 3 × 2 array of Prewitt filter groups. These are vital functions for neural system hardware in efficient in-memory computing neural systems with massive parallelism beyond a von Neumann architecture.

Effect of repetitive transcranial magnetic stimulation-assisted training on lower limb motor function in children with hemiplegic cerebral palsy.

OBJECTIVE: To explore the effect of repetitive transcranial magnetic stimulation (rTMS)-assisted training on lower limb motor function in children with hemiplegic cerebral palsy (HCP). METHOD: Thirty-one children with HCP who met the inclusion criteria were selected and randomly divided into a control group (n = 16) and an experimental group (n = 15). The control group received routine rehabilitation treatment for 30 min each time, twice a day, 5 days a week for 4 weeks. Based on the control group, the experimental group received rTMS for 20 min each time, once a day, 5 days a week for 4 weeks. The outcome measures included a 10-metre walk test (10MWT), a 6-minute walk distance (6MWD) test, D- and E-zone gross motor function measurements (GMFM), the symmetry ratio of the step length and stance time and the muscle tone of the triceps surae and the hamstrings (evaluated according to the modified Ashworth scale), which were obtained in both groups of children before and after treatment. RESULTS: After training, the 10MWT (P < 0.05), 6MWD (P < 0.01), GMFM (P < 0.001) and the symmetry ratio of the step length and stance time of the two groups were significantly improved (P < 0.05), there was more of an improvement in the experimental group compared with the control group. There was no significant change in the muscle tone of the hamstrings between the two groups before and after treatment (P > 0.05). After treatment, the muscle tone of the triceps surae in the experimental group was significantly reduced (P < 0.05), but there was no significant change in the control group (P > 0.05). CONCLUSION: Repetitive TMS-assisted training can improve lower limb motor function in children with HCP.

Efficacy and safety of stapokibart (CM310) in uncontrolled seasonal allergic rhinitis (MERAK): an investigator-initiated, placebo-controlled, randomised, double-blind, phase 2 trial.

Background: There is no trial to assess the benefits of periodically using biologics during the pollen season in patients with uncontrolled seasonal allergic rhinitis (SAR), who have moderate-to-severe symptoms even after standard-of-care. This trial aimed to evaluate the efficacy and safety of the add-on administration of stapokibart, a humanised monoclonal antibody that targets interleukin-4 receptor alpha, in patients with uncontrolled SAR. Methods: In this investigator-initiated, randomised, double-blind, placebo-controlled trial, eligible patients received either stapokibart 600-300 mg weekly (QW), every 2 weeks (Q2W), or placebo QW for 4 weeks. All patients were given mometasone furoate nasal spray and loratadine throughout the trial. The primary endpoint was the mean change from baseline in daily reflective total nasal symptom score (rTNSS) during 2-week treatment. Secondary efficacy outcomes included: the mean change from baseline in daily rTNSS during 4-week treatment; the mean changes and the mean percentage changes from baseline during 2-week and 4-week treatment in 1) daily rTNSS and reflective total ocular symptom score (rTOSS), 2) morning (AM)/evening (PM) rTNSS and rTOSS, 3) AM instantaneous total nasal symptom score (iTNSS) and instantaneous total ocular symptom score (iTOSS), 4) individual nasal and ocular symptoms; the change from baseline in Rhinoconjunctivitis Quality of-Life Questionnaire score during 4-week treatment. Exploratory endpoints included the change of prespecified markers related to type 2 inflammation pre- and post-treatment. Safety, immunogenicity, and pharmacokinetics were also evaluated. This study is registered with www.clinicaltrials.gov (NCT05470647). Findings: Between August 17, 2022, and December 28, 2022, 92 patients with uncontrolled SAR were enrolled from 4 centres in China and randomly assigned to receive stapokibart 600-300 mg QW (n = 31), stapokibart 600-300 mg Q2W (n = 30), or placebo QW (n = 31), of whom 86 (93%) completed the study. Both stapokibart Q2W and QW did not significantly improve mean change from baseline in daily rTNSS compared with placebo in 2 weeks. The least-squares (LS) mean differences (97.5% confidence interval [CI]) compared with placebo were -1.0 (-2.3, 0.2) in stapokibart Q2W group (p = 0.065) and -0.2 (-1.5, 1.0) in stapokibart QW group (p = 0.67). For the secondary outcomes, compared with placebo, stapokibart Q2W presented significant improvements in the mean percentage change from baseline in daily rTNSS in 2 weeks (LS mean difference -12.9%, 95% CI -25.3%, -0.4%, p = 0.043), as well as AM iTNSS over 2 weeks (LS mean difference -17.4%, 95% CI -31.0%, -3.8%, p = 0.013) and 4 weeks (LS mean difference -15.4%, 95% CI -29.0%, -1.9%, p = 0.026). Additionally, the nasal congestion score was significantly lower in stapokibart Q2W than placebo during 2-week (LS mean difference -0.4, 95% CI -0.7, -0.1, p = 0.014) and 4-week (LS mean difference -0.4, 95% CI -0.7, -0.04, p = 0.028) treatment. Treatment-emergent adverse events (TEAEs) occurred in 48% (15/31), 33% (10/30), and 61% (19/31) of patients receiving stapokibart QW, Q2W, and placebo, respectively. Most reported TEAEs were sinus bradycardia, hyperlipidaemia, and blood uric acid increased. Interpretation: In this phase 2 trial, both stapokibart regimens had an acceptable safety and tolerability profile but did not significantly improve daily rTNSS in patients with uncontrolled SAR. The efficacy of stapokibart in patients with uncontrolled SAR is being further investigated in ongoing phase 3 trials (clinicaltrials.gov, NCT05908032). Funding: Ministry of Science and Technology of the People's Republic of China; Ministry of Education of the People's Republic of China; National Natural Science Foundation of China; Chinese Academy of Medical Sciences.

Quantum heat valve and diode of strongly coupled defects in amorphous material.

The mechanical strain can control the frequency of two-level atoms in amorphous material. In this work, we would like to employ two coupled two-level atoms to manipulate the magnitude and direction of heat transport by controlling mechanical strain to realize the function of a thermal switch and valve. It is found that a high-performance heat diode can be realized in the wide piezo voltage range at different temperatures. We also discuss the dependence of the rectification factor on temperatures and couplings of heat reservoirs. We find that the higher temperature differences correspond to the larger rectification effect. The asymmetry system-reservoir coupling strength can enhance the magnitude of heat transfer, and the impact of asymmetric and symmetric coupling strength on the performance of the heat diode is complementary. It may provide an efficient way to modulate and control heat transport's magnitude and flow preference. This work may give insight into designing and tuning quantum heat machines.

Understanding community-dwelling older adults' preferences for home- and community-based services: A conjoint analysis.

BACKGROUND: Older adults' preference for home- and community-based service programs has been highlighted as an essential but usually ignored ingredient in current care models. Disentangling how preferences contribute to older adults' decision-making could facilitate finding optimal ways to deliver home- and community-based services in times of increasing scarcity. OBJECTIVE: To identify Chinese community-dwelling older adults' preference structure for home- and community-based services and thus to optimize service provision. METHODS: Conjoint analysis, a preference-based technique, was employed to study older adults' preferences. A stepwise qualitative approach was first adopted to identify the attributes and attribute levels of home- and community-based services. Scenarios were defined through an orthogonal fractional factorial design, and a cross-sectional survey was conducted through a face-to-face, anonymous questionnaire. Conjoint analysis was performed to determine preference weights representing the relative importance of the identified attributes, and cluster analysis was performed to identify clusters of participants with similar preference structures. All data analyses were performed using SAS v9.4 and SPSS 22.0. RESULTS: A total of 321 of 350 invited participants completed the questionnaire. Four attributes were identified and used to create the conjoint scenarios: care-giving attitude, price, technical care-giving skills, and the type of service provider. Care-giving attitude was the most valued attribute for older adults when making decisions (relative importance score = 48.28), followed by price (relative importance score = 21.618), technical care-giving skills (relative importance score = 19.518), and finally, the type of service provider (relative importance score = 10.585). Three preference phenotypes were identified by applying cluster analysis: "price-oriented", "comprehensively balanced", and "attitude-oriented". CONCLUSION: The present study underscored the importance of considering attributes valued by Chinese older adults in the design and delivery of home- and community-based services. The preference structure, including the utility score of the attribute levels, differs among older adults. The findings could inform future research and practice and suggest incorporating flexibility during the service delivery stage.

The improvement effects of Lentinus edodes powder marination on sous vide cooked chicken patties: Physicochemical attributes, oxidative properties and flavor characteristics.

The improvement effects of Lentinus edodes powder (LEP) marination with different concentrations (0, 6-14 %) on physicochemical, oxidative and flavor quality of chicken patties were evaluated. Greater pH, redness, yellowness, water holding capacity and their strong correlations were observed in LEP-marinated samples. Changed water distribution, inhibited lipid oxidation and enhanced protein oxidation occurred through LEP marination. The highest gel strength and resilience and the lowest hardness and chewiness were obtained in 10 % LEP-marinated sample. Meanwhile, taste activity values of amino acids and saltiness peaked and umami rose in this sample. 124 volatiles were detected and 16 compounds were simultaneously detected by gas chromatography-ion mobility spectrometry and gas chromatography-mass spectrometry. Hexanal, 1,2,4-trithiolane and 1-hexanol were considered as the key differential aroma-active compounds according to odor activity values and chemometric analysis. This study confirmed LEP as a prospective ingredient to improve the quality of meat products.

Contamination and health risk of pesticides in eight popular Chinese traditional medicines from Zhejiang Province.

Zhejiang Province is one of the top five major provinces producing traditional Chinese medicines (TCMs) and is famous for Zhebawei (in Chinese), the eight popular geo-authentic TCMs including Rhizoma Atractylodis Macrocephalae, Radix Paeoniae Alba, Thunberg Fritillary Bulb, Chrysanthemum morifolium, Corydalis yanhusuo W. T. Wang, Scrophulariae Radix, Ophiopogonis Radix, and Curcuma Wenyujin Y. H. Chen et C. Ling. High proportion application and residue of pesticides directly affect the quality and yield of TCMs. In this study, pesticides residual levels in crude and processing samples were assessed along with their health risks in Zhebawei primarily produced in Zhejiang Province. In total, the exceeded ratios of pesticides residual concentrations in above mentioned eight species were 15/23, 4/7, 26/70, 22/44, 10/19, 8/12, 7/15, and 0/2, respectively. No acute dietary intake health risks were found but the long-term risks from permethrin in S. Radix should be carefully considered, with all quotient values being higher than 2.1 for all groups between 7 and 70 years. Furthermore, the risks of total benzene hexachloride in T. Fritillary Bulb and carbendazim in C. morifolium should be closely monitored. Suggestions for the cultivation and pesticide management of herbal medicines have been proposed to promote the quality of medicinal materials.

Dexmedetomidine Prevents Chronic Incisional Pain After Brain Tumor Resection: A Secondary Analysis of the Randomized Control Trial.

BACKGROUND: Dexmedetomidine was reported to reduce postoperative acute pain after neurosurgery. However, the efficacy of dexmedetomidine for preventing chronic incisional pain is uncertain. METHODS: This article is a secondary analysis of a randomized, double-blind, placebo-controlled trial. Eligible patients were randomly allocated to either the dexmedetomidine group or the placebo group. Patients assigned to the dexmedetomidine group were given a 0.6 µg kg -1 dexmedetomidine bolus followed by a 0.4 µg kg -1 h -1 maintenance dose until dural closure; placebo patients were given comparable amounts of normal saline. The primary end point was the incidence of incisional pain at 3 months after craniotomy evaluated by numerical rating scale scores and defined as any score >0. The secondary end points were postoperative acute pain scores, sleep quality, and Short-Form McGill Pain Questionnaire (SF-MPQ-2) at 3 months after craniotomy. RESULTS: From January 2021 to December 2021, a total of 252 patients were included in the final analysis: the dexmedetomidine group (n = 128) and the placebo group (n = 124). The incidence of chronic incisional pain was 23.4% (30 of 128) in the dexmedetomidine group versus 42.7% (53 of 124) in the placebo group (risk ratio, 0.55; 95% confidence interval, 0.38-0.80; P = .001). The overall severity of chronic incisional pain was mild in both groups. Patients in the dexmedetomidine group had lower acute pain severity on movement than those in the placebo group for the first 3 days after surgery (all adjusted P < .01). Sleep quality did not differ between groups. However, the SF-MPQ-2 total sensory ( P = .01) and neuropathic pain descriptor ( P = .023) scores in the dexmedetomidine group were lower than those in the placebo group. CONCLUSIONS: Prophylactic intraoperative dexmedetomidine infusion reduces the incidence of chronic incisional pain as well as acute pain score after elective brain tumor resections.

Resveratrol Inhibits Zinc Deficiency-Induced Mitophagy and Exerts Cardiac Cytoprotective Effects.

Resveratrol (Res) possesses various beneficial effects, including cardioprotective, anti-inflammatory, anti-aging, and antioxidant properties. However, the precise mechanism underlying these effects remains unclear. Here we investigated the protective effects of resveratrol on cardiomyocytes, focusing on the role of Zn2+ and mitophagy. Using the MTT/lactate dehydrogenase assay, we found that addition of a zinc chelator TPEN for 4 h induced mitophagy and resulted in a significant reduction in cell viability, increased cytotoxicity, and apoptosis in H9c2 cells. Notably, resveratrol effectively mitigated these detrimental effects caused by TPEN. Similarly, Res inhibited the TPEN-induced expression of mitophagy-associated proteins, namely P62, LC3, NIX, TOM20, PINK1, and Parkin. The inhibitory action of resveratrol on mitophagy was abrogated by the mitophagy inhibitor 3-MA. Additionally, we discovered that silencing of the Mfn2 gene could reverse the inhibitory effects of resveratrol on mitophagy via the AMPK-Mfn2 axis, thereby preventing the opening of the mitochondrial permeability transition pore (mPTP). Collectively, our data suggest that Res can safeguard mitochondria protection by impeding mitophagy and averting mPTP opening through the AMPK-Mfn2 axis in myocardial cells.

Pharmacokinetic and Bioequivalence Evaluation of Single-Tablet and Separate-Tablet Regimens for Ainuovirine, Lamivudine, and Tenofovir Disoproxil Fumarate in Chinese Healthy Subjects.

This was a single-dose, randomized, open-label, 2-period crossover study to evaluate the bioequivalence of the ACC008 (test formulation [T]) versus coadministered ainuovirine (ANV) 150 mg, lamivudine (3TC) 300 mg, and tenofovir disoproxil fumarate 300 mg (reference formulation [R]) in the fasted state among the Chinese healthy adults. Eligible subjects were randomized into 2 cohorts to received treatment in 1 of 2 sequences (T â†’ R, R â†’ T). PK samples were collected from 1 hour before dosing to 144 hours after dosing in each period. The concentrations of ANV, 3TC, and tenofovir in plasma were determined by liquid chromatography-tandem mass spectrometry. Phoenix WinNonlin software was used for pharmacokinetic parameter calculation and bioequivalence evaluation. All the 90% confidence intervals of maximum concentration, area under the concentration-time curve from time zero to the last detectable time, and area under the concentration-time curve from time zero to infinity fell within the bioequivalence range. The safety was comparable between the 2 treatments, with no Grade III/VI or serious adverse events. ACC008 was bioequivalent to administration of its individual components, including ANV 150 mg, 3TC 300 mg, and tenofovir disoproxil fumarate 300 mg with favorable safety profile.

Puerarin inhibits cisplatin-induced ototoxicity in mice through regulation of TRPV1-dependent calcium overload.

Puerarin (PUE), a flavonoid derivative with vasodilatory effects found in the traditional Chinese medicine kudzu, has anti-sensorineural hearing loss properties. However, the mechanism of its protective effect against ototoxicity is not well understood. In this study, we used in vitro and in vivo methods to investigate the protective mechanism of puerarin against cisplatin (CDDP)-induced ototoxicity. We established an ototoxicity model of CDDP in BALB/c mice and assessed the degree of hearing loss and cochlear cell damage. We used bioinformatics analysis, molecular docking, histological analysis, and biochemical and molecular biology to detect the expression of relevant factors. Our results show that puerarin improved CDDP-induced hearing loss and reduced hair cell loss. It also blocked CDDP-induced activation of TRPV1 and inhibited activation of IP3R1 to prevent intracellular calcium overload. Additionally, puerarin blocked CDDP-stimulated p65 activation, reduced excessive ROS production, and alleviated cochlear cell apoptosis. Our study provides new evidence and potential targets for the protective effect of puerarin against drug-induced hearing loss. Puerarin ameliorates cisplatin-induced ototoxicity and blocks cellular apoptosis by inhibiting CDDP activated TRPV1/IP3R1/p65 pathway, blocking induction of calcium overload and excessive ROS expression.

A randomized double-blind phase Ib clinical trial of SY-009 in patients with type 2 diabetes mellitus.

INTRODUCTION: SY-009 produces a hypoglycemic effect via inhibiting sodium/glucose cotransporter 1 (SGLT1) in type 2 diabetes mellitus (T2DM) patients. This randomized, double-blind, placebo-controlled, and multiple-dose escalation clinical trial aimed to evaluate the pharmacokinetic and pharmacodynamical characteristics as well as the safety and tolerability of SY-009 in T2DM patients. METHOD: Fifty T2DM patients were randomized into experimental and placebo groups, and hospitalized for 9 days managed with a unified diet and rest management. Subjects were given SY-009 or placebo from day 1 to day 7 at different frequencies and dosages. Single dose cohort was defined as the first dose on day 1 and multiple dose cohort included all the dose from day 1 to 7. Blood samples were collected for pharmacokinetic analysis. Mixed meal tolerance tests were performed. Blood samples were collected to determine glucose, C-peptide, insulin, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP). RESULTS: PK parameters were not obtained because blood SY-009 concentrations were below the limit of quantitation in all subjects. SY-009 decreased the postprandial glucose. Blood glucose was controlled within 4 hours after taking the drug. Short-term administration of SY-009 (7 days) had no significant effects on fasting glucose but reduced the secretion of C-peptide, insulin, and GIP and increased GLP-1 secretion. The most common adverse event was gastrointestinal disorder manifesting abdominal pain, diarrhea, and bloating. CONCLUSION: Plasma exposure of SY-009 and its metabolites was fairly low in T2DM patients at doses of 1.0-4.0 mg. SY-009 reduced postprandial glucose, C-peptide, and insulin levels, showing relative safety and tolerability in the dose range of 1.0-4.0 mg. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT04345107.

An overview of systematic reviews of acupuncture for neurodegenerative disease.

BACKGROUND: Acupuncture has been widely used in the treatment of neurodegenerative diseases and a large number of systematic reviews (SRs) have been published, but the results are controversial. Therefore, it is necessary to comprehensively summarize and objectively evaluate the clinical evidence of acupuncture for neurodegenerative diseases. OBJECTIVE: To evaluate the SRs that assess the efficacy and safety of acupuncture for neurodegenerative diseases. This overview is intended to provide evidence for clinical decision making by healthcare providers and policymakers and to provide evidence for clinical decision making by healthcare providers and policymakers and to provide recommendations for researchers to conduct high quality SRs and clinical studies. METHODS: We searched four Chinese databases (SinoMed, CNKI, Wanfang and VIP) and four international databases (Cochrane Library, Embase, PubMed and Web of Science) for SRs of acupuncture for neurodegenerative diseases. The search period ran from the beginning of the database to March 5, 2023. Literature screening and data extraction were performed independently by two individuals. Methodological quality, risk of bias and associated evidence levels were assessed for all SRs using AMSTER 2, ROBIS and GRADE tools. In addition, the RCT overlap between SRs was calculated by corrected coverage area (CCA). We also conducted quantitative synthesis or descriptive analysis of the relevant data. RESULTS: Finally, we identified 53 SRs (three were qualitative descriptions and fifty were meta-analyses). Under AMSTAR 2, only one SR was rated as moderate quality, six SRs as low quality and 46 SRs as very low quality. According to ROBIS, 33 SRs were rated as a high risk of bias and 20 as a low risk of bias. Cognitive functions in neurodegenerative diseases, activities of daily living and the motor and non-motor outcomes associated with PD were included to summary description. The pooled results show that acupuncture combined with conventional treatment may have an overall advantage over conventional treatment, but the quality of evidence is low. Specific adverse reactions/events were reported in 20 SRs. Common needle-related adverse events included pain, dizziness, bleeding, or subcutaneous hematoma. No severe adverse events were reported in any SRs. CONCLUSION: Evidence suggests that acupuncture is generally effective and relatively safe for cognitive function and activities of daily living in neurodegenerative diseases. In addition, acupuncture may have some benefits in improving motor and non-motor symptoms in patients with PD. However, high-quality RCTs and SRs are still needed to further clarify the efficacy and safety of acupuncture in treating neurodegenerative diseases.