Molecular pathways of liver regeneration:A comprehensive review

The liver is a unique parenchymal organ with a regenerative capacity allowing it to restore up to 70%of its volume.Although knowledge of this phenomenon dates back to Greek mythology(the story of Prometheus),many aspects of liver regeneration are still not understood.A variety of different factors,including inflammatory cytokines,growth factors,and bile acids,promote liver regeneration and control the final size of the organ during typical regeneration,which is performed by mature hepatocytes,and during alternative regeneration,which is performed by recently identified resident stem cells called“hepatic progenitor cells”.Hepatic progenitor cells drive liver regeneration when hepatocytes are unable to restore the liver mass,such as in cases of chronic injury or excessive acute injury.In liver maintenance,the body mass ratio is essential for homeostasis because the liver has numerous functions;therefore,a greater understanding of this process will lead to better control of liver injuries,improved transplantation of small grafts and the discovery of new methods for the treatment of liver diseases.The current review sheds light on the key molecular pathways and cells involved in typical and progenitor-dependent liver mass regeneration after various acute or chronic injuries.Subsequent studies and a better understanding of liver regeneration will lead to the development of new therapeutic methods for liver diseases.

Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update

Hepatocellular carcinoma(HCC)is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancerrelated deaths worldwide.In recent years,uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets.Despite the vast amount of data on this topic,HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile.Therefore,the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase.In this context,the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior.In line with these efforts,this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus(HBV)and hepatitis C virus(HCV)participate in oncogenesis and tumor progression in HCC and summarize new findings.Cumulative evidence indicates that HBV DNA integration promotes genomic instability,resulting in the overexpression of genes related to cancer development,metastasis,and angiogenesis or inactivation of tumor suppressor genes.In addition,genetic variations in HBV itself,especially preS2 deletions,may play a role in malignant transformation.Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs.Similarly,viral proteins of both HBV and HCV can affect pathways that are important anticancer targets.The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated.Additional,comprehensive studies are also needed to determine these viruses'interaction with integrins,farnesoid X,and the apelin system in malignant transformation and tumor progression.Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined,further studies are warranted to decipher the relationship among inflam masomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.

Epidermal growth factor receptor:a key manipulator in molecular pathways of malignant glioma

The epidermal growth factor receptor （EGFR） is a member of the ErbB/EGFR family, including EGFR/Herl, ErbB2/Her2, ErbB-3/Her3, and ErbB-4/Her4. EGFR exerts its effects through the receptor tyrosine kinase phosphorylation and activation of important downstream signaling pathways in normal and neoplastic cells, mainly the Ras GTPase/MAP kinase （MAPK）, STAT3, and phosphatidylinositide 3 kinase-AKT pathways. EGFR deregulation is common in malignant glioma, especially primary glioblastoma, and exists in three forms： gene overexpression （amplification）, autocrine effects of EGFR activation, and activating receptor mutation （EGFRvlII）. However, some EGFR abnormalities have also been found in low-grade gliomas, including the nuclear localization of EGFR, expression in the microfoci of anaplastic transformation, and association with neovascularization in the mesenchyma of the glioma, which suggests that some unknown EGFR-related mechanisms are possibly responsible for its central role in the initiation and progression of malignant glioma. Uncovering these mechanisms will have potential value in the development of radio- therapy, chemotherapy, and EGFR-targeted therapy for glioma.

Uncovering the impact of alcohol on internal organs and reproductive health:Exploring TLR4/NF-kB and CYP2E1/ROS/Nrf2 pathways

This review delves into the detrimental impact of alcohol consumption on internal organs and reproductive health,elucidating the underlying mechanisms involving the Toll-like receptor 4(TLR4)/Nuclear factor kappa light chain enhancer of activated B cells(NF-kB)pathway and the Cytochrome P4502E1(CYP2E1)/reactive oxygen spe-cies(ROS)/nuclear factor erythroid 2-related factor 2(Nrf2)pathways.The TLR4/NF-kB pathway,crucial for inflammatory and immune responses,triggers the production of pro-inflammatory agents and type-1 interferon,disrupting the balance between inflammatory and antioxidant responses when tissues are chronically exposed to al-cohol.Alcohol-induced dysbiosis in gut microbes heightens gut wall permeability to pathogen-associated molecular patterns(PAMPs),leading to liver cell infection and subsequent inflammation.Concurrently,CYP2E1-mediated alcohol metabolism gen-erates ROS,causing oxidative stress and damaging cells,lipids,proteins,and deoxy-ribonucleic acid(DNA).To counteract this inflammatory imbalance,Nrf2 regulates gene expression,inhibiting inflammatory progression and promoting antioxidant re-sponses.Excessive alcohol intake results in elevated liver enzymes(ADH,CYP2E1,and catalase),ROS,NADH,acetaldehyde,and acetate,leading to damage in vital organs such as the heart,brain,and lungs.Moreover,alcohol negatively affects reproduc-tive health by inhibiting the hypothalamic-pituitary-gonadal axis,causing infertility in both men and women.These findings underscore the profound health concerns associated with alcohol-induced damage,emphasizing the need for public awareness regarding the intricate interplay between immune responses and the multi-organ im-pacts of alcohol consumption.

Cardiac fibrosis: Histological features, molecular pathways and therapeutic targets

Cardiac fibrosis is defined as the unbalanced production and degradation of cardiac interstitial extracellular matrix(ECM),leading to systolic and diastolic dysfunction,arrhythmias,and adverse outcomes of many cardiac pathophysiological conditions.The accumulation of myocardial ECM increases the risk of arrhythmias and impairs cardiac function,ultimately leading to the development of heart failure.Although slowing or reversing the development of excessive accumulation of ECM and cardiac fibrosis is important for maintaining cardiac function,there is currently no approved treatment for them.Activated cardiac fibroblasts are the main effector cells of cardiac fibrosis.Their expansion after pathophysiologic stimuli such as pressure overload,volume overload,metabolic dysfunction,wound healing,and aging is primarily driven by activating resident interstitial populations.While cardiac fibroblasts are the primary effector cells in the fibrotic heart,monocytes/macrophages,lymphocytes,mast cells,vascular cells,and cardiomyocytes may also contribute to the fibrotic response,by secreting critical fibrotic factors and matricellular proteins.This review discusses histological features,molecular pathways involved in the pathogenesis of cardiac fibrosis and possible therapeutic targets.Understanding the occurrence,development and diffusion mechanisms of cardiac fibrosis has important clinical implications for the discovery of drugs to prevent the progression of cardiac fibrosis.

NMI,POLR3G and APIP are the key molecules connecting glaucoma with high intraocular pressure:a clue for early diagnostic biomarker candidates

AIM:To understand the molecular connectivity between the intraocular pressure(IOP)and glaucoma which will provide possible clues for biomarker candidates.METHODS:The current study uncovers the important genes connecting IOP with the core functional modules of glaucoma.An integrated analysis was performed using glaucoma and IOP microarray datasets to screen for differentially expressed genes(DEGs)in both conditions.To the selected DEGs,the protein interaction network was constructed and dissected to determine the core functional clusters of glaucoma.For the clusters,the connectivity of IOP DEGs was determined.Further,enrichment analyses were performed to assess the functional annotation and potential pathways of the crucial clusters.RESULTS:The gene expression analysis of glaucoma and IOP with normal control showed that 408 DEGs(277 glaucoma and 131 IOP genes)were discovered from two GEO datasets.The 290 DEGs of glaucoma were extended to form a network containing 1495 proteins with 9462 edges.Using ClusterONE,the network was dissected to have 12 clusters.Among them,three clusters were linked with three IOP DEGs[N-Myc and STAT Interactor(NMI),POLR3G(RNA Polymerase Ⅲ Subunit G),and APAF1-interacting protein(APIP)].In the clusters,ontology analysis revealed that RNA processing and transport,p53 class mediators resulting in cell cycle arrest,cellular response to cytokine stimulus,regulation of phosphorylation,regulation of type Ⅰ interferon production,DNA deamination,and cellular response to hypoxia were significantly enriched to be implicated in the development of glaucoma.Finally,NMI,POLR3G,and APIP may have roles that were noticed altered in glaucoma and IOP conditions.CONCLUSION:Our findings could help to discover new potential biomarkers,elucidate the underlying pathophysiology,and identify new therapeutic targets for glaucoma.

Role of glioma stem cells in promoting tumor chemo- and radioresistance: A systematic review of potential targeted treatments

BACKGROUND Gliomas pose a significant challenge to effective treatment despite advancements in chemotherapy and radiotherapy.Glioma stem cells(GSCs),a subset within tumors,contribute to resistance,tumor heterogeneity,and plasticity.Recent studies reveal GSCs’role in therapeutic resistance,driven by DNA repair mechanisms and dynamic transitions between cellular states.Resistance mechanisms can involve different cellular pathways,most of which have been recently reported in the literature.Despite progress,targeted therapeutic approaches lack consensus due to GSCs’high plasticity.AIM To analyze targeted therapies against GSC-mediated resistance to radio-and chemotherapy in gliomas,focusing on underlying mechanisms.METHODS A systematic search was conducted across major medical databases(PubMed,Embase,and Cochrane Library)up to September 30,2023.The search strategy utilized relevant Medical Subject Heading terms and keywords related to including“glioma stem cells”,“radiotherapy”,“chemotherapy”,“resistance”,and“targeted therapies”.Studies included in this review were publications focusing on targeted therapies against the molecular mechanism of GSC-mediated re-sistance to radiotherapy resistance(RTR).RESULTS In a comprehensive review of 66 studies on stem cell therapies for SCI,452 papers were initially identified,with 203 chosen for full-text analysis.Among them,201 were deemed eligible after excluding 168 for various reasons.The temporal breakdown of studies illustrates this trend:2005-2010(33.3%),2011-2015(36.4%),and 2016-2022(30.3%).Key GSC models,particularly U87(33.3%),U251(15.2%),and T98G(15.2%),emerge as significant in research,reflecting their representativeness of glioma characteristics.Pathway analysis indicates a focus on phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(mTOR)(27.3%)and Notch(12.1%)pathways,suggesting their crucial roles in resistance development.Targeted molecules with mTOR(18.2%),CHK1/2(15.2%),and ATP binding cassette G2(12.1%)as frequent targets underscore their importance in overcoming GSC-mediated resistance.Various therapeutic agents,notably RNA inhibitor/short hairpin RNA(27.3%),inhibitors(e.g.,LY294002,NVP-BEZ235)(24.2%),and monoclonal antibodies(e.g.,cetuximab)(9.1%),demonstrate versatility in targeted therapies.among 20 studies(60.6%),the most common effect on the chemotherapy resistance response is a reduction in temozolomide resistance(51.5%),followed by reductions in carmustine resistance(9.1%)and doxorubicin resistance(3.0%),while resistance to RTR is reduced in 42.4%of studies.CONCLUSION GSCs play a complex role in mediating radioresistance and chemoresistance,emphasizing the necessity for precision therapies that consider the heterogeneity within the GSC population and the dynamic tumor microenvironment to enhance outcomes for glioblastoma patients.

Innovation in pathogenesis and management of aortic aneurysm

Aortic aneurysm(AA)refers to the persistent dilatation of the aorta,exceeding three centimeters.Investigating the pathophysiology of this condition is important for its prevention and management,given its responsibility for more than 25000 deaths in the United States.AAs are classified based on their location or morphology.various pathophysiologic pathways including inflammation,the immune system and atherosclerosis have been implicated in its development.Inflammatory markers such as transforming growth factorβ,interleukin-1β,tumor necrosis factor-α,matrix metalloproteinase-2 and many more may contribute to this phenomenon.Several genetic disorders such as Marfan syndrome,Ehler-Danlos syndrome and Loeys-Dietz syndrome have also been associated with this disease.Recent years has seen the investigation of novel management of AA,exploring the implication of different immune suppressors,the role of radiation in shrinkage and prevention,as well as minimally invasive and newly hypothesized surgical methods.In this narrative review,we aim to present the new contributing factors involved in pathophysiology of AA.We also highlighted the novel management methods that have demonstrated promising benefits in clinical outcomes of the AA.

Molecular and genetic markers in hepatocellular carcinoma:In silico analysis to clinical validation(current limitations and future promises)

Hepatocellular carcinoma(HCC)is the second cause of cancer-related mortality.The diagnosis of HCC depends mainly on-fetoprotein,which is limited in its diagnostic and screening capabilities.There is an urgent need for a biomarker that detects early HCC to give the patients a chance for curative treatment.New targets of therapy could enhance survival and create future alternative curative methods.In silico analysis provides both;discovery of biomarkers,and understanding of the molecular pathways,to pave the way for treatment development.This review discusses the role of in silico analysis in the discovery of biomarkers,molecular pathways,and the role the author has contributed to this area of research.It also discusses future aspirations and current limitations.A literature review was conducted on the topic using various databases(PubMed,Science Direct,and Wiley Online Library),searching in various reviews,and editorials on the topic,with overviewing the author’s own published and unpublished work.This review discussed the steps of the validation process from in silico analysis to in vivo validation,to incorporation into clinical practice guidelines.In addition,reviewing the recent lines of research of bioinformatic studies related to HCC.In conclusion,the genetic,molecular and epigenetic markers discoveries are hot areas for HCC research.Bioinformatics will enhance our ability to accomplish this understanding in the near future.We face certain limitations that we need to overcome.

Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms

The possible relationship between diabetes mellitus (DM) and colorectal cancer (CRC), concerning pathophysiological and molecular mechanisms is highlighted in this review. The most recent and complete articles and developments in this particular field were thoroughly reviewed. Common risk factors, such as obesity, sedentary lifestyle, and Western diet between DM and CRC, led to the theory that DM might be a causal agent for CRC development. Various studies have connected type 2 DM and CRC, either proximal or distal, in both sexes. Additionally, chronic insulin treatment has been linked with increased colorectal tumor risk among type 2 diabetic patients. Interestingly, elevated hemoglobin A1c has been proven to be an independent predictor of aggressive clinical behavior in CRC patients. These mechanisms include the insulin-like growth factor-hyperinsulinemia theory and the participation of oncogenic intracellular signaling pathways. Furthermore, it has been proposed that Cox-2 inhibitors might have a role in decreasing the incidence of CRC. Finally, the use of statins to reduce the risk for colon cancer in patients with diabetes has remained controversial. Diabetic patients over 50 should receive counseling regarding their elevated risk for CRC, and screening colonoscopy should be recommended before initiating insulin therapy. However, there are no current guidelines, and this strategy is not yet applicable to some countries, as the corresponding risk would not allow screening colonoscopy to be adopted. There is strong evidence to indicate that DM is a causal agent for CRC development. This conclusion provides new impetus for re-evaluating CRC screening worldwide.

Molecules related to diabetic retinopathy in the vitreous and involved pathways

Diabetic retinopathy(DR)is one of the most common complications of diabetes and major cause of blindness among people over 50 years old.Current studies showed that the vascular endothelial growth factor(VEGF)played a central role in the pathogenesis of DR,and application of anti-VEGF has been widely acknowledged in treatment of DR targeting retinal neovascularization.However,anti-VEGF therapy has several limitations such as drug resistance.It is essential to develop new drugs for future clinical practice.The vitreous takes up 80%of the whole globe volume and is in direct contact with the retina,making it possible to explore the pathogenesis of DR by studying related factors in the vitreous.This article reviewed recent studies on DR-related factors in the vitreous,elaborating the VEGF upstream hypoxia-inducible factor(HIF)pathway and downstream pathways phosphatidylinositol diphosphate(PIP2),phosphoinositide-3-kinase(PI3 K),and mitogenactivated protein kinase(MAPK)pathways.Moreover,factors other than VEGF contributing to the pathogenesis of DR in the vitreous were also summarized,which included factors in four major systems,kallikrein-kinin system such as bradykinin,plasma kallikrein,and coagulation factor XII,oxidative stress system such as lipid peroxide,and superoxide dismutase,inflammation-related factors such as interleukin-1β/6/13/37,and interferon-γ,matrix metalloproteinase(MMP)system such as MMP-9/14.Additionally,we also introduced other DR-related factorssuch as adiponectin,certain specific amino acids,noncoding RNA and renin(pro)receptor in separate studies.

Stem cell therapy: A paradigm shift in breast cancer treatment

As per the latest Globocan statistics,the high prevalence rate of breast cancer in low-and middle-income countries has led to it becoming the most common cancer to be diagnosed,hence posing a major public health challenge.As per this data,more than 11.7%of the estimated new cancer cases in 2020 were due to breast cancer.A small but significant subpopulation of cells with self-renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells(CSCs).These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype.This attribute of CSCs allows them to differentiate into various cell types having diverse functions.Breast CSCs have a pivotal role in development,metastasis,treatment resistance and relapse of breast cancers.This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel,targeted,therapeutic approaches for limiting and eradicating this aberrant stem cell population.

High intensity interval training and molecular adaptive response of skeletal muscle

Increased cardiovascular fitness,VO_(2max),is associated with enhanced endurance capacity and a decreased rate of mortality.High intensity interval training(HIIT)is one of the best methods to increase VO_(2max)and endurance capacity for top athletes and for the general public as well.Because of the high intensity of this type of training,the adaptive response is not restricted to Type I fibers,as found for moderate intensity exercise of long duration.Even with a short exercise duration,HIIT can induce activation of AMPK,PGC-1α,SIRT1 and ROS pathway as well as by the modulation of Ca^(2+)homeostasis,leading to enhanced mitochondrial biogenesis,and angiogenesis.The present review summarizes the current knowledge of the adaptive response of HIIT.

Transgenerational bone toxicity in F3 medaka (Oryzias latipes) induced by ancestral benzo[a]pyrene exposure: Cellular and transcriptomic insights

Benzo[a]pyrene(BaP),a ubiquitous pollutant,raises environmental health concerns due to induction of bone toxicity in the unexposed offspring.Exposure of F0 ancestor medaka(Oryzias latipes)to 1μg/L BaP for 21 days causes reduced vertebral bone thickness in the unexposed F3 male offspring.To reveal the inherited modifications,osteoblast(OB)abundance and molecular signaling pathways of transgenerational BaP-induced bone thinning were assessed.Histomorphometric analysis showed a reduction in OB abundance.Analyses of the miRNA and mRNA transcriptomes revealed the dysregulation of Wnt signaling(frzb/ola-miR-1–3p,sfrp5/ola-miR-96–5p/miR-455–5p)and bone morphogenetic protein(Bmp)signaling(bmp3/ola-miR-96–5p/miR-181b-5p/miR-199a-5p/miR-205–5p/miR-455–5p).Both pathways are major indicators of impaired bone formation,while the altered Rank signaling in osteoclasts(c-fos/miR-205–5p)suggests a potentially augmented bone resorption.Interestingly,a typical BaP-responsive pathway,the Nrf2-mediated oxidative stress response(gst/ola-miR-181b-5p/miR-199a-5p/miR-205),was also affected.Moreover,mRNA levels of epigenetic modification enzymes(e.g.,hdac6,hdac7,kdm5b)were found dysregulated.The findings indicated that epigenetic factors(e.g.,miRNAs,histone modifications)may directly regulate the expression of genes associated with transgenerational BaP bone toxicity and warrants further studies.The identified candidate genes and miRNAs may serve as potential biomarkers for BaP-induced bone disease and as indicators of historic exposures in wild fish for conservation purposes.

Trends in clinical use of targeted therapy for gastrointestinal cancers

Targeted drugs therapies that block the molecular pathways involved in the development and progression of gastro-intestinal(GI)cancers have recently gained considerable attention.In addition to agents targeting vascular endothelial growth factor(VEGF),epidermal growth factor receptor,the multi-kinase inhibitor,and regorafenib have also become available for the treatment of metastatic colorectal cancer patients.Currently,trastuzumab,an antibody targeting human epidermal growth factor receptor-2(HER-2),in combination with cytotoxic drugs is considered as the standard treatment for patients with HER-2 positive gastric cancer(GC).The efficacy of ramucirumab,a human monoclonal antibody that inhibits VEGF from binding to its receptor in GC,has also been recently demonstrated.At present,a great number of novel targeted drugs are in pre-clinical or clinical studies.In this review,we summarize trends in the use of molecularly targeted drugs that have proven to be effective for treating GI cancers,with a focus on emerging strategies for personalized treatment.