Advancements in Non-Addictive Analgesic Diterpenoid Alkaloid Lappaconitine: A Review.

The perennial herb Aconitum sinomontanum Nakai (Ranunculaceae) has been utilized as a traditional oriental medicine in China for numerous years. The principal pharmacological constituent of A. sinomontanum, lappaconitine (LA), exhibits analgesic, anti-inflammatory, anti-tumor, anti-arrhythmic, and anti-epileptic activities. Due to its potent efficacy and non-addictive nature, LA is widely utilized in the management of cancer pain and postoperative analgesia. This review encompasses the research advancements pertaining to LA including extraction methods, separation techniques, pharmacological properties, chemical modifications, and clinical applications. Additionally, it offers insights into the potential applications and current challenges associated with LA to facilitate future research endeavors.

The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Due to its uncertain pathogenesis, there is currently no treatment available for AD. Increasing evidences have linked cellular senescence to AD, although the mechanism triggering cellular senescence in AD requires further exploration. To investigate the involvement of cellular senescence in AD, we explored the effects of cadmium chloride (CdCl2) exposure, one of the potential environmental risk factors for AD, on neuron senescence in vivo and in vitro. ß-amyloid (Aß) and tubulin-associated protein (tau) pathologies were found to be enhanced by CdCl2 exposure in the in vitro models, while p53/p21/Rb cascade-related neuronal senescence pathways were activated. Conversely, the use of melatonin, a cellular senescence inhibitor, or a cadmium ion chelator suppressed CdCl2-induced neuron senescence, along with the Aß and tau pathologies. Mechanistically, CdCl2 exposure activated the suppressor enhancer Lin-12/Notch 1-like (SEL1L)/HMG-CoA reductase degradation 1 (HRD1)-regulated endoplasmic reticulum-associated degradation (ERAD), which enhanced the ubiquitin degradation of sigma-1 receptor (SigmaR1) by specifically recognizing its K142 site, resulting in the activation of the p53/p21/Rb pathway via the induction of Ca2+ dyshomeostasis and mitochondrial dysfunction. In the in vivo models, the administration of the SigmaR1 agonist ANAVEX2-73 rescues neurobehavioral inhibition and alleviates cellular senescence and AD-like pathology in the brain tissue of CdCl2-exposed mice. Consequently, the present study revealed a novel senescence-associated regulatory route for the SEL1L/HRD1/SigmaR1 axis that affects the pathological progression of CdCl2 exposure-associated AD. CdCl2 exposure activated SEL1L/HRD1-mediated ERAD and promoted the ubiquitinated degradation of SigmaR1, activating p53/p21/Rb pathway-regulated neuronal senescence. The results of the present study suggest that SigmaR1 may function as a neuroprotective biomarker of neuronal senescence, and pharmacological activation of SigmaR1 could be a promising intervention strategy for AD therapy.

Study on the Therapeutic Value of Shexiang Tongxin Dropping Pills in Patients with Stable Angina Pectoris of Coronary Heart Disease Complicated with Cognitive Impairment.

BACKGROUND: There is a pressing need to identify pharmaceuticals that are both safe and efficacious, with lower toxicity, for the treatment of stable angina pectoris in individuals suffering from coronary heart disease. The aim of this paper is to explore the therapeutic value of Shexiang Tongxin Dropping Pills in patients with stable angina pectoris of coronary heart disease complicated with cognitive impairment. METHODS: 200 patients with stable angina pectoris combined with cognitive dysfunction and coronary heart disease admitted to our hospital from January 2022 to June 2023 were retrospectively selected as the study objects. According to the treatment method, the subjects were divided into a control group and a study group, with 100 cases in each group. The control group received conventional oral Western medicine, and the study group underwent treatment with Shexiang Tongxin Dropping Pills in addition to traditional Western medicine. The course of treatment was eight weeks. The enhancement in angina pectoris, cognitive function level, self-care ability, and clinical efficacy of both groups were assessed by comparing the conditions before and after the treatment. RESULTS: After treatment, the frequency and duration of angina pectoris attacks in both groups were significantly lower than before, and the study group was lower than the control group (p < 0.05). The Montreal Cognitive Assessment (MoCA) score of both groups was higher than before, and the score of the study group was significantly higher than that of the control group (p < 0.05). Neuropsychiatric Inventory (NPI) scores in both groups were significantly lower than before, and the scores of the study group were significantly lower than those of the control group (p < 0.05). Traditional Chinese Medicine (TCM) syndrome scores in both groups were significantly lower than before, and the scores of the study group were significantly lower than those of the control group (p < 0.05). After treatment, the total effective rate of the control group and the study group was 81.00% and 93.00%, respectively, and the total clinical effective rate of the study group was significantly higher than that of the control group (p < 0.05). CONCLUSION: Shexiang Tongxin Dropping Pills can effectively reduce the incidence of angina pectoris in patients with stable angina pectoris complicated with coronary heart disease and cognitive dysfunction. It can also regulate the patient's neurological function, improve their cognitive level, and significantly improve clinical efficacy.

Novel and safe debranched starch-zinc complexes with endoconcave structure as zinc supplements.

Zinc deficiency is a serious risk to human health and growth, especially in children. The development of zinc supplements can effectively reduce this harm. Here, a series of debranched starch­zinc complexes (DS-Zn) were prepared, whose zinc complexation was inversely proportional to the amylopectin content in the debranched starch (DS). The physicochemical properties of DS-Zn were characterized using the conductivity, XRD, iodine staining and thermogravimetry. Combined with XPS, solid-state 13C NMR and IR, it was elucidated that the structure of DS-Zn is endoconcave structure with 2-O and 3-O of DS on the inner side and 6-O of DS on the outer side, where zinc is located. The DS-Zn exhibits good biosafety including blood, cellular and mutagenicity. In vitro simulations of digestion and zinc-deficient cellular models showed that DS-Zn was more tolerant to the gastrointestinal environment and more effective in zinc supplementation (increased by 33 %) than inorganic zinc supplements. Utilizing the compressibility of starch, DS-Zn was prepared as a more palatable oral cartoon tablet for children. This study will provide important support to advance the development and application of novel starch-based zinc nutritional supplements.

Nitrogen- and fluorine-doped bimetallic carbide as active and stable oxygen reduction reaction electrocatalyst.

Nitrogen- and fluorine-doped bimetallic carbide composites with graphite matrix (abbreviated as C19Cr7Mo24/NG and C19Cr7Mo24/FG) are synthesized through carbonization at 1300 °C. The C19Cr7Mo24/NG displays an initial half-wave potential (E1/2) of 0.873 V and suffers merely 3 mV decrease in E1/2 within 60,000 CV cycles for oxygen reduction reaction (ORR) in alkaline media. A H2/O2 fuel cell testing system using the C19Cr7Mo24/NG as cathode maintains 95.9% of the initial peak power density (1.08 W cm-2) within 60,000 cycles. The C19Cr7Mo24/FG shows higher ORR activity than the C19Cr7Mo24/NG. The positive and negative charge centers caused by the N or F dopants are the critical reasons to their high activities. While F and bimetallic carbide more favor electron transfer respectively than the N and monometallic carbide. Their excellent stabilities originate from interactions among atoms due to electron transfer and the intrinsic chemical inertness of graphite and bimetallic carbides.

Identification of SARS-CoV-2 m6A modification sites correlate with viral pathogenicity.

It has recently been found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) m6A modifications can affect viral replication and function. However, no studies to date have shown a correlation between SARS-CoV-2 m6A modifications and viral pathogenicity. In this study, we analyzed m6A modification in 2,190,667 SARS-CoV-2 genomic RNAs. m6A modifications of SARS-CoV-2 from different lineages, causing mild or severe COVID-19 and showing breakthrough for different vaccines were analyzed to explore correlations with viral pathogenicity. The results suggested that the presence of more m6A modifications in the SARS-CoV-2 N region (positive strand) correlates with weaker pathogenicity. In addition, we identified three m6A modification sites correlating with weak pathogenicity (924 in ORF1ab, 15,659 in ORF1ab, 28,288 in N, 28,633 in N and 29,385 in N, 29,707 in 3'UTR) and one with strong pathogenicity (74 in 5'UTR). These results provide new information for understanding the prevalence of SARS-CoV-2 and controlling the virus.

HLA-targeted sequencing reveals the pathogenic role of HLA-B*15:02/HLA-B*13:01 in albendazole-induced liver failure: a case report and a review of the literature.

Drug-induced liver injury (DILI) is one of the serious adverse drug reactions (ADRs), which belongs to immune-mediated adverse drug reactions (IM-ADRs). As an essential health drug, albendazole has rarely been reported to cause serious liver damage. A young man in his 30 s developed severe jaundice, abnormal transaminases, and poor blood coagulation mechanism after taking albendazole, and eventually developed into severe liver failure. The patient was found heterozygous of HLA-B*15:02 and HLA-B*13:01 through HLA-targeted sequencing, which may have a pathogenic role in the disease. This case report summarizes his presentation, treatment, and prognosis. A useful summary of the diagnosis and associated genetic variant information is provided.

A wearable-based sports health monitoring system using CNN and LSTM with self-attentions.

Sports performance and health monitoring are essential for athletes to maintain peak performance and avoid potential injuries. In this paper, we propose a sports health monitoring system that utilizes wearable devices, cloud computing, and deep learning to monitor the health status of sports persons. The system consists of a wearable device that collects various physiological parameters and a cloud server that contains a deep learning model to predict the sportsperson's health status. The proposed model combines a Convolutional Neural Network (CNN), Long Short-Term Memory (LSTM), and self-attention mechanisms. The model is trained on a large dataset of sports persons' physiological data and achieves an accuracy of 93%, specificity of 94%, precision of 95%, and an F1 score of 92%. The sports person can access the cloud server using their mobile phone to receive a report of their health status, which can be used to monitor their performance and make any necessary adjustments to their training or competition schedule.

The binding profile of SARS-CoV-2 with human leukocyte antigen polymorphisms reveals critical alleles involved in immune evasion.

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), astonished the world and led to millions of deaths. Due to viral new mutations and immune evasion, SARS-CoV-2 ranked first in transmission and influence. The binding affinity of human leukocyte antigen (HLA) polymorphisms to SARS-CoV-2 might be related to immune escape, but the mechanisms remained unclear. In this study, we obtained the binding affinity of SARS-CoV-2 strains with different HLA proteins and identified 31 risk alleles. Subsequent structural predictions identified 10 active binding sites in these HLA proteins that may promote immune evasion. Particularly, we also found that the weak binding ability with HLA class I polymorphisms could contribute to the immune evasion of Omicron. These findings suggest important implications for preventing the immune evasion of SARS-CoV-2 and providing new insights for the vaccine design.

Rotenone nanoparticles based on mesoporous silica to improve the stability, translocation and insecticidal activity of rotenone.

Nanotechnology has been widely applied for pesticide carriers, which is an important way to improve the utilization, stability, and sustained release of pesticides. Mesoporous silica nanoparticles (MSNs) are a nanomaterial with adjustable particle and pore sizes, with a high specific surface area and good biocompatibility. Rotenone is a non-systemic botanical insecticide that is easily degraded in the environment. We used a modified soft-template method to prepare MSNs, in which rotenone was loaded using the solvent evaporation method. The prepared rotenone nanopesticide based on mesoporous silica showed considerable drug loading rates of 33.2%. Moreover, the prepared rotenone nanoparticles showed improved photostability and sustained release behavior, which improved the translocation of rotenone in tomato plants. Finally, the rotenone nanoparticles displayed superior insecticidal activity compared to traditional preparations. In summary, the rotenone nanopesticide improved the persistence and utilization rates of rotenone. These findings are of significance in reducing pesticide usage, mitigating environmental pollution, and ensuring food safety.

Toxicity effects of pesticides based on zebrafish (Danio rerio) models: Advances and perspectives.

Pesticides inevitably enter aquatic environments, posing potential risks to organisms. The common aquatic model organism, zebrafish (Danio rerio), are widely used to evaluate the toxicity of pesticides. In this review, we searched the Web of Science database for articles published between 2012 and 2022, using the keywords "pesticide", "zebrafish", and "toxicity", retrieving 618 publications. Furthermore, we described the main pathways by which pesticides enter aquatic environments and the fate of their residues in these environments. We systematically reviewed the toxicity effects of pesticides on zebrafish, including developmental toxicity, endocrine-disrupting effects, reproductive toxicity, neurotoxicity, immunotoxicity, and genotoxicity. Importantly, we summarized the latest research progress on the toxicity mechanism of pesticides to zebrafish based on omics technologies, including transcriptomics, metabolomics, and microbiomics. Finally, we discussed future research prospects, focusing on the combined exposure of multiple pollutants including pesticides, the risk of multigenerational exposure to pesticides, and the chronic toxicity of aquatic nanopesticides. This review provides essential data support for ecological risk assessments of pesticides in aquatic environments, and has implications for water management in the context of pesticide pollution.

The MSH2 c.793-1G>A variant disrupts normal splicing and is associated with Lynch syndrome.

Instruction: Lynch syndrome (LS) is the most common inherited cancer predisposition disorder of colorectal cancer (CRC) which is associated with pathogenic variants in 4 mismatch repair (MMR) genes. Here, we reported a multi-generation Chinese family clinically diagnosed with LS. Methods: To identify the underlying pathogenic gene variants, 30 whole blood samples and 4 colorectal cancer tissue samples and their clinical data were obtained from this four-generation family. Microsatellite instability-high (MSI) testing, immunohistochemistry (IHC), and Whole-Exome Sequencing (WES) were performed to identify the MMR/MSI and the underlying gene variants. The minigene splicing assay and in vitro splicing assay were used to explore the function of this variant. Results: MSI-H and dMMR was revealed by the MSI testing and IHC, Whole-Exome Sequencing (WES) in 3 patients successfully identified a splicing variant (c.793-1G>A) in intron 4 of MSH2. Sanger sequencing validated the WES results, and all the "healthy" individuals carrying the variant have been identified in the family by PCR. Bioinformatics analysis and in vitro minigene assay showed that the pathogenic variant affected the splicing process of MSH2 gene to generate 2 kinds defective transcription products, and consequently reduced the expression of MSH2 protein. The mutation carriers were later recommended for colonoscopy and other important cancer diagnostic inspections every 1-2 years because they both have a higher risk of LS. Discussion: We found a pathogenic splicing variant (rs863225397, c.793-1G>A) of MSH2 gene, and furtherly confirmed that this mutation plays an important role in LS patients of this pedigree based on the vitro study. Our study indicates that one splicing mutation in the MSH2 gene (c.793-1G>A) causes LS and highlights the importance of LS gene testing.

NMR-based metabolomics approach to assess the ecotoxicity of prothioconazole on the earthworm (Eisenia fetida) in soil.

Prothioconazole (PTC) is a widely used agricultural fungicide. In recent years, studies have confirmed that it exerts adverse effects on various species, including aquatic organisms, mammals, and reptiles. However, the toxicological effects of PTC on soil organisms are poorly understood. Here, we investigated the toxic effects, via oxidative stress and metabolic responses, of PTC on earthworms (Eisenia fetida). PTC exposure can induce significant changes in oxidative stress indicators, including the activities of superoxide dismutase (SOD) and catalase (CAT) and the content of glutathione (GSH), which in turn affect the oxidative defense system of earthworms. In addition, metabolomics revealed that PTC exposure caused significant changes in the metabolic profiles of earthworms. The relative abundances of 16 and 21 metabolites involved in amino acids, intermediates of the tricarboxylic acid (TCA) cycle and energy metabolism were significantly altered after 7 and 14 days of PTC exposure, respectively. Particularly, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that multiple different metabolic pathways could be disturbed after 7 and 14 days of PTC exposure. Importantly, these alterations in oxidative stress and metabolic responses in earthworms reveal that the effects of PTC on earthworms were time dependent, and vary with exposure time. In conclusion, this study highlights that the effects of PTC on soil organisms are of serious concern.

Toxicity effects of chlorantraniliprole in zebrafish (Danio rerio) involving in liver function and metabolic phenotype.

Chlorantraniliprole (CAP), a representative bisamide insecticide, is widely used in rice fields around the world, posing potential toxicity risks to aquatic organisms. In this study, we examined the effects of exposure to CAP on growth and metabolic phenotype of zebrafish (Danio rerio) and oxidative stress and apoptosis in the liver of zebrafish (Danio rerio). First, we identified that CAP had a low bioaccumulation in zebrafish. Subsequently, growth phenotype analysis revealed that CAP could significantly increase liver weight and liver index in zebrafish. In addition, we found that CAP exposure could cause significant changes in indicators of oxidative stress, resulting in a significant increase in the content of malondialdehyde (MDA), causing oxidative stress in the liver of zebrafish. Meanwhile, the expression levels of apoptosis-related genes were also significantly changed and apoptosis was promoted in the liver of zebrafish with CAP exposure. Importantly, the results of metabolomics analysis shown that CAP exposure could significantly disrupt the metabolic phenotype of zebrafish, interfering with multiple metabolic pathways, mainly including valine, leucine and isoleucine biosynthesis and degradation, alanine, aspartate and glutamate metabolism and d-glutamine and D-glutamate metabolism. Last but not least, correlation analysis identified strong links between changes in liver function involving oxidative stress and apoptosis and changes in metabolic phenotype of zebrafish following CAP exposure. In brief, these results indicate that potential environmental risks of CAP to aquatic organisms should receive more attention.

Malvidin protects against lipopolysaccharide-induced acute liver injury in mice via regulating Nrf2 and NLRP3 pathways and suppressing apoptosis and autophagy.

Sepsis-related acute liver injury (ALI) is a fatal disease associated with many complications. Recent studies indicate that malvidin, an active flavonoid, has multiple bioactivities including anti-oxidant and anti-inflammation. However, the protective roles of malvidin against LPS-induced ALI are unknown. The purpose of this research is to explore whether malvidin has biological activities on LPS-induced ALI in mice and the underlying mechanisms. Male C57 mice were injected intraperitoneally with malvidin for five days and the mice were euthanized 6 h after LPS (10 mg/kg body weight) intraperitoneal injection. Multiple methods of H&E staining, biochemical kits, qRT-PCR assay, western blotting analysis, TUNEL and transmission electron microscope (TEM) were used. Results showed that decreased ALT, AST levels and alleviated histopathological damage of liver tissue were observed in malvidin pretreatment group in mice. Then, malvidin prevented LPS-induced reduction of antioxidant enzyme activities such as superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) via up-regulating nuclear factor E2-related factor2 (Nrf2) pathway. In addition, in malvidin pretreatment groups, mRNA levels of pro-inflammatory cytokines (TNF-α，IL-1ß, IL-6) and protein levels of NOD-like receptor protein 3 (NLRP3) inflammasome in the liver were significantly down-regulated. We also found that the malvidin could reduce the expression of apoptosis key protein and TUNEL-labeled apoptotic hepatocytes. Furthermore, malvidin inhibited the protein expression of ATG5, p62 and the ratio of LC3-II/LC3-I. In conclusion, our study firstly suggests that malvidin is a potentially protective agent against LPS-induced ALI through up-regulating Nrf2 signaling pathway, suppressing NLRP3 inflammasome and inhibiting apoptosis and autophagy.

Systematic evaluation of chiral pesticides at the enantiomeric level: A new strategy for the development of highly effective and less harmful pesticides.

Over the past few decades, pesticides have been used in large quantities, and they pose potential risks to organisms across various environments. Reducing the use of pesticides and their environmental risks has been an active research focus and difficult issue worldwide. As a class of pesticides with special structures, chiral pesticides generally exhibit enantioselectivity differences in biological activity, ecotoxicity, and environmental behavior. At present, replacing the racemates of chiral pesticides by identifying and developing their individual enantiomers with high efficiency and environmentally friendly characteristics is an effective strategy to reduce the use of pesticides and their environmental risks. In this study, we review the stereoselective behaviors of chiral pesticide, including their environmental behavior, stereoselective biological activity, and ecotoxicity. In addition, we emphasize that the systematic evaluation of chiral pesticides at the enantiomeric level is a promising novel strategy for developing highly effective and less harmful pesticides, which will provide important data support and an empirical basis for reducing pesticide application.

Reprogramming the tumor microenvironment by genome editing for precision cancer therapy.

The tumor microenvironment (TME) is essential for immune escape by tumor cells. It plays essential roles in tumor development and metastasis. The clinical outcomes of tumors are often closely related to individual differences in the patient TME. Therefore, reprogramming TME cells and their intercellular communication is an attractive and promising strategy for cancer therapy. TME cells consist of immune and nonimmune cells. These cells need to be manipulated precisely and safely to improve cancer therapy. Furthermore, it is encouraging that this field has rapidly developed in recent years with the advent and development of gene editing technologies. In this review, we briefly introduce gene editing technologies and systematically summarize their applications in the TME for precision cancer therapy, including the reprogramming of TME cells and their intercellular communication. TME cell reprogramming can regulate cell differentiation, proliferation, and function. Moreover, reprogramming the intercellular communication of TME cells can optimize immune infiltration and the specific recognition of tumor cells by immune cells. Thus, gene editing will pave the way for further breakthroughs in precision cancer therapy.

Model-based assessment of cardiopulmonary autonomic regulation in paced deep breathing.

Autonomic dysfunction can lead to many physical and psychological diseases. The assessment of autonomic regulation plays an important role in the prevention, diagnosis, and treatment of these diseases. A physiopathological mathematical model for cardiopulmonary autonomic regulation, namely Respiratory-Autonomic-Sinus (RSA) regulation Model, is proposed in this study. A series of differential equations are used to simulate the whole process of RSA phenomenon. Based on this model, with respiration signal and ECG signal simultaneously acquired in paced deep breathing scenario, we manage to obtain the cardiopulmonary autonomic regulation parameters (CARP), including the sensitivity of respiratory-sympathetic nerves and respiratory-parasympathetic nerves, the time delay of sympathetic, the sensitivity of norepinephrine and acetylcholine receptor, as well as cardiac remodeling factor by optimization algorithm. An experimental study has been conducted in healthy subjects, along with subjects with hypertension and coronary heart disease. CARP obtained in the experiment have shown their clinical significance.

Systemic inflammation response index (SIRI) as a novel biomarker in patients with rheumatoid arthritis: a multi-center retrospective study.

OBJECTIVES: To evaluate the potential ability of systemic inflammation response index (SIRI) as a novel biomarker in patients with rheumatoid arthritis (RA) and explore the mechanisms. METHOD: Patients fulfilling the 2010 ACR/EULAR classification criteria for RA were enrolled in this study. Demographic, clinical, and laboratory characteristics of all subjects were collected. Neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR), and SIRI were calculated. Statistical analysis was performed, and P-values < 0.05 were considered statistically significant. RESULTS: One thousand four hundred ninety-nine RA patients from five hospitals were included, with 366 healthy volunteers served as controls. The NLR, MLR, PLR, and SIRI significantly increased in RA patients. Receiver operating characteristics (ROC) curve analysis showed SIRI, and NLR could distinguish RA from healthy controls. Correlation analysis and multiple linear regression analysis indicated that SIRI and PLR positively correlated with disease activity in RA. The NLR, MLR, and SIRI increased significantly in patients with RA-associated interstitial lung disease (ILD). There was a good accuracy of SIRI in differentiating RA-ILD from RA patients without ILD. SIRI was also found to be higher in RA patients with tumor and could differentiate them from RA patients without tumor. CONCLUSIONS: SIRI could be evaluated as a novel, non-invasive, and suitable biomarker for assisting in the diagnosis process and demonstrating the disease activity of RA, as well as predicting RA-ILD and tumor development of RA patients. Key Points • As a novel biomarker, systemic inflammation response index (SIRI) may assist in the diagnosis process and indicate the disease activity of RA patients • SIRI may predict the development of RA-associated interstitial lung disease (RA-ILD) and tumor in RA patients • SIRI is more satisfactory than other blood cells-based indexes in the assessment of RA patients.