Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

A review of the neurotransmitter system associated with cognitive function of the cerebellum in Parkinson's disease

The dichotomized brain system is a concept that was generalized from the‘dual syndrome hypothesis’to explain the heterogeneity of cognitive impairment,in which anterior and posterior brain systems are independent but partially overlap.The dopaminergic system acts on the anterior brain and is responsible for executive function,working memory,and planning.In contrast,the cholinergic system acts on the posterior brain and is responsible for semantic fluency and visuospatial function.Evidence from dopaminergic/cholinergic imaging or functional neuroimaging has shed significant insight relating to the involvement of the cerebellum in the cognitive process of patients with Parkinson’s disease.Previous research has reported evidence that the cerebellum receives both dopaminergic and cholinergic projections.However,whether these two neurotransmitter systems are associated with cognitive function has yet to be fully elucidated.Furthermore,the precise role of the cerebellum in patients with Parkinson’s disease and cognitive impairment remains unclear.Therefore,in this review,we summarize the cerebellar dopaminergic and cholinergic projections and their relationships with cognition,as reported by previous studies,and investigated the role of the cerebellum in patients with Parkinson’s disease and cognitive impairment,as determined by functional neuroimaging.Our findings will help us to understand the role of the cerebellum in the mechanisms underlying cognitive impairment in Parkinson’s disease.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Lipid metabolism analysis in esophageal cancer and associated drug discovery

Esophageal cancer is an upper gastrointestinal malignancy with a bleak prognosis.It is still being explored in depth due to its complex molecular mechanisms of occurrence and development.Lipids play a crucial role in cells by participating in energy supply,biofilm formation,and signal transduction processes,and lipid metabolic reprogramming also constitutes a significant characteristic of malignant tumors.More and more studies have found esophageal cancer has obvious lipid metabolism abnormalities throughout its beginning,progress,and treatment resistance.The inhibition of tumor growth and the enhancement of antitumor therapy efficacy can be achieved through the regulation of lipid metabolism.Therefore,we reviewed and analyzed the research results and latest findings for lipid metabolism and associated analysis techniques in esophageal cancer,and comprehensively proved the value of lipid metabolic reprogramming in the evolution and treatment resistance of esophageal cancer,as well as its significance in exploring potential therapeutic targets and biomarkers.

Leukocyte immunoglobulin-like receptor B2:A promising biomarker for colorectal cancer

According to the latest global cancer statistics,colorectal cancer(CRC)has emerged as the third most prevalent malignant tumor across the globe.In recent decades,the medical field has implemented several levels of CRC screening tests,encompassing fecal tests,endoscopic examinations,radiological examinations and blood tests.Previous studies have shown that leukocyte immunoglobulin-like receptor B2(LILRB2)is involved in inhibiting immune cell function,immune evasion,and promoting tumor progression in acute myeloid leukemia and nonsmall cell lung cancer.However,its interaction with CRC has not been reported yet.Recently,a study published in the World Journal of Gastroenterology revealed that LILRB2 and its ligand,angiopoietin-like protein 2,are markedly overexpressed in CRC.This overexpression is closely linked to tumor progression and is indicative of a poor prognosis.The study highlights the potential of utilizing the concentration of LILRB2 in serum as a promising biomarker for tumors.However,there is still room for discussion regarding the data processing and analysis in this research.

Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage

Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

Glycolytic dysregulation in Alzheimer's disease:unveiling new avenues for understanding pathogenesis and improving therapy

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments.The current therapeutic strategies,primarily based on cholinesterase inhibitors and N-methyl-Daspartate receptor antagonists,offer limited symptomatic relief without halting disease progression,highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease.Recent studies have provided insights into the critical role of glycolysis,a fundamental energy metabolism pathway in the brain,in the pathogenesis of Alzheimer's disease.Alterations in glycolytic processes within neurons and glial cells,including microglia,astrocytes,and oligodendrocytes,have been identified as significant contributors to the pathological landscape of Alzheimer's disease.Glycolytic changes impact neuronal health and function,thus offering promising targets for therapeutic intervention.The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression.Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments,emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

Ferroptosis in liver diseases:Fundamental mechanism and clinical implications

This editorial discusses a recently published paper in the World Journal of Gastroenterology.Our research focuses on p53's regulatory mechanism for controlling ferroptosis,as well as the intricate connection between ferroptosis and liver diseases.Ferroptosis is a specific form of programmed cell death that is dependent on iron and displays unique features in terms of morphology,biology,and genetics,distinguishing it from other forms of cell death.Ferroptosis can affect the liver,which is a crucial organ responsible for iron storage and metabolism.Mounting evidence indicates a robust correlation between ferroptosis and the advancement of liver disorders.P53 has a dual effect on ferroptosis through various distinct signaling pathways.However,additional investigations are required to clarify the regulatory function of p53 metabolic targets in this complex association with ferroptosis.In the future,researchers should clarify the mechanisms by which ferroptosis and other forms of programmed cell death contribute to the progression of liver diseases.Identifying and controlling important regulatory factors associated with ferroptosis present a promising therapeutic strategy for liver disorders.

Cholecystokinin and cholecystokinin-A receptor: An attractive treatment strategy for biliary dyskinesia?

Biliary dyskinesia is a relatively common gastrointestinal disease that is increas-ing in incidence as living standards improve.However,its underlying pathogenesis remains unclear,hindering the development of therapeutic drugs.Recently,“Expression and functional study of cholecystokinin-A receptors on the interstitial Cajal-like cells of the guinea pig common bile duct”demonstrated that cholecystokinin(CCK)regulates the contractile function of the common bile duct through interaction with the CCK-A receptor in interstitial Cajal-like cells,contributing to improving the academic understanding of biliary tract dynamics and providing emerging directions for the pathogenesis and clinical management of biliary dyskinesia.This letter provides a brief overview of the role of CCK and CCK-A receptors in biliary dyskinesia from the perspective of animal experiments and clinical studies,and discusses prospects and challenges for the clinical application of CCK and CCK-A receptors as potential therapeutic targets.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

New insight into the role of exosomes in idiopathic membrane nephropathy

Exosomes,nanoscale extracellular vesicles(EVs)derived from the invagination of the endosomal membrane,are secreted by a majority of cell types.As carriers of DNA,mRNA,proteins,and microRNAs,exosomes are implicated in regulating biological activities under physiological and pathological conditions.Kidney-derived exosomes,which vary in origin and function,may either contribute to the pathogenesis of disease or represent a potential therapeutic resource.Membranous nephropathy(MN),an autoimmune kidney disease characterized by glomerular damage,is a predominant cause of nephrotic syndrome.Notably,MN,especially idiopathic membranous nephropathy(IMN),often results in end-stage renal disease(ESRD),affecting approximately 30%of patients and posing a considerable economic challenge to healthcare systems.Despite substantial research,therapeutic options remain ineffective at halting IMN progression,underscoring the urgent need for innovative strategies.Emerging evidence has implicated exosomes in IMN’s pathophysiology;Providing a fresh perspective for the discovery of novel biomarkers and therapeutic strategies.This review aims to scrutinize recent developments in exosome-related mechanisms in IMN and evaluate their potential as promising therapeutic targets and diagnostic biomarkers,with the hope of catalyzing further investigations into the utility of exosomes in MN,particularly IMN,ultimately contributing to improved patient outcomes in these challenging disease settings.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Unraveling autophagy-related pathogenesis in active ulcerative colitis:A bioinformatics approach

In this editorial,we provide commentary on the study by Gong et al.In this original research article,Gong et al employed a bioinformatics approach to investigate the involvement of autophagy in active ulcerative colitis(UC).Through differential gene expression analysis,they identified 58 differentially expressed autophagy-related genes in UC patients compared to healthy controls.Notably,HSPA5,CASP1,SERPINA1,CX3CL1,and BAG3,were found to be upregulated in active UC patients,suggesting their significance as core autophagyrelated targets.Enrichment analysis unveiled associations with crucial signaling pathways and diseases such as middle cerebral artery occlusion and glomerulonephritis.Moreover,immune cell infiltration analysis revealed notable differences in immune cell composition between UC patients and healthy controls.These findings offer valuable insights into the role of autophagy in UC pathogenesis and potential therapeutic targets.

Multifaceted role of microRNAs in gastric cancer stem cells: Mechanisms and potential biomarkers

MicroRNAs(miRNAs)have received much attention in the past decade as potential key epigenomic regulators of tumors and cancer stem cells(CSCs).The abnormal expression of miRNAs is responsible for different phenotypes of gastric cancer stem cells(GCSCs).Some specific miRNAs could be used as promising biomarkers and therapeutic targets for the identification of GCSCs.This review summarizes the coding process and biological functions of miRNAs and demon-strates their role and efficacy in gastric cancer(GC)metastasis,drug resistance,and apoptosis,especially in the regulatory mechanism of GCSCs.It shows that the overexpression of onco-miRNAs and silencing of tumor-suppressor miRNAs can play a role in promoting or inhibiting tumor metastasis,apart from the initial formation of GC.It also discusses the epigenetic regulation and potential clinical applications of miRNAs as well as the role of CSCs in the pathogenesis of GC.We believe that this review may help in designing novel therapeutic approaches for GC.

APOBEC3G Role on HIV Infection in Africa: A Systematic Review

The highly active antiretroviral treatment (HAART) has allowed people living with HIV to live longer with a better quality of life. However, toxicity and the emergence of drug resistance arise from HAART use. Therefore, new antiretroviral therapy is needed since no cure or vaccine is available against HIV. Virus-host interaction has been proven to be important in the last decade. Host factors such as the C-C chemokine receptor type 5 (CCR5), a receptor used by HIV to penetrate host cells, have led to the discovery of the Maraviroc, which is an antiretroviral medication used in the United States. In contrast, other factors like C-X-C Motif Chemokine Receptor 4 (CXCR4) and the Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G), a potent host defense factor against HIV, is under investigation. APOBEC3G antiviral activity remains a possible therapeutic target against HIV. This systematic review aimed to synthesize the available evidence on the role of APOBEC3G polymorphisms and their expression on HIV infection disease progression in Africa. We used Web of Science, PubMed, Embase, and Google Scholar and searched for relevant publications in French or English reporting on APOBEC3G polymorphisms association with HIV infection in African populations from January 2009 to May 2023. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyzes) was used to process for reporting systematic review. Fifteen studies were included, of which seven were on APOBEC3G polymorphisms and eight were on APOBEC3G expression. Among the APOBEC3G polymorphisms, the most studied was H186R or rs8177832. The average of the minor allele frequency of H186R of APOBEC3G available for the studies included in this study was 0.29 with a 95% CI (0.172;0.401) and varied from 0.108 reported in Uganda to 0.47 recorded from Burkina Faso. The polymorphism H186R was not associated with HIV status in Southern Africa. However, the referent allele of H186R was protective against HIV infection in Western Central Africa, while in West Africa, it was the minor allele (G) of H186R which was protective against HIV. This review warrants a need to increase research on APOBEC3G, from its variants to its hypermutations on the continent with an essential variety of HIV-1 subtypes, to impact the research on A3G-based anti-HIV strategies.

Receptor tyrosine kinase-like orphan receptor 1:A novel antitumor target in gastrointestinal cancers

Receptor tyrosine kinase-like orphan receptor 1(ROR1)is a member of the type I receptor tyrosine kinase family.ROR1 is pivotal in embryonic development and cancer,and serves as a biomarker and therapeutic target.It has soluble and membrane-bound subtypes,with the latter highly expressed in tumors.ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms.Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis.Additionally,ROR1 may regulate the cell cycle,stem cell characteristics,and interact with other signaling pathways to affect cancer progression.This review explores the structure,expression and role of ROR1 in the development of gastrointestinal cancers.It discusses current antitumor strategies,outlining challenges and prospects for treatment.

Aryl hydrocarbon receptor dynamics in esophageal squamous cell carcinoma:From immune modulation to therapeutic opportunities

Esophageal squamous cell carcinoma(ESCC)is a substantial global health burden.Immune escape mechanisms are important in ESCC progression,enabling cancer cells to escape the surveillance of the host immune system.One key player in this process is the Aryl Hydrocarbon Receptor(AhR),which influences multiple cellular processes,including proliferation,differentiation,metabolism,and immune regulation.Dysregulated AhR signaling participates in ESCC development by stimulating carcinogenesis,epithelial-mesenchymal transition,and immune escape.Targeting AhR signaling is a potential therapeutic approach for ESCC,with AhR ligands showing efficacy in preclinical studies.Additionally,modification of AhR ligands and combination therapies present new opportunities for therapeutic intervention.This review aims to address the knowledge gap related to the role of AhR signaling in ESCC pathogenesis and immune escape.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

MicroRNAs in mouse and rat models of experimental epilepsy and potential therapeutic targets

Epilepsy is a common and serious neurological disease that causes recurrent seizures. The brain damage caused by seizures can lead to depression, anxiety, cognitive impairment, or disability. In almost all cases chronic seizures are difficult to cure. MicroRNAs are widely expressed in the central nervous system and play important roles in the pathogenesis of several neurological disorders, including epilepsy. A variety of animals(mostly mice and rats) have been used to induce experimental epilepsy using different protocols and miRNA profiling performed. Most of the recent studies reviewed had performed miRNA profiling in hippocampal tissues and a large number of microRNAs were dysregulated when compared to controls. Most notably, miR-132-3p,-146a-5p,-10a-5p,-21a-3p,-27a-3p,-142a-5p,-212-3p,-431-5p, and-155 were upregulated in both the mouse and rat studies. Overexpression of miR-137 and miR-219 decreased seizure severity in a mouse epileptic model, and suppression of miR-451,-10a-5p,-21a-5p,-27a-5p,-142a-5p,-431-5p,-155, and-134 had a positive influence on seizure behavior. In the rat studies, overexpression of miR-139-5p decreased neuronal damage in drug-resistant rats and inhibition of miR-129-2-3p,-27a-3p,-155,-134,-181a, and-146a had a positive effect on seizure behavior and/or reduced the loss of neuronal cells. Further studies are warranted using adult female and immature male and female animals. It would also be helpful to test the ability of specific agomirs and antagomirs to control seizure activity in a subhuman primate model of epilepsy such as adult marmosets injected intraperitoneally with pilocarpine or cynomolgus monkeys given intrahippocampal injections of kainic acid.

Treatment of liver fibrosis:Past,current,and future

Liver fibrosis accompanies the progression of chronic liver diseases independent of etiologies,such as hepatitis viral infection,alcohol consumption,and metabolicassociated fatty liver disease.It is commonly associated with liver injury,inflammation,and cell death.Liver fibrosis is characterized by abnormal accumulation of extracellular matrix components that are expressed by liver myofibroblasts such as collagens and alpha-smooth actin proteins.Activated hepatic stellate cells contribute to the major population of myofibroblasts.Many treatments for liver fibrosis have been investigated in clinical trials,including dietary supplementation(e.g.,vitamin C),biological treatment(e.g.,simtuzumab),drug(e.g.,pegbelfermin and natural herbs),genetic regulation(e.g.,non-coding RNAs),and transplantation of stem cells(e.g.,hematopoietic stem cells).However,none of these treatments has been approved by Food and Drug Administration.The treatment efficacy can be evaluated by histological staining methods,imaging methods,and serum biomarkers,as well as fibrosis scoring systems,such as fibrosis-4 index,aspartate aminotransferase to platelet ratio,and non-alcoholic fatty liver disease fibrosis score.Furthermore,the reverse of liver fibrosis is slowly and frequently impossible for advanced fibrosis or cirrhosis.To avoid the lifethreatening stage of liver fibrosis,anti-fibrotic treatments,especially for combined behavior prevention,biological treatment,drugs or herb medicines,and dietary regulation are needed.This review summarizes the past studies and current and future treatments for liver fibrosis.