Clinical Drugs Research Articles

Toxicological profile using mass-spectrometry in sudden cardiac arrest patients

Abstract Background Many drugs are known to increase the risks of ventricular arrythmias and sudden cardiac death, and current guidelines recommends collection of a blood sample at presentation for toxicological testing. To our knowledge, a broad toxicological analysis based on liquid-chromatography combined with high-resolution mass spectrometry (LC-HRMS) has not previously been performed in a resuscitated sudden cardiac arrest (SCA) cohort. Purpose We aimed to determine the qualitative and quantitative drug composition present in a well-defined SCA population by using a forensic toxicology approach for prescribed, non-prescribed, and recreational drugs, and further investigate whether these drugs were in therapeutic or toxic levels. Methods This study comprised a series of SCA patients (age 18-90 years) admitted to a cardiac intensive care unit in 2019-2020 in Denmark. Data from the SCA hospitalization was collected from the medical reports, including clinical characteristics and drugs prior to the blood sample was drawn. Drugs used during resuscitation were identified in each patient and excluded. Mass-spectrometry based toxicological analyses were performed to determine the absence or presence of any drugs and drug quantification. Results Of the 186 prospectively enrolled SCA patients (median age 62 years [IQR 54-72], 83% men), 167 (90%) had a shockable rhythm, and the majority (n=122, 66%) were caused by ischemic heart disease. We identified 92 different drugs (excluding metabolites), where each patient had a median of 2 detected drugs (IQR: 1-4). A total of 34 (18%) patients did not have any drugs detected. The most frequent drugs detected were analgesics or non-steroidal anti-inflammatory drugs (NSAID) (n=68, 37%), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (n=45, 24%), and beta-blockers (n=42, 23%). We detected QT-prolonging drugs in two of three patients with long QT-syndrome, and in both cases the QT-prolonging drug were considered the triggering factor of SCA. Moreover, polypharmacy (≥5 drugs) was common (n=37, 20%), excluding caffeine that was detected in 184 patients (99%). The drug combinations were often analgesics/NSAID, or beta-blockers combined with other drugs. A total of 32 (17%) patients had one or more recreational drugs detected, with the most common being opioid agonists in 14 patients. Importantly, none had toxic concentrations of any drugs. Conclusion We found that 82% had at least one drug detected at SCA, and polypharmacy was displayed in a considerable proportion. Potentially abusable drugs were encountered in 17%. We did not identify any occult overdose related cardiac arrests among resuscitated SCA patients, but in some patients, drugs were considered a contributing factor of SCA. When evaluating the utility of toxicological screening, it would in our setting (90% shockable primary rhythm) not be beneficial to screen SCA patients who are not suspected overdosed.

Abstract 13079: Prevalence and Incidence of Transthyretin Amyloid Cardiomyopathy in the USA From 2004 to 2022: An Observational Database Study

Introduction: Improved diagnosis and awareness have resulted in global increases in the incidence and prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM). However, current US epidemiology data are lacking. Aims: To estimate the prevalence and incidence of ATTR-CM in a large US population and describe characteristics of patients with ATTR-CM. Methods: Data from 2004–2022 were extracted from TriNetX, a US database of EMRs covering in- and outpatient data. An algorithm using ICD-9/10 codes and RxNorm codes for clinical drugs (amyloidosis + cardiac manifestation – light chain amyloidosis) was used to identify patients with ATTR-CM. Included were adults ≥ 18 years old at index date (first ATTR-CM diagnosis per the algorithm) with ≥ 1 year of database history. The incidence and prevalence of ATTR-CM were assessed annually. Demographic characteristics at index and ATTR-CM-related comorbidities any time pre-index were assessed in cross-sectional cohorts over time. Results: In total, 12 209 patients were identified (2004–08, n = 332; 2009–13, n = 913; 2014–18, n = 3392; 2019–22, n = 7572). The incidence and prevalence of ATTR-CM per 100 000 people increased over time (incidence, 2004: 3.7; 2022: 11.5; prevalence, 2004: 5.1; 2022: 35.1) ( Figure ). Across cohorts, approximately 40% of patients were women, and 20% were Black. Median age increased over time (2004–08: 65 years; 2019–22: 74 years). In the 2019–22 cohort, the cardiac manifestations of ATTR-CM were cardiomyopathy (56.3%), atrial fibrillation (56.1%), and heart failure (20.9%). The proportion of patients with ATTR-CM-related comorbidities increased over time (2004–08 vs 2019–22: polyneuropathy, 15.1 vs 19.0%; carpal tunnel syndrome, 10.5 vs 13.4%; lumbar spinal stenosis, 4.2 vs 13.3%; aortic stenosis, 9.3 vs 13.2%). Conclusion: In this US population, the incidence and prevalence of ATTR-CM diagnoses increased over 19 years. Age at diagnosis and ATTR-CM comorbidity burden increased during this period.

Abstract 13090: Clinical Burden of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) in the USA From 2004 to 2022

Introduction: Advances in diagnosis and disease awareness have led to increased prevalence and incidence of diagnosed transthyretin amyloid cardiomyopathy (ATTR-CM) worldwide. At the same time, patients are being diagnosed at an older age and with multiple comorbidities. Current data on the clinical burden of ATTR-CM in the USA are lacking. Aims: To assess the clinical burden of ATTR-CM in terms of comorbidities, medication use, and healthcare resource utilization in a large US population over time. Methods: Data from 2004–2022 were extracted from TriNetX, a US database of electronic medical records covering in- and outpatient data. An algorithm using ICD-9/10 codes and RxNorm codes for clinical drugs (amyloidosis + cardiac manifestation – light chain amyloidosis) was used to identify patients with ATTR-CM. Included were adults ≥ 18 years old at index date (first ATTR-CM diagnosis per the algorithm) with ≥ 1 year of database history. Demographic characteristics at index, medication use and clinical encounters in the year pre-index, and comorbidities at any time pre-index were assessed in cross-sectional cohorts over time. Results: Of more than 78 million patients in the database, 12 209 fulfilled all inclusion criteria (2004–2008, n = 332; 2009–2013, n = 913; 2014–2018, n = 3392; 2019–2022, n = 7572). The prevalence of both ATTR-CM-related comorbidities and other comorbidities, as well as associated medication use, generally increased over time ( Table ). In the year before ATTR-CM diagnosis, a considerable proportion of patients had outpatient, inpatient and emergency visits; among patients with one or more clinical encounter, the median number of encounters (any encounter) was ≥ 10 across all cohorts ( Table ). Conclusion: In patients with ATTR-CM in this large US population, the clinical burden has become more complex over time, with an increasing proportion of patients having multiple morbidities and clinical encounters in the time before diagnosis.

Potentiality of Nucleoside as Antioxidant by Analysis on Oxidative Susceptibility, Drug Discovery, and Synthesis.

Nucleosides are sensitive sites towards oxidations caused by endogenous and exogenous oxidative resources, and a large number of the produced DNA lesions behave as pathogenesis event1ually. We herein analyze oxidative modes of nucleosides and structure-activity relationships of some clinical nucleoside drugs. Together with our previous findings on the inhibitory effects of nucleoside derivatives against DNA oxidation, all these results imply a possibility for nucleoside to be a new member in the family of antioxidants. Then, some novel synthetic routines of nucleoside analogs are collected to reveal the applicability in the construction of nucleoside antioxidants. Therefore, it is reasonable to envision that the nucleoside antioxidant will be a novel topic in the research of both nucleosides and antioxidants.

Targeted metabolomics reveals PFKFB3 as a key target for elemene-mediated inhibition of glycolysis in prostate cancer cells

BackgroundElemene, an active anticancer extract derived from Curcuma wenyujin, has well-documented anticarcinogenic properties. Nevertheless, the role of elemene in prostate cancer (PCa) and its underlying molecular mechanism remain elusive. PurposeThis study focuses on investigating the anti-PCa effects of elemene and its underlying mechanisms. MethodsCell-based assays, including CCK-8, scratch, colony formation, cell cycle, and apoptosis experiments, to comprehensively assess the impact of elemene on PCa cells (LNCaP and PC3) in vitro. Additionally, we used a xenograft model with PC3 cells in nude mice to evaluate elemene in vivo efficacy. Targeted metabolomics analysis via HILIC-MS/MS was performed to investigate elemene potential target pathways, validated through molecular biology experiments, including western blotting and gene manipulation studies. ResultsIn this study, we discovered that elemene has remarkable anti-PCa activity in both in vitro and in vivo settings, comparable to clinical chemotherapeutic drugs but with fewer side effects. Using our established targeted metabolomics approach, we demonstrated that β-elemene, elemene's primary component, effectively inhibits glycolysis in PCa cells by downregulating 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression. Furthermore, we found that β-elemene accomplishes this downregulation by upregulating p53 and FZR1. Knockdown and overexpression experiments conclusively confirmed the pivotal role of PFKFB3 in mediating β-elemene's anti-PCa activity. ConclusionThis finding presents compelling evidence that elemene exerts its anti-PCa effect by suppressing glycolysis through the downregulation of PFKFB3. This study not only improves our understanding of elemene in PCa treatment but also provides valuable insights for developing more effective and safer therapies for PCa.

Cu-based nanozymes effectively inhibit proliferation of fungal pathogens by catalyzing ROS yield

The fungal pathogens Fusarium solani are the causative agents of mycotic keratitis, a global serious ocular disease affecting visual impairment or blindness. In view of limitations in current treatment method and the severe impact of fungal keratitis on vison, developing alternative agents for effective control of these diseases has become urgent. Herein, copper-doped imidazole zeolite structure as a nanozyme (Cu nanozyme) and modified the surface of Cu nanozymes through polyethyleneimine (PEI) (p-Cu nanozymes) is successfully constructed. The p-Cu nanozymes showed excellent antibacterial activity, significantly superior to commonly used clinical antifungal drugs (voriconazole and natamycin). We also monitored that the intracellular reactive oxygen species (ROS) production acts as an important mediator for exerting antifungal effects. The aim of the current study was to evaluate the antifungal activity of Cu nanozymes against F. solani, and the results will form the basis of further research about the growth inhibition mechanisms of fungi by MOFs-based nanozymes. This will represent a promising new non-antibiotic antifungal drug and provide a new idea for the antifungal research of new materials.

SARS‐CoV‐2 ORF7a blocked autophagy flux by intervening in the fusion between autophagosome and lysosome to promote viral infection and pathogenesis

AbstractThe coronavirus disease 2019 (COVID‐19) continues to pose a major threat to public health worldwide. Although many studies have clarified the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection process, the underlying mechanisms of viral invasion and immune evasion were still unclear. This study focused on SARS‐CoV‐2 ORF7a (open reading frame‐7a), one of the essential open reading frames (ORFs) in infection and pathogenesis. First, by analyzing its physical and chemical characteristics, SARS‐CoV‐2 ORF7a is an unstable hydrophobic transmembrane protein. Then, the ORF7a transmembrane domain three‐dimensional crystal structure model was predicted and verified. SARS‐CoV‐2 ORF7a localized in the endoplasmic reticulum and participated in the autophagy‐lysosome pathway via interacting with p62. In addition, we elucidated the underlying molecular mechanisms by which ORF7a intercepted autophagic flux, promoted double membrane vesicle formation, and evaded host autophagy‐lysosome degradation and antiviral innate immunity. This study demonstrated that ORF7a could be a therapeutic target, and Glecaprevir may be a potential drug against SARS‐CoV‐2 by targeting ORF7a. A comprehensive understanding of ORF7a's functions may contribute to developing novel therapies and clinical drugs against COVID‐19.

Crystal Structure Determination of Nucleotide-sugar Binding Domain of Human UDP-glucuronosyltransferases 2B10.

UDP-glucuronosyltransferases (UGTs) play a crucial role in maintaining endobiotic homeostasis and metabolizing xenobiotic compounds, particularly clinical drugs. However, the detailed catalytic mechanism of UGTs has not been fully elucidated due to the limited availability of reliable protein structures. Determining the catalytic domain of human UGTs has proven to be a significant challenge, primarily due to the difficulty in purifying and crystallizing the full-length protein. This study focused on the human UGT2B10 C-terminal cofactor binding domain, aiming to provide structural insights into the fundamental catalytic mechanisms. In this study, the C-terminal sugar-donor binding domain of human UGT2B10 was purified and crystallized using the vapor-diffusion method. The resulting UGT2B10 CTD crystals displayed high-quality diffraction patterns, allowing for data collection at an impressive resolution of 1.53 Å using synchrotron radiation. Subsequently, the structure of the UGT2B10 CTD was determined using the molecule replacement method with a homologous structure. The crystals were monoclinic, belonging to the space C2 with unit-cell parameters a = 85.90 Å, b = 58.39 Å, c = 68.87 Å, α = γ = 90°, and β = 98.138°. The Matthews coefficient VM was determined to be 2.24 Å3 Da-1 (solvent content 46.43%) with two molecules in the asymmetric unit. The crystal structure of UGT2B10 CTD was solved at a high resolution of 1.53 Å, revealing a conserved cofactor binding pocket. This is the first study determining the C-terminal cofactor binding domain of human UGT2B10, which plays a key role in additive drug metabolism.

Cell membrane-camouflaged bufalin targets NOD2 and overcomes multidrug resistance in pancreatic cancer.

Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer. The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo. CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells. Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.

Structural and signaling mechanisms of TAAR1 enabled preferential agonist design

Trace amine-associated receptor 1 (TAAR1) senses a spectrum of endogenous amine-containing metabolites (EAMs) to mediate diverse psychological functions and is useful for schizophrenia treatment without the side effects of catalepsy. Here, we systematically profiled the signaling properties of TAAR1 activation and present nine structures of TAAR1-Gs/Gq in complex with EAMs, clinical drugs, and synthetic compounds. These structures not only revealed the primary amine recognition pocket (PARP) harboring the conserved acidic D3.32 for conserved amine recognition and "twin" toggle switch for receptor activation but also elucidated that targeting specific residues in the second binding pocket (SBP) allowed modulation of signaling preference. In addition to traditional drug-induced Gs signaling, Gq activation by EAM or synthetic compounds is beneficial to schizophrenia treatment. Our results provided a structural and signaling framework for molecular recognition by TAAR1, which afforded structural templates and signal clues for TAAR1-targeted candidate compounds design.

Clinical comprehensive evaluation of Ruyi Zhenbao Pills in treatment of osteoarthritis

This study evaluated the clinical effectiveness of Ruyi Zhenbao Pills in the treatment of osteoarthritis, aiming to clarify its clinical advantages and promote rational drug use and related policy transformation. Following the relevant standards in Guidelines for the Comprehensive Evaluation of Drugs in Clinical Practice and Technical Specifications for the Clinical Comprehensive Evaluation of Chinese Patent Medicine, comprehensive research and related data on Ruyi Zhenbao Pills in the treatment of osteoarthritis were collected in the dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and traditional Chinese medicine(TCM) cha-racteristics(referred to as the "6+1" dimensions). Through evidence-based medicine, questionnaire surveys, health technology assessment, pharmacoeconomic evaluation, and other methods, a multi-criteria decision analysis(MCDA) model and CSC v2.0 software were used to comprehensively evaluate the clinical value of Ruyi Zhenbao Pills. Spontaneous reporting system data on adverse reactions and literature data indicate that the adverse reactions of Ruyi Zhenbao Pills are mostly general adverse reactions, with no reports of se-rious adverse reactions. The known risks are small, and its safety is rated as class A. It has been shown to effectively relieve joint pain and restore joint function in the treatment of osteoarthritis. However, more high-quality, large-sample randomized controlled trials are needed to further validate its effectiveness, which is rated as class B. There is evidence supporting its economic viability, and its economic is rated as class B. It demonstrates good clinical innovation, innovative enterprise service system, and industrial innovation, and innovation is rated as class A. Medical professionals and patients have a favorable perception of the suitability of Ruyi Zhenbao Pills, and further improvement can be made in terms of convenience of administration and promotion to facilitate rational drug use by healthcare professionals and patients. Suitability is rated as class B. The drug has a favorable price level, availability, and affordability, and accessibility is rated as class A. Ruyi Zhenbao Pills are a classic Tibetan medicinal prescription with excellent TCM theoretical characteristics. However, further research is needed on its use in human studies. TCM characteristics are rated as class B. Based on the evaluation results of the "6+1" dimensions, the comprehensive clinical evaluation is rated as grade B. Ruyi Zhenbao Pills have good clinical value in the treatment of osteoarthritis, and it is recommended to undergo the necessary procedures for conditional transformation into a policy for the management of essential clinical drugs.

Thermally engineered MSC-derived extracellular vesicles ameliorate colitis in mice by restoring the imbalanced Th17/Treg cell ratio

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have garnered extensive interest for their immunomodulatory properties in immune-mediated inflammatory diseases. However, the development of EVs as clinical drugs often faces challenges such as low production yield and suboptimal therapeutic efficacy. In this study, we discovered that thermally engineering was able to enhance the yield of MSC-EVs. Moreover, the PD-L1 expression of EVs released from the thermal engineering MSCs was found to be upregulated significantly, and these EVs ameliorated the symptoms and pathological damages in murine dextran sulfate sodium (DSS)-induced colitis model. The therapeutic effect on DSS-induced colitis was mediated through the regulation of the Th17/Treg cell balance, demonstrating the immunomodulatory properties of the thermally engineering MSC-EVs. Overall, our findings suggest that thermal engineering can be utilized as a promising strategy for enhancing EV production and may provide a potential therapeutic approach for clinical treatment of colitis.

Methods and research progress in the construction of animal models of osteosarcopenia: a scoping review.

Osteosarcopenia(OS) is a significant health concern resulting from the ageing process. Currently, as the population grows older, the prevalence of OS, a disease that entails the synchronous degeneration of muscles and bones, is mounting. This poses a serious threat to the health of the elderly while placing an enormous burden on social care. In order to comprehend the pathological mechanism of OS and develop clinical drugs, it is pertinent to construct an efficient animal model of OS. To investigate the modeling techniques of diverse experimental models of OS and elucidate their respective benefits and drawbacks, with the purpose of furnishing a theoretical foundation to advance experimental research on OS. We searched PubMed, Embase database, China Knowledge Network, Wanfang data platform and Vipshop journal platform databases from 2000 through to September 1, 2023. We included animal studies on sarcopenia or osteoporosis or osteosarcopenia or sarcopenia-osteoporosis, modeling methods for osteosarcopenia. Two independently screened study abstracts and full reports and complete data extraction. Eventually, Of 112, 106 citations screened. 4938 underwent full-text review and 38 met the inclusion criteria. we reviewed and analyzed the literature and categorized the animal models of OS into the following five categories: Aging OS models; Hormonal deficiency model of OS;Chemical injection to induce OS;Disuse OS models and Genetic engineering OS models. This review outlines animal modeling approaches for OS, providing a comprehensive summary of their advantages and disadvantages. The different models were evaluated and selected based on their respective strengths and weaknesses to enable higher quality research outcomes in various research directions. The most widely used and established approach is considered to be the ageing and chemical injection OS model, which has the advantages of excellent reproducibility and low cost. To gain a profound comprehension of the pathological mechanism of OS and to devise efficacious clinical treatments, it is imperative to establish a viable laboratory animal model of OS. This article surveys various modeling techniques assessing their benefits, drawbacks and areas of applicability while predominantly employing mice as the primary model animal. Additionally, the evaluation indicators of OS models are briefly described.

Precisely Inhibiting Excessive Intestinal Epithelial Cell Apoptosis to Efficiently Treat Inflammatory Bowel Disease with Oral Pifithrin-α Embedded Nanomedicine (OPEN).

The increased incidence of inflammatory bowel disease (IBD) has seriously affected the life quality of patients. IBD develops due to excessive intestinal epithelial cell (IEC) apoptosis, disrupting the gut barrier, colonizing harmful bacteria, and initiating persistent inflammation. The current therapeutic approaches that reduce inflammation are limited. Although IBD can be treated significantly by directly preventing IEC apoptosis, achieving this therapeutic approach remains challenging. Accordingly, we are the first to develop an oral pifithrin-α (PFTα, a highly specific p53 inhibitor) embedded nanomedicine (OPEN) to effectively treat IBD by inhibiting excessive IEC apoptosis. As a major hub for various stressors, p53 is a central determinant of cell fate, and its inhibition can effectively reduce excessive IEC apoptosis. The tailored OPEN can precisely inhibit the off-target and inactivation resulting from PFTα entry into the bloodstream. Subsequently, it persistently targets IBD lesions with high specificity to inhibit the pathological events caused by excessive IEC apoptosis. Eventually, OPEN exerts a significant curative effect compared with the clinical first-line drugs 5-aminosalicylic acid (5-ASA) and dexamethasone (DEX). Consequently, the OPEN therapeutic strategy provides new insights into comprehensive IBD therapy. This article is protected by copyright. All rights reserved.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1β and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.

Chinese guidelines for the treatment of chronic pain disorders with non-opioid analgesics

Non-opioid analgesics are one of the important clinical treatment drugs for chronic pain disorders, which mainly include non-steroidal anti-inflammatory analgesics, ion channel drugs, antidepressants, glucocorticoids, neurotrophic drugs, muscle relaxants, α2 adrenergic receptor agonists, bone metabolism regulating drugs, N-methyl-D-aspartate receptor antagonists and traditional Chinese patent medicines. The guidelines for the treatment of chronic pain disorders based on international classification of diseases (ICD)-11 with non-opioid analgesics have not been reported. This guideline was formulated under the leadership of expert group on Pain Disease Diagnosis and Treatment Special Ability Training Project of National Health Commission Capacity Building and Continuing Education Center (hereinafter referred to as the expert group). The expert group systematically searches and evaluates the effectiveness evidence related to the indications, contraindications, precautions, and other issues of non-opioid analgesics treatment for the seven major categories of chronic pain diseases in ICD-11. It also recommends non-opioid analgesic drug treatment for special chronic pain patients such as the elderly, women and children, as well as patients with liver and kidney dysfunction. This guide aims to provide reference for the application of non-opioid analgesics in the treatment of chronic pain disorders in different disciplines.

Potential therapeutic effect of olfactory ensheathing cells in neurological diseases: neurodegenerative diseases and peripheral nerve injuries.

Neurological diseases are destructive, mainly characterized by the failure of endogenous repair, the inability to recover tissue damage, resulting in the increasing loss of cognitive and physical function. Although some clinical drugs can alleviate the progression of these diseases, but they lack therapeutic effect in repairing tissue injury and rebuilding neurological function. More and more studies have shown that cell therapy has made good achievements in the application of nerve injury. Olfactory ensheathing cells (OECs) are a special type of glial cells, which have been proved to play an important role as an alternative therapy for neurological diseases, opening up a new way for the treatment of neurological problems. The functional mechanisms of OECs in the treatment of neurological diseases include neuroprotection, immune regulation, axon regeneration, improvement of nerve injury microenvironment and myelin regeneration, which also include secreted bioactive factors. Therefore, it is of great significance to better understand the mechanism of OECs promoting functional improvement, and to recognize the implementation of these treatments and the effective simulation of nerve injury disorders. In this review, we discuss the function of OECs and their application value in the treatment of neurological diseases, and position OECs as a potential candidate strategy for the treatment of nervous system diseases.

Systematic analysis of glutamine metabolism family genes and exploration of the biological role of GPT in colorectal cancer.

Colorectal cancer (CRC) is a malignancy of the digestive system with high incidence rate and mortality, and reliable diagnostic and prognostic markers for CRC are still lacking. Glutamine metabolism is crucial to the occurrence and development of CRC. However, no research has systematically analyzed the biological role of glutamine metabolism-related genes (GMRGs) in CRC. We downloaded gene expression data and clinical data of CRC patients from the TCGA database. The UCSC database downloads pan-cancer gene expression data and prognosis data. Characteristic GMRGs were screened out using differential analysis and two types of machine learning (SVM-REF and RandomForest). Single-cell RNA-sequencing data from CRC patients were downloaded from GEO data. ROC curve was used to evaluate the diagnostic value. Kaplan-Meier method and univariate Cox regression analysis were used to evaluate the prognostic value. The oncopredict package is used to calculate IC50 values for common drugs in CRC patients. A total of 31 differentially expressed GMRGs were identified, 9 of which were identified as characteristic GMRGs. Further evaluation of diagnostic and prognostic value finally identified GPT as the most important GMRGs in CRC. scRNA-seq analysis revealed that GPT is almost exclusively expressed in epithelial cells. GPT expression is closely related to the tumor microenvironment and can effectively distinguish the sensitivity of different CRC patients to clinical drugs. In addition, pan-cancer analysis showed that GPT is an excellent diagnostic and prognostic marker for multiple cancers. GPT is a reliable diagnostic, prognostic marker and therapeutic target in CRC.

Design, Synthesis, anti-inflammatory activity Evaluation, preliminary exploration of the Mechanism, molecule Docking, and structure-activity relationship analysis of batatasin III analogs

Most clinical drugs used to treat inflammation have serious gastrointestinal, renal, and cardiovascular side effects during long-term treatment. The development of new anti-inflammatory agents from natural products and their derivatives is a powerful approach to overcome these adverse effects. Batatasin III, a bibenzyl natural product, has been found to have anti-inflammatory activity. Compared with other anti-inflammatory agents, batatasin III has a simple and unique structure. Therefore, batatasin III and its analogs might have the potential to treat inflammation with only mild adverse effects as a new type of anti-inflammatory agent. Herein, we synthesized 26 batatasin III analogs and evaluated the anti-inflammatory activity in vitro. Analog 21 significantly inhibited (p < 0.01) nitric oxide production with an IC50 value of 12.95 μM. Western blot analysis further revealed that 21 reduced iNOS, phosphorylated p65, and β-catenin expression in a concentration-dependent manner. These results indicated that 21 could be a potential lead compound for developing a drug candidate for ulcerative colitis. Molecular docking analysis showed that p65 might be a potential target of 21 for the treatment of inflammatory disease. In addition, we analyzed the structure–activity relationship of the analogs, which provides a basis for future structural modifications.

Benzopyrone-mediated quinolones as potential multitargeting antibacterial agents

A new type of benzopyrone-mediated quinolones (BMQs) was rationally designed and efficiently synthesized as novel potential antibacterial molecules to overcome the global increasingly serious drug resistance. Some synthesized BMQs effectively suppressed the growth of the tested strains, outperforming clinical drugs. Notably, ethylidene-derived BMQ 17a exhibited superior antibacterial potential with low MICs of 0.5–2 μg/mL to clinical drugs norfloxacin, it not only displayed rapid bactericidal performance and inhibited bacterial biofilm formation, but also showed low toxicity toward human red blood cells and normal MDA-kb2 cells. Mechanistic investigation demonstrated that BMQ 17a could effectually induce bacterial metabolic disorders and promote the enhancement of reactive oxygen species to disrupt the bacterial antioxidant defense system. It was found that the active molecule BMQ 17a could not only form supramolecular complex with lactate dehydrogenase, which disturbed the biological functions, but also effectively embed into calf thymus DNA, thus affecting the normal function of DNA and achieving cell death. This work would provide an insight into developing new molecules to reduce drug resistance and expand antibacterial spectrum.