Target Of Action Research Articles

Aronia Melanocarpa Elliot Anthocyanins Inhibits Alcoholic Liver Disease by Activation of α7nAChR.

The study wanted to explore the preventative effects of Aornia melanocarpa Elliot anthocyanins (AMA) to Alcoholic liver disease (ALD) by bioinformatics prediction and experimental verification. We founded 419 differentially expressed genes (DEGs) in GSE28619 related to ALD from GEO database, COL1A1 was selected by the core gene module construction and molecular docking. Mice were treated by intragastric administration of gradient 50% ethanol, AMA alleviated liver injury by ALD and ameliorated the model's body weight, lessened the liver inflammation according to histopathological evaluation, increased serum liver biochemical index (AST, ALT, TC, TG and LDL-C) and decreased HDL-C, reversed the expression of enzymes (ALDH and GSH-PX), decreased cytokines expression (Ki67, TNF-α and IL-6), reversed the expression of α7nAChR and collagen I, downregulated the PI3K-Akt pathway and Keap1/HO-1 pathway (p-PI3K, PI3K, p-Akt, Akt, Keap1, Nrf2, HO-1,GSK-3β and Bcl-2), indicated that α7nAChR and collagen I may be the AMA action targets.

Tissue- and liquid-biopsy based NGS profiling in advanced non-small-cell lung cancer in a real-world setting: the IMMINENT study.

To date, for all non-small cell lung cancer (NSCLC) cases, it is recommended to test for driver alterations to identify actionable therapeutic targets. In this light, comprehensive genomic profiling (CGP) with next generation sequencing (NGS) has progressively gained increasing importance in clinical practice. Here, with the aim of assessing the distribution and the real-world frequency of gene alterations and their correlation with patient characteristics, we present the outcomes obtained using FoundationOne (F1CDx) and FoundationLiquid CDx (F1L/F1LCDx) NGS-based profiling in a nationwide initiative for advanced NSCLC patients. F1CDx (324 genes) was used for tissue samples, and F1L (70 genes) or F1LCDx (324 genes) for liquid biopsy, aiming to explore the real-world occurrence of molecular alterations in aNSCLC and their relationship with patients' characteristics. Overall, 232 advanced NSCLC patients from 11 Institutions were gathered [median age 63 years; never/former or current smokers 29.3/65.9%; adenocarcinoma/squamous 79.3/12.5%; F1CDx/F1L+F1LCDx 59.5/40.5%]. Alterations were found in 170 different genes. Median number of mutated genes per sample was 4 (IQR 3-6) and 2 (IQR 1-3) in the F1CDx and F1L/F1LCDx cohorts, respectively. TP53 (58%), KRAS (22%), CDKN2A/B (19%), and STK11 (17%) alterations were the most frequently detected. Actionability rates (tier I and II) were comparable: 36.2% F1CDx vs. 34% ctDNA NGS assays (29.5% and 40.9% F1L and F1LCDx, respectively). Alterations in KEAP1 were significantly associated with STK11 and KRAS, so as TP53 with RB1. Median tumor mutational burden was 6 (IQR 3-10) and was significantly higher in smokers. Median OS from metastatic diagnosis was 23 months (IQR 18.5-19.5) and significantly lower in patients harboring ≥3 gene mutations. Conditional three-year survival probabilities increased over time for patients profiled at initial diagnosis and exceeded those of individuals tested later in their clinical history after 12 months. This study confirms that NGS-based molecular profiling of aNSCLC on tissue or blood samples offers valuable predictive and prognostic insights.

Research Progress on using Omics Technology to Examine the Antimicrobial Mechanisms of Natural Active Substances

Pathogenic microbial metabolism during food storage can lead to food spoilage, which can cause food poisoning and foodborne infections, posing a significant risk to human health and safety. Additionally, food spoilage generates greenhouse gases, which could contribute to global warming and have significant impacts. These challenges prompt us to explore effective solutions to reduce food spoilage, aiming to mitigate its adverse impacts. Many secondary plant metabolites have been used in the food and pharmaceutical industries due to their natural antimicrobial activity and low drug resistance. However, the reported targets of antibacterial action are complex, and with the continuous development of research methods, it has become possible to deeply analyze the antibacterial mechanisms using omics technologies. This article discussed the trends and application of transcriptomics, metabolomics, and proteomics in investigating the antimicrobial and antifungal properties of essential oils (EOs) and their active ingredients, aiming to provide a theoretical basis for the use of plant EOs and their active ingredients in addressing health risks and environmental challenges posed by food spoilage.

Collagen modification remodels the sarcoma tumor microenvironment and promotes resistance to immune checkpoint inhibition.

Molecular mechanisms underlying immune checkpoint inhibitor (ICI) response heterogeneity in solid tumors, including soft tissue sarcomas (STS), remain poorly understood. Herein, we demonstrate that the collagen-modifying enzyme, procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (Plod2), which is over-expressed in many tumors relative to normal tissues, promotes immune evasion in undifferentiated pleomorphic sarcoma (UPS), a relatively common and aggressive STS subtype. This finding is consistent with our earlier observation that Plod2 promotes tumor metastasis in UPS, and its enzymatic target, collagen type VI (ColVI), enhances CD8+ T cell dysfunction. We determined that genetic and pharmacologic inhibition of Plod2 with the pan-Plod transcriptional inhibitor minoxidil, reduces UPS growth in an immune competent syngeneic transplant system and enhances the efficacy of anti-Pd1 therapy. These findings suggest that PLOD2 is an actionable cancer target and its modulation could augment immunotherapy responses in patients with UPS, and potentially other sarcomas and carcinomas.

Exploring the mechanism of Si-Miao-Yong-An decoction on heart failure based on molecular docking and network pharmacology

The SwissTargetPrediction was employed to predict the potential drug targets of the active component of Si-Miao-Yong-An decoction (SMYAD). The therapeutic targets for HF were searched in the Genecard database, and Cytoscape3.9.1 software was used to construct the "drug-component-target-disease network" diagram. In addition, the String platform was used to construct Protein-Protein Interaction (PPI) network, and the DAVID database was used for GO and KEGG analysis. AutoDockTools-1.5.6 software was used for molecular docking verification. Network pharmacology studies have shown that AKT 1, ALB, and CASP 3 are the key targets of action of SMYAD against heart failure. The active compounds are quercetin and kaempferol.

The antiherpetic and anti-inflammatory activity of the frog-derived peptide Hylin-a1.

The high incidence of virus-related infections and the large diffusion of drug-resistant pathogens stimulate the search and identification of new antiviral agents with a broad spectrum of action. Antivirals can be designed to act on a single target by interfering with a specific step in the viral lifecycle. On the contrary, antiviral peptides (AVPs) are known for acting on a wide range of viruses, with a diversified mechanism of action targeting virus and/or host cell. In the present study, we evaluated the antiviral potential of the peptide Hylin-a1 secreted by the frog Hypsiobas albopunctatus against members of the Herpesviridae family. The inhibitory capacity of the peptide was evaluated in vitro by plaque assays in order to understand the possible mechanism of action. The results were also confirmed by real-time PCR and Western blot evaluating the expression of viral genes. Hylin-a1 acts to block the herpetic infection interfering at the early stages of both herpes simplex virus type 1 (HSV-1) and type 2 infection. Its mechanism is mainly directed on the membrane, probably by damaging the viral envelope. The same effect was also observed against HSV-1 strains resistant to acyclovir. The data presented in this study, such as the increased activity of the peptide when combined to acyclovir, a weak hemolytic profile, an anti-inflammatory effect, and a tolerable half-life in serum, indicates Hylin-a1 as a novel antiherpetic molecule with promising potential in the clinical setting.

Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.

People with primary sclerosing cholangitis (PSC) have a 20% lifetime risk of biliary tract cancer (BTC). Using whole-exome sequencing, we characterized genomic alterations in tissue samples from BTC with underlying PSC. We extracted DNA from formalin-fixed, paraffin-embedded tumor and paired nontumor tissue from 52 resection or biopsy specimens from patients with PSC and BTC and performed whole-exome sequencing. Following copy number analysis, variant calling, and filtering, putative PSC-BTC-associated genes were assessed by pathway analyses and annotated to targeted cancer therapies. We identified 53 candidate cancer genes with a total of 123 nonsynonymous alterations passing filtering thresholds in 2 or more samples. Of the identified genes, 19% had not previously been implicated in BTC, including CNGA3, KRT28, and EFCAB5. Another subset comprised genes previously implicated in hepato-pancreato-biliary cancer, such as ARID2, ELF3, and PTPRD. Finally, we identified a subset of genes implicated in a wide range of cancers such as the tumor suppressor genes TP53, CDKN2A, SMAD4, and RNF43 and the oncogenes KRAS, ERBB2, and BRAF. Focal copy number variations were found in 51.9% of the samples. Alterations in potential actionable genes, including ERBB2, MDM2, and FGFR3 were identified and alterations in the RTK/RAS (p = 0.036), TP53 (p = 0.04), and PI3K (p = 0.043) pathways were significantly associated with reduced overall survival. In this exome-wide characterization of PSC-associated BTC, we delineated both PSC-specific and universal cancer genes. Our findings provide opportunities for a better understanding of the development of BTC in PSC and could be used as a platform to develop personalized treatment approaches.

Features of emotional burnout of a personality at various stages of subjectogenesis of young teachers

Introduction. Emotional burnout ranks third among the main causes of staff turnover in educational institutions. Pedagogical activity at all levels of education, due to its content and conditions of implementation, is stressful and vulnerable to the effects of emotional burnout. The profession of a teacher involves the performance of a large number of tasks: the organization of the educational process, educational, research, educational and methodological work. The study of the features of emotional burnout at various stages of subjectogenesis will reveal the picture of changes and the target of preventive action. Materials and methods. The sample consisted of 119 teachers of higher and secondary levels of education aged 22 to 36 years, with professional experience from one year to 13 years. Of these, 64 teachers of higher education from the Federal State Budgetary Educational Institution of the KSMU of the Ministry of Health of the Russian Federation and Southwestern State University and 55 teachers from the Lyceum Boarding School named after Marshal Zhukov, Secondary Secondary School No. 58 named after Major General M.V. Ovsyannikov. The study of emotional burnout of young teachers of higher education with different length of professional experience (up to 5 years, over 5 years and up to 10 years and over 10 years) was carried out using the questionnaire "Emotional burnout" (V.V. Boyko), mathematical and statistical methods of data processing (descriptive statistics, U-Manna–Whitney, the method of structural psychological analysis). The obtained results were processed using the computer program "Statistica 10.0". Results and discussion. The stages of subjectogenesis of young teachers (higher school teachers and secondary school teachers) determine emotional burnout. It has been empirically proven that the degree of integration of its structures among young teachers of higher education, in contrast to teachers of secondary schools, is maximum with a length of professional experience of up to 5 years and over 10 years. Unlike young teachers, young teachers “burn” most intensely, and those who have more than 5 years of experience, but no more than 10 years. At this stage of their subjectogenesis, the formation of all phases of emotional burnout is diagnosed and its highest level is observed. Conclusion. The identified stages of subjectogenesis can be considered as sensitive periods in the formation of professional competence of young teachers, when their personality is most susceptible to the effects of emotional burnout, and taken into account in the development of a system of preventive measures (Mental Burnout Index” scale: Xav.± σ=200.67±32.73, U= 29.00*, p= 0.0001).

Future climate warming threatens coral reef function on World Heritage reefs.

Climate change is the most significant threat to natural World Heritage (WH) sites, especially in the oceans. Warming has devastated marine faunas, including reef corals, kelp, and seagrass. Here, we project future declines in species and ecosystem functions across Australia's four WH coral reef regions. Model simulations estimating species-level abundances and probabilities of ecological persistence were combined with trait space reconstructions at "present," 2050 (+1.5°C of warming), and 2100 (+2°C) to explore biogeographical overlaps and identify key functional differences and forecast changes in function through time. Future climates varied by region, with Shark Bay projected to warm the most (>1.29°C), followed by Lord Howe, when standardized to marine park size. By 2050, ~40% of the Great Barrier Reef will exceed critical thresholds set by the warmest summer month (mean monthly maximum [MMM]), triggering mortality. Functional diversity was greatest at Ningaloo. At +1.5°C of warming, species and regions varied drastically in their functional responses, declined 20.2% in species richness (~70 extinctions) and lost functions across all reefs. At +2°C, models predicted a complete collapse of functions, consistent with IPCC forecasts. This variability suggests a bespoke management approach is needed for each region and is critical for understanding WH vulnerability to climate change, identifying thresholds, and quantifying uncertainty of impacts. This knowledge will aid in focusing management, policy and conservation actions to direct resources, rapid action, and set biodiversity targets for these reefs of global priority. As reefs reassemble into novel or different configurations, determining the winners and losers of functional space will be critical for meeting global landmark biodiversity goals.

Patient Experience in a Remote Patient Monitoring Program for Hypertension: A Qualitative Study

Abstract BACKGROUND Remote patient monitoring (RPM), which includes out-of-office blood pressure (BP) measurement, coupled with interventions including telehealth and team-based care, is recommended for hypertension (HTN) management. We aimed to assess participant experience with RPM for HTN (RPM-HTN) to understand barriers and facilitators to implementing RPM-HTN in a primary care population where health disparities and social inequities are prevalent. METHODS This is a qualitative implementation study of participants’ experiences with an RPM-HTN program for primary care patients with uncontrolled HTN at an academic health system. We recruited participants with high and low levels of engagement (≥16 or <16 days of transmitted BP readings per month). Semi-structured interviews were conducted, and descriptive statistics and rapid qualitative analysis were used to identify factors affecting the implementation of RPM-HTN, specifically adoption, acceptability, appropriateness, and feasibility. RESULTS Multiple themes emerged from interviews with 14 participants. A doctor’s recommendation and wanting help with BP management were facilitators for engagement, while work conflicts and forgetfulness were barriers to engagement. Participants enjoyed the format and content of nurse and clinical pharmacist phone calls and forming a relationship with the team; expressed improved understanding of HTN and BP management; and appreciated the convenience of remote monitoring. CONCLUSIONS Participants found RPM-HTN acceptable and appropriate, highlighting the team-based and out-of-office approach to care. This study provides actionable targets to overcome feasibility barriers to implementation. In order to increase engagement, RPM policies and procedures should take into account barriers including the quantity of required BP measurements and mechanisms of telehealth communication.

A global multi-indicator assessment of the environmental impact of livestock products

Driven by a growing and more affluent population, changing diets and lifestyles, the demand for livestock products is expected to surge in the next decades. Satisfying this demand will result in additional pressures on land systems. The increasingly globalized supply chains of the livestock economy will further decouple many of these impacts from the places where livestock are reared. In this study, we determined the impact intensities of global livestock production across three environmental indicators: deforestation, biodiversity loss and marine eutrophication. To this end, we used global data on the production of crops (and grass), their trade and use as feed in livestock-production systems, as well as livestock production data. We found the highest deforestation and biodiversity impact intensities in the tropics in Central and South America, Southeast Asia and Central Western Africa. In contrast, the highest values for marine eutrophication intensities were found in countries located in Northern Europe and in South and in East Asia. Our analyses show differences caused by varying efficiencies in livestock production systems and by the sourcing patterns of feed items. In grazing systems for the production of ruminant meat, for example, the resulting impact intensities are dominated by the consumption of grass. In intensive and industrialized production systems, the bulk of the deforestation and, to a lesser extent, biodiversity impacts are linked to imported soybean feed. Our results can help identify livestock production systems and countries that would qualify as priority action targets, as well as potential entry points to make their livestock production systems more sustainable. They can also be used to assist consumers in comparing impacts across and within livestock food product types. Ultimately, understanding the environmental impacts embodied in global supply chains of livestock products can help create better regulatory policies and science-based interventions for protecting terrestrial and marine ecosystems.

Pharmacological Activity of Plant Extracts in Self-Nanoemulsifying Drug Delivery System Dosage Form: Narrative Review

The utilization of medicinal plants as therapeutic agents has obstacles to achieving the target action due to their low solubility. Self-Nanoemulsifying Drug Delivery System (SNEDDS) is a method developed to increase the solubility of poorly water-soluble substances, such as medicinal plant extracts. This review aims to present a narrative overview of the potential utilization of SNEDDS in enhancing the pharmacological activity of plant extracts. Article searches were conducted on several websites, such as Google Scholar, PubMed, and ScienceDirect. Literature studies showed that the use of SNEDDS formulations in several medicinal plants such as dayak onion, soursop leaf, papaya leaf, bay leaf, kale, sidaguri, black cumin, mangosteen peel, harendong, pineapple peel, and cocoa is more effective than the administration of extracts alone because it can increase the solubility and bioavailability of a compound. Pharmacologically, SNEDDS shows its success in enhancing antioxidant, anti-inflammatory, analgesic, antidiabetic, antihyperglycemic, antimalarial, immunostimulant, antimicrobial, anticancer, wound healing, and hepatoprotective activities in various plant extracts. The utilization of SNEDDS formulations in plant-based drugs has a positive impact on the advancement of drug therapy, especially for compounds that have low solubility.

Potential New Inflammatory Markers in Bronchiectasis: A Literature Review.

Specific molecular and inflammatory endotypes have been identified for chronic respiratory disorders, including asthma and COPD (chronic obstructive pulmonary disease). These endotypes correspond with clinical aspects of disease, enabling targeted medicines to address certain pathophysiologic pathways, often referred to as "precision medicine". With respect to bronchiectasis, many comorbidities and underlying causes have been identified. Inflammatory endotypes have also been widely studied and reported. Additionally, several genes have been shown to affect disease progression. However, the lack of a clear classification has also hampered our understanding of the disease's natural course. The aim of this review is, thus, to summarize the current knowledge on biomarkers and actionable targets of this complex pathologic condition and to point out unmet needs, which are required in the design of effective diagnostic and therapeutic trials.

Tumor-Agnostic Genomic and Clinical Analysis of BRAF Fusions Identifies Actionable Targets.

Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, and intact BRAF kinase domain). We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. Thirty-nine fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliogliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. Twenty-four patients spanning multiple histologies were treated with MAPK-directed therapies, of which 20 were evaluable for RECIST. Best response was partial response (N = 2), stable disease (N = 11), and progressive disease (N = 7). The median time on therapy was 1 month with MEK plus BRAF inhibitors [(N = 11), range 0-18 months] and 8 months for MEK inhibitors [(N = 14), range 1-26 months]. Nine patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N = 6), Erdheim-Chester disease (N = 1), extraventricular neurocytoma (N = 1), and melanoma (N = 1)]. Fifteen patients had acquired BRAF fusions. BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy, underscoring the importance of postprogression biopsies to optimize treatment at relapse in these patients.

Alkylamine-tethered molecules recruit FBXO22 for targeted protein degradation

Targeted protein degradation (TPD) relies on small molecules to recruit proteins to E3 ligases to induce their ubiquitylation and degradation by the proteasome. Only a few of the approximately 600 human E3 ligases are currently amenable to this strategy. This limits the actionable target space and clinical opportunities and thus establishes the necessity to expand to additional ligases. Here we identify and characterize SP3N, a specific degrader of the prolyl isomerase FKBP12. SP3N features a minimal design, where a known FKBP12 ligand is appended with a flexible alkylamine tail that conveys degradation properties. We found that SP3N is a precursor and that the alkylamine is metabolized to an active aldehyde species that recruits the SCFFBXO22 ligase for FKBP12 degradation. Target engagement occurs via covalent adduction of Cys326 in the FBXO22 C-terminal domain, which is critical for ternary complex formation, ubiquitylation and degradation. This mechanism is conserved for two recently reported alkylamine-based degraders of NSD2 and XIAP, thus establishing alkylamine tethering and covalent hijacking of FBXO22 as a generalizable TPD strategy.

Pharmacological mechanisms of Taohe Chengqi decoction in diabetic cardiovascular complications: A systematic review, network pharmacology and molecular docking

BackgroundDiabetic cardiovascular complications are the leading cause of diabetes-related deaths. These complications place an enormous and growing burden on global health systems and economies. The objective of this study was to conduct a systematic review on the therapeutic mechanisms of Taohe Chengqi Decoction (THCQD) in the treatment of diabetic cardiovascular complications. To predict the potential mechanisms of action of THCQD on diabetic cardiovascular complications using network pharmacology, and to validate these predictions through molecular docking analysis. MethodsTo collect relevant animal experiments, we searched a total of 6 databases. Eligibility for the study was determined based on inclusion and exclusion criteria. Data extraction was then performed on the literature. Methodological quality of animal studies was assessed using SYRCLE criteria. Based on network pharmacology, intersecting genes for THCQD and diabetic cardiovascular complications were obtained using Venny, PPI analysis and topology analysis of intersecting genes were performed; GO and KEGG were used for enrichment analysis and prediction of new targets of action. Molecular docking techniques were employed to model the interactions between drug components and target genes, thereby validating the results of network pharmacology predictions. ResultsA total of 16 studies were finally identified that fit the direction of this review. Included 6 studies of the myocardium, 1 study of the aortic arch, 5 studies of the femoral artery, 4 studies of the thoracic aorta. THCQD exhibited anti-inflammatory, anti-fibrotic and anti-atherosclerotic effects on cardiovascular complications in diabetic rats. Network pharmacology results showed that C0363 (Resveratrol), C0041 (Emodin), and C1114 (Baicalein) were the key components in the treatment of diabetic cardiovascular complications by THCQD. PPI results showed that INS, AKT1, TNF, ALB, IL6, IL1B as the genes that interact with the top 6. KEGG enrichment analysis identified the AGE-RAGE signaling pathway in diabetic complications as the most prominent pathway enriched by THCQD for diabetic cardiovascular complications genes. The results of molecular docking showed that the key active components demonstrated favorable interactions with their corresponding target genes. ConclusionIn conclusion, the results of both basic and web-based pharmacological studies support the beneficial effects of the natural herbal formulation THCQD on diabetic cardiovascular complications. This decoction has anti-inflammatory and antifibrotic properties and is effective in ameliorating diabetic cardiovascular disease. The network pharmacology results further support these ideas and identify the AGE-RAGE signaling pathway in diabetic complications as possibly the most relevant pathway for THCQD in the treatment of diabetic cardiovascular complications. The extent of the therapeutic potential of all-natural herbal components in the treatment of diabetic cardiovascular disease merits further investigation.

The regulation of GSH/GPX4-mediated lipid accumulation confirms that schisandra polysaccharides should be valued equally as lignans

Ethnopharmacological relevanceAcetaminophen (APAP) induced liver injury (AILI) is a common cause of clinical hepatic damage and even acute liver failure. Our previous research has shown that Schisandra chinensis lignan extract (SLE) can exert a hepatoprotective effect by regulating lipid metabolism. Although polysaccharides from Schisandra chinensis (S. chinensis), like lignans, are important components of S. chinensis, their pharmacological activity and target effects on AILI have not yet been explored. Aim of the studyThis study aims to quantitatively reveal the role of SCP in the pharmacological activity of S. chinensis, and further explore the pharmacological components, potential action targets and mechanisms of S. chinensis in treating AILI. Materials and methodsThe therapeutic effect of SCP on AILI was systematically determined via comparing the efficacy of SCP and SLE on in vitro and in vivo models. Network pharmacology, molecular docking and multi-omics techniques were then used to screen and verify the action targets of S. chinensis against AILI. ResultsSCP intervention could significantly improve AILI, and the therapeutic effect was comparable to that of SLE. Notably, the combination of SCP and SLE did not produce mutual antagonistic effects. Subsequently, we found that both SCP and SLE could significantly reverse the down-regulation of GPX4 caused by the APAP modeling, and then further improving lipid metabolism abnormalities. ConclusionsHepatoprotective effects of SCP and SLE is most correlated with their regulation of GSH/GPX4-mediated lipid accumulation. This is the first exploration of the hepatoprotective effect and potential mechanism of SCP in treating AILI, which is crucial for fully utilizing S. chinensis and developing promising AILI therapeutic agents.

Investigating the role of miR-26b-5p and PTGS2 in schizophrenia treatment using Wendan decoction: Network pharmacology and experimental validation

IntroductionThis study aimed to identify the target of action of Wendan decoction, a classical Chinese herbal formula used for the treatment of psychiatric disorders, specifically schizophrenia, using network pharmacology. MethodsTraditional Chinese Medicine (TCM) bioinformatics and network pharmacology were employed to predict the genes regulated by miR-26b-5p and identify the active ingredients and related targets of the Wendan decoction from public databases. Key components and targets were screened by constructing a "TCM-component-target" network, followed by pathway enrichment analysis of the related targets. The expression levels of miR-26b-5p and prostaglandin-endoperoxide synthase 2 (PTGS2) in the peripheral blood of patients with schizophrenia patients and healthy individuals were determined using RT-qPCR. Molecular docking was performed to explore the interaction between the active ingredients of the Wendan decoction and key differentially expressed molecules, investigating the role of miR-26b-5p in the treatment of schizophrenia with the Wendan decoction. ResultsA total of 135 active constituents were extracted from the Wendan decoction, and 144 molecules, including PTGS2 and other derivatives, were screened for drug-target and disease-target inter-mapping. Compared to peripheral blood samples from healthy controls and patients with depression, peripheral blood samples from patients with schizophrenia patients showed low miR-26b-5p expression and elevated PTGS2 expression, with no significant difference observed in the expression between healthy controls and patients with depression. Molecular docking revealed that several active compounds were found in five of the six constituents of the Wendan decoction bound with PTGS2. Pathway enrichment analysis suggested that the Wendan decoction may have a potential therapeutic role in treating schizophrenia by regulating the circadian rhythm, N-methyl-d-aspartate glutamate receptor activity, inflammatory mediator regulation of transient receptor potential channels, and other pathways implicated in schizophrenia. ConclusionWendan decoction may treat schizophrenia via the miR-26b-5p targeting factor PTGS2 and inflammation-related pathways. miR-26b-5p, combined with PTSG2, holds the potential as a differential diagnostic marker for schizophrenia.

Selection of Candidate Monoclonal Antibodies for Therapy of Botulinum Toxin Type A Intoxications.

Botulism is one of the most serious food intoxications, manifesting as prolonged paralytic conditions. This disease is usually the result of the consumption of poor quality canned or smoked foods, so the inhabitants of many countries of the world are exposed to the risk of this kind of poisoning every year. In view of the severity of poisonings caused by botulinum neurotoxins, monoclonal antibodies (mAbs) show great promise because of their targeting action, lack of allergic reactions and serum sickness. The use of a cocktail of mAbs increases the "functional specificity" of their mixture, allowing them to bind to the active domains of different toxin chains and block their action. In this work, we obtained 14 murine mAbs to the catalytic and receptor-binding domain of botulinum toxin type A. The Sp2/0-Ag14 murine myeloma cell line and splenocytes from immunized mice of the BALB/c line were used as fusion partners. We have shown that the selected cocktail of three antibodies neutralizes native toxin more effectively than antibodies separately-complete neutralization is achieved at a toxin dose of 3LD50 and partial neutralization at 5LD50. We presume that this cocktail may be promising as a prototype for the creation of a therapeutic drug capable of neutralizing the toxin in the blood of patients.

Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.

Aloperine (ALO), a quinolizidine-type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non-small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome-1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO-induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti-PD-L1/TGF-β bispecific antibody in inhibiting LLC-derived subcutaneous tumor models. Thus, ALO is first identified as a novel late-stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A.