Strategies for translating proteomics discoveries into drug discovery for dementia

Tauopathies,diseases characterized by neuropathological aggregates of tau including Alzheimer's disease and subtypes of fro ntotemporal dementia,make up the vast majority of dementia cases.Although there have been recent developments in tauopathy biomarkers and disease-modifying treatments,ongoing progress is required to ensure these are effective,economical,and accessible for the globally ageing population.As such,continued identification of new potential drug targets and biomarkers is critical."Big data"studies,such as proteomics,can generate information on thousands of possible new targets for dementia diagnostics and therapeutics,but currently remain underutilized due to the lack of a clear process by which targets are selected for future drug development.In this review,we discuss current tauopathy biomarkers and therapeutics,and highlight areas in need of improvement,particularly when addressing the needs of frail,comorbid and cognitively impaired populations.We highlight biomarkers which have been developed from proteomic data,and outline possible future directions in this field.We propose new criteria by which potential targets in proteomics studies can be objectively ranked as favorable for drug development,and demonstrate its application to our group's recent tau interactome dataset as an example.

Practice of Perioperative Rational Use of Antibacterial Drugs Based on Drug Pathway

[Objectives]To establish a new management model for rational use of perioperative antibacterial drugs in surgical departments.[Methods]Based on evidence-based medicine,the department s drug pathway was formulated,and the new mode of rational drug use control was established by using fine pharmaceutical technology intervention,and the intervention effect was evaluated by the intensity of antibacterial drug use,per capita drug costs and the proportion of drugs.[Results]After adopting drug pathway in departments,the intensity of antibacterial drug use,per capita drug costs and the proportion of drugs decreased significantly,and the effect of rational drug use control was remarkable.[Conclusions]The drug pathway provides a new management and control mode for the rational use of perioperative antibacterial drugs in surgical departments of hospitals.Thus,it is worthy of popularization and application.

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer

Colorectal cancer(CRC)is a form of cancer that is often resistant to chemotherapy,targeted therapy,radiotherapy,and immunotherapy due to its genomic instability and inflammatory tumor microenvironment.Ferroptosis,a type of non-apoptotic cell death,is characterized by the accumulation of iron and the oxidation of lipids.Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells.Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance.Moreover,the gut,responsible for regulating iron absorption and release,could influence CRC susceptibility through iron metabolism modulation.Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management,potentially revolutionizing treatment approaches for therapy-resistant cancers.

Repurposing Loperamide as an Anti-Infection Drug for the Treatment of Intracellular Bacterial Pathogens

Infections caused by intracellular bacterial pathogens are difficult to treat since most antibiotics have low cell permeability and undergo rapid degradation within cells.The rapid development and dissemination of antimicrobial–resistant strains have exacerbated this dilemma.With the increasing knowledge of host–pathogen interactions,especially bacterial strategies for survival and proliferation within host cells,host-directed therapy(HDT)has attracted increased interest and has emerged as a promising antiinfection method for treating intracellular infection.Herein,we applied a cell-based screening approach to a US Food and Drug Administration(FDA)-approved drug library to identify compounds that can inhibit the intracellular replication of Salmonella Typhimurium(S.Typhimurium).This screening allowed us to identify the antidiarrheal agent loperamide(LPD)as a potent inhibitor of S.Typhimurium intracellular proliferation.LPD treatment of infected cells markedly promoted the host autophagic response and lysosomal activity.A mechanistic study revealed that the increase in host autophagy and elimination of intracellular bacteria were dependent on the high expression of glycoprotein nonmetastatic melanoma protein B(GPNMB)induced by LPD.In addition,LPD treatment effectively protected against S.Typhimurium infection in Galleria mellonella and mouse models.Thus,our study suggested that LPD may be useful for the treatment of diseases caused by intracellular bacterial pathogens.Moreover,LPD may serve as a promising lead compound for the development of anti-infection drugs based on the HDT strategy.

Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.

Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Stem cell technology for antitumor drug loading and delivery in oncology

The main aim of antineoplastic treatment is to maximize patient benefit by augmenting the drug accumulation within affected organs and tissues,thus incrementing drug effects and,at the same time,reducing the damage of non-involved tissues to cytotoxic agents.Mesenchymal stromal cells(MSC)represent a group of undifferentiated multipotent cells presenting wide self-renewal features and the capacity to differentiate into an assortment of mesenchymal family cells.During the last year,they have been proposed as natural carriers for the selective release of antitumor drugs to malignant cll,s thus optimizing cytotoxic action on cancer cll,while significantly reducing adverse side efect on healthy cells.MSC chemotherapeutic drug loading and delivery is an encouraging new area of cell therapy for several tumors,especially for those with unsatisfactory prognosis and limited treatment options available.Although some experim ental models have been sucesfuly developed,phase I dinical studies are needed to confirm this potential application of cell therapy,in particular in the case of primary and secondary lung cancers.

Beware of the serious harm of veterinary drug poisoning:a case report

Veterinary drugs are substances(including pharmaceutical feed additives)used to prevent,treat,and diagnose diseases or regulate the physiological functions of animals.Veterinary drug poisoning in humans is relatively rare both in China and the rest of the world.Here,we report a case of death from veterinary drug poisoning from avermectin-closantel.Avermectin-closantel is a broad-spectrum antiparasitic drug,which has high efficacy against a variety of trematodes and nematodes.

3D bioprinting of in vitro porous hepatoma models:establishment,evaluation,and anticancer drug testing

Traditional tumor models do not tend to accurately simulate tumor growth in vitro or enable personalized treatment and are particularly unable to discover more beneficial targeted drugs.To address this,this study describes the use of threedimensional(3D)bioprinting technology to construct a 3D model with human hepatocarcinoma SMMC-7721 cells(3DP-7721)by combining gelatin methacrylate(GelMA)and poly(ethylene oxide)(PEO)as two immiscible aqueous phases to form a bioink and innovatively applying fluorescent carbon quantum dots for long-term tracking of cells.The GelMA(10%,mass fraction)and PEO(1.6%,mass fraction)hydrogel with 3:1 volume ratio offered distinct pore-forming characteristics,satisfactorymechanical properties,and biocompatibility for the creation of the 3DP-7721 model.Immunofluorescence analysis and quantitative real-time fluorescence polymerase chain reaction(PCR)were used to evaluate the biological properties of the model.Compared with the two-dimensional culture cell model(2D-7721)and the 3D mixed culture cell model(3DM-7721),3DP-7721 significantly improved the proliferation of cells and expression of tumor-related proteins and genes.Moreover,we evaluated the differences between the three culture models and the effectiveness of antitumor drugs in the three models and discovered that the efficacy of antitumor drugs varied because of significant differences in resistance proteins and genes between the three models.In addition,the comparison of tumor formation in the three models found that the cells cultured by the 3DP-7721 model had strong tumorigenicity in nude mice.Immunohistochemical evaluation of the levels of biochemical indicators related to the formation of solid tumors showed that the 3DP-7721 model group exhibited pathological characteristics of malignant tumors,the generated solid tumors were similar to actual tumors,and the deterioration was higher.This research therefore acts as a foundation for the application of 3DP-7721 models in drug development research.

Ultra-conservative noncoding RNA uc.243 confers chemo-resistance by facilitating the efflux of the chemotherapeutic drug in ovarian cancer

Background:Despite improvements in objective response rates to cisplatin-based combination chemotherapy,the majority of advanced ovarian cancer remains suboptimal,resulting in poor survival.it has been found that non-coding RNAs(ncRNAs)not only participate in the transmission of signals between various cells but also participate in tumor immunity and anti-tumor immune responses,thereby regulating tumor occurrence and development.However,the function and detailed mechanism of ultraconserved RNA(ucRNA)in ovarian cancer chemoresistance is still unclear.Methods:Western blotting assay,Quantitative real-time PCR analysis(qPCR),and Kaplan-Meier Plotter analysis were performed to analyze the expression and prognosis of uc.243 in ovarian carcinoma.Cytotoxicity assay and Annexin V assay were performed to analyze the function of uc.243 in cisplatin resistance in ovarian cancer cells.RNA pull-down and qPCR experiments were performed to explore the molecular mechanism of uc.243 enhancing cisplatin resistance in ovarian cancer cells.Results:Herein,we found that uc.243 was remarkably upregulated and correlated with patient survival in chemoresistance ovarian cancer patients compared with chemo-sensitive ovarian cancer.Functional experiment displayed that uc.243 induced cisplatin resistance on ovarian cancer cells by facilitating the efflux of cisplatin(CDDP);but inhibiting the expression of uc.243 significantly reverses this function.Mechanistically,uc.243 can inhibit the binding of RNA binding protein DGCR8 microprocessor complex subunit to pri-miR-155,thereby inhibiting the cleavage of pri-miR-155 and decrease in mature miR-155,subsequently upregulates the expression of ATP binding cassette subfamily B member(ABCB1,ABCC2).Conclusion:Our research findings indicate that uc.243 can induce chemotherapy resistance in ovarian cancer,suggesting that it may become a new prognostic biomarker for malignant ovarian cancer.

Association of Cytokines with Clinical Indicators in Patients with Drug-Induced Liver Injury

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators.Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),antiinfective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed.Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group.Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-αand IL-6 may partake the inflammatory process of DILI.

Glucocorticoids-based prodrug design:Current strategies and research progress

Attributing to their broad pharmacological effects encompassing anti-inflammation,antitoxin,and immunosuppression,glucocorticoids(GCs)are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus,nephritis,arthritis,ulcerative colitis,asthma,keratitis,macular edema,and leukemia.However,longterm use often causes undesirable side effects,including metabolic disorders-induced Cushing's syndrome(buffalo back,full moon face,hyperglycemia,etc.),osteoporosis,aggravated infection,psychosis,glaucoma,and cataract.These notorious side effects seriously compromise patients'quality of life,especially in patients with chronic diseases.Therefore,glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention.Among them,prodrugs have the advantages of low investment,low risk,and high success rate,making them a promising strategy.In this review,we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades,including polymer-based prodrugs,dendrimer-based prodrugs,antibody-drug conjugates,peptide-drug conjugates,carbohydrate-based prodrugs,aliphatic acid-based prodrugs and so on.Besides,we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs.This review is expected to be helpful for the research and development of novel GCs and prodrugs.

Drug-Drug Interactions in Patients with Breast Cancer

The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary and alternative medicine (CAM). The study underscores the heightened susceptibility of elderly patients to DDIs due to the prevalence of polypharmacy and the widespread utilization of CAM among breast cancer patients. The potential ramifications of DDIs, encompassing adverse drug events and diminished treatment efficacy, are elucidated. The paper accentuates the imperative for healthcare providers to comprehensively understand both conventional and CAM therapies, enabling them to provide patients with informed guidance regarding safe and efficacious treatment options, culminating in enhanced patient outcomes.

Artificial intelligence as a tool in drug discovery and development

The rapidly advancing field of artificial intelligence(AI)has garnered substantial attention for its potential application in drug discovery and development.This opinion review critically examined the feasibility and prospects of integrating AI as a transformative tool in the pharmaceutical industry.AI,encompassing machine learning algorithms,deep learning,and data analytics,offers unprecedented opportunities to streamline and enhance various stages of drug development.This opinion review delved into the current landscape of AI-driven approaches,discussing their utilization in target identification,lead optimization,and predictive modeling of pharmacokinetics and toxicity.We aimed to scrutinize the integration of large-scale omics data,electronic health records,and chemical informatics,highlighting the power of AI in uncovering novel therapeutic targets and accelerating drug repurposing strategies.Despite the considerable potential of AI,the review also addressed inherent challenges,including data privacy concerns,interpretability of AI models,and the need for robust validation in realworld clinical settings.Additionally,we explored ethical considerations surrounding AI-driven decision-making in drug development.This opinion review provided a nuanced perspective on the transformative role of AI in drug discovery by discussing the existing literature and emerging trends,presenting critical insights and addressing potential hurdles.In conclusion,this study aimed to stimulate discourse within the scientific community and guide future endeavors to harness the full potential of AI in drug development.

The Efficacy and Safety of Drug-Coated Balloons in the Treatment of Acute Myocardial Infarction

The incidence of acute myocardial infarction (AMI) is increasing year by year, which seriously endangers human health around the world. The preferred treatment strategy for AMI patients is the use of drug-eluting stents (DES), as there is ample evidence to suggest that stent implantation can reduce major adverse cardiovascular events (MACEs). With the application of drug-coated balloons (DCBs) and the enhancement of the concept of interventional without implantation, the question is whether DCBs can be safely and effectively used in patients with AMI? The purpose of this study was to investigate the safety and effectiveness of DCBs in the treatment of AMI. A retrospective review of clinical data was conducted on 55 AMI patients who underwent primary percutaneous coronary intervention (PCI) from January 2020 to December 2021. Of these patients, 25 were treated with DCBs and 30 were treated with DESs. Optical coherence tomography (OCT) was used to measure the minimum lumen diameter, lumen stenosis, and coronary artery dissection before and after surgery, and angina pectoris attacks and various MACEs were recorded at 1, 6, and 12 months after surgery. The results showed that there were no significant differences in clinical baseline data between the two groups. However, the minimum lumen diameter of the DCB group immediately after the operation was smaller than that of the DES group, and the stenosis degree of the lumen in the DCB group was higher than that in the DES group. The incidence of coronary artery dissection in the DCB group was significantly higher than that in the DES group, but the majority of them were type B. At 1, 6, and 12 months after treatment, there was no significant difference in the occurrence of MACEs between the two groups. In conclusion, DCBs is a safe and effective treatment for AMI. However, the incidence of coronary artery dissection in DCB patients is higher than that in DES patients, but the majority of them are type B. .

Analytic Hierarchy Process for Technological Risks in the Process of Innovative Drug Development in China

Objective To identify the critical risks in the process of innovative drug research and development,and to provide reference for improving the efficiency of innovative drug development and risk control in China.Methods Expert investigation and analytic hierarchy process were used to determine the weights of different risks.Results and Conclusion The research and analysis results showed that the risks at different stages of development had different effects on the success rate of drug development,among which the risk at the drug discovery stage influenced the most.In the drug discovery stage,inappropriate target selection had the greatest impact on the success rate of drug development.The lack of appropriate cell tissue or animal models had the greatest impact on the success rate of drug development from the discovery of a compound to the application for clinical trials.The difference in changes between nonclinical and clinical studies had the greatest impact on the success rate of drug development from early clinical studies to pivotal clinical studies.Incorrect dose selection had the greatest impact on the success rate of drug development from pivotal clinical studies to marketing authorization applications.The biggest impact from the marketing authorization application to the approval stage was inadequate communication with regulators.After investigating the weight of risk factors in the process of innovative drug development based on scientific methods,a new perspective for the risk control of new drug development and improving the research and development efficiency is provided.

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

Peptide drugs: a new direction in cancer immunotherapy

Cancer immunotherapy has emerged as a promising approach in cancer treatment and is considered a major advancement after surgical interventions, radiotherapy, chemotherapy, and targeted therapy. The clinical use of immunotherapeutic drugs, particularly antibody-based drugs that target immune checkpoints, has notably increased~1.

Vitamin D,selenium,and antidiabetic drugs in the treatment of type 2 diabetes mellitus with Hashimoto's thyroiditis

BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.

Microglia in drug addiction:A perspective from neuroimmunopharmacology

Drug addiction refers to a state of dependence that arises from habitual drug intake and can result in specific withdrawal symptoms upon cessation.The most commonly abused substances include psychostimulants,cannabinoids,and opioids.When drugs are consumed,they stimulate the release of dopamine,a neurotransmitter crucial for the pleasure and reward centers of the brain.With repeated drug use,the brain undergoes various changes,leading to tolerance,dependence,and addiction(Lüscher et al.,2020).The mechanisms involved in drug addiction are highly complex and involve diverse cell types within the brain.