Agrizim and bayleton,two commonly usedagricultural fungicides in India,wereinvestigated for their genotoxicpotentialities on cultured humanlymphocytes by studying chromosomalaberrations and sister chromatid exchangesi...Agrizim and bayleton,two commonly usedagricultural fungicides in India,wereinvestigated for their genotoxicpotentialities on cultured humanlymphocytes by studying chromosomalaberrations and sister chromatid exchangesin the presence and absence of展开更多
N-myc downstream regulated gene 1 (NDRG1), also known as differentiation related gene 1, was previously identified as an up-regulated gene upon cellular differentiation. Even though its sequence along with its express...N-myc downstream regulated gene 1 (NDRG1), also known as differentiation related gene 1, was previously identified as an up-regulated gene upon cellular differentiation. Even though its sequence along with its expressional pattern in cancer cell lines are evident, the functional aspects concerning cell proliferation, viability, differentiation and cell cycle regulation of NDRG1 remains vague. The aim of the present study was to elucidate the functional role of NDRG1 in human prostate cancer. Our results showed basal levels of NDRG1 expression in PC-3 (poorly differentiated, null p53), DU-145 (moderately differentiated, mutant p53) and LNCaP (well-differentiated, wiled type p53). Nevertheless, NDRG1 sequencing assay disclosed no mutations in the gene. Furthermore, human cDNA of NDRG1 from normal placenta was cloned into a eukaryotic expression vector and transfected into the three cancer cell lines. This resulted in over-expression of NDRG1, which in turn markedly up regulated two differentiation markers of the prostate tissue, p21 and cytokeratin 8/18. Unpredictably, cell cycle progression, cell proliferation and DNA synthesis were unaffected following NDRG1 expression. These results revealed that NDRG1 is functional in prostate cancer cells and able to induce expression of differentiation factors through p53 independent pathway. However, the pathway downstream NDRG1, involving p21 and c8/18, regulating cell cycle progression and DNA synthesis is unfunctional. Loss of sensitivity to p21 cell cycle control may be associated with prostatic cancer behavior. Further studies are required to clarify the intra cellular molecular pathways affecting NDRG1 function in human prostate cancer.展开更多
Inactivation of tumor suppressor genes is a key factor in cancer regulation. N-myc downstream regulated gene 1 (NDRG1) is a tumor suppressor gene well known to be involved in carcinogenesis of numerous cancer types. T...Inactivation of tumor suppressor genes is a key factor in cancer regulation. N-myc downstream regulated gene 1 (NDRG1) is a tumor suppressor gene well known to be involved in carcinogenesis of numerous cancer types. The present study was designed to investigate the role of NDRG1 in human ovarian cancer, using SKOV-3 and SW626 (moderately and well differentiated cancer cells, respectively). Our results revealed that over-expressed NDRG1 significantly up-regulated the differentiation marker p21, in the ovarian cancer cell lines. This regulation led to decrease in cell viability and DNA synthesis rates in SW626 cells (83% and 89.5%, respectively). However, no effect on viability or on DNA synthesis was observed in SKOV-3 NDRG1-transfected cells. These findings prove that NDRG1 is indubitably functional in human ovarian cancer cells, as it up-regulated p21 expression. Nevertheless, this regulation showed differential effect on cell viability and DNA formation thus promoting the perception that downstream regulation of p21 could be inefficient in some cancer cells, a concept that needs to be further explored in order to understand its disability to play as regulator of cell cycle progression.展开更多
Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transforma...Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transformative potential of artificial intelligence(AI)and machine learning(ML)in revolutionizing DR care.AI and ML technologies have demonstrated remarkable advancements in enhancing the accuracy,efficiency,and accessibility of DR screening,helping to overcome barriers to early detection.These technologies leverage vast datasets to identify patterns and predict disease progression with unprecedented precision,enabling clinicians to make more informed decisions.Furthermore,AI-driven solutions hold promise in personalizing management strategies for DR,incorpo-rating predictive analytics to tailor interventions and optimize treatment path-ways.By automating routine tasks,AI can reduce the burden on healthcare providers,allowing for a more focused allocation of resources towards complex patient care.This review aims to evaluate the current advancements and applic-ations of AI and ML in DR screening,and to discuss the potential of these techno-logies in developing personalized management strategies,ultimately aiming to improve patient outcomes and reduce the global burden of DR.The integration of AI and ML in DR care represents a paradigm shift,offering a glimpse into the future of ophthalmic healthcare.展开更多
Gestational diabetes mellitus(GDM)is increasingly recognized not only for its immediate obstetric complications but also for its long-term metabolic consequences in both mothers and their offspring.Traditionally,resea...Gestational diabetes mellitus(GDM)is increasingly recognized not only for its immediate obstetric complications but also for its long-term metabolic consequences in both mothers and their offspring.Traditionally,research has emphasized the roles of pancreaticβ-cell dysfunction and placental dysregulation in GDM.However,emerging evidence highlights the maternal liver as a central metabolic hub during pregnancy coordinating glucose,lipid,and hormonal adaptations essential for fetal development.This review synthesizes current findings on how GDM disrupts the maternal liver’s adaptive roles,transforming it from a metabolic coordinator into a source of maladaptive endocrine,inflammatory,and nutrient signals.It outlines key mechanistic pathways through which maternal hepatic dysfunction may increase offspring susceptibility to non-alcoholic fatty liver disease and type 2 diabetes mellitus.These include hepatokine dysregulation,altered lipid metabolism,impaired insulin signaling,inflammatory and oxidative stress pathways,and epigenetic and transcriptomic reprogramming.In addition,it explores novel axes such as the gut-liver-placenta interplay,bile acid signaling disruptions,endoplasmic reticulum stress responses,and extracellular vesiclemediated communication.By reframing the maternal liver’s role in GDM pathophysiology,this review identifies critical windows for early clinical intervention and highlights the potential for liver-focused strategies to prevent the intergenerational transmission of metabolic disease.展开更多
The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,...The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,which could lead to Type II Diabetes mellitus(T2DM).Central to drug-induced insulin resistance is mitochondrial dysfunction.Amongst disturbed pathways in drug-inducedmitochondrial toxicity is mitophagy,a process that removes dysfunctionalmitochondria through the lysosomal pathways to maintain mitochondrial quality.A balancemust always be maintained between mitochondrial dynamics and mitophagy,as any alterations may contribute to the pathogenesis of metabolic diseases such as diabetes mellitus.If damaged mitochondria are not removed,their accumulation leads to increased production of reactive oxygen species(ROS)and release of calcium and cytochrome C,which leads to apoptosis.This review paper focuses on the implications of the mitophagy initiation pathways,such as Adenosine Monophosphate-activated Protein Kinase/Mammalian Target of Rapamycin(AMPK/mTOR),PTEN-induced kinase 1,and Parkin RBR E3 ubiquitin-protein ligase,PINK/Parkin,and the receptor-mediated pathways,such as FUN14 domain containing 1(FUNDC1)and Bcl-2 interacting protein 3(BNIP3/NIX),as a crucial link between drug-induced mitochondrial dysfunction and insulin sensitivity impairment.It also focuses on the implications of mitochondrial dynamics in drug-induced insulin impairments.Pharmacological agents such as simvastatin,clarithromycin,olanzapine,and dexamethasone have been investigated and shown to induce insulin resistance in part through altered mitochondrial function.In this review paper,we further illuminate disturbances in mitophagy and mitochondrial dynamics that could also be pivotal in insulin resistance development as a result of exposure to these drugs.Mitophagy and mitochondrial dynamics remain understudied.Exploring the implications of mitophagy pathways and mitochondrial dynamics on drug-induced insulin resistance could lead to the development of new approaches that can be used to mitigate insulin resistance associated with different classes of pharmacological modalities.展开更多
Microglial functions are linked to Ca2+signaling,with endoplasmic reticulum(ER)calcium stores playing a crucial role.Microglial abnormality is a hallmark of Alzheimer’s disease(AD),but how ER Ca2+receptors regulate m...Microglial functions are linked to Ca2+signaling,with endoplasmic reticulum(ER)calcium stores playing a crucial role.Microglial abnormality is a hallmark of Alzheimer’s disease(AD),but how ER Ca2+receptors regulate microglial functions under physiological and AD conditions remains unclear.We found reduced ryanodine receptor 2(Ryr2)expression in microglia from an AD mouse model.Modulation of RyR2 using S107,a RyR-Calstabin stabilizer,blunted spontaneous Ca2+transients in controls and normalized Ca2+transients in AD mice.S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia;however,these effects were absent in AD microglia.Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia,a mechanism impaired in AD.These results highlight the role of ER Ca2+receptors in both homeostatic and AD microglia,providing insights into microglial Ca2+malfunctions in AD.展开更多
Background:This prospective study explored the effects of endurance running(ER) in minimal versus standard running shoes on the foot’s superficial layer intrinsic muscles and the function of the longitudinal arch.Our...Background:This prospective study explored the effects of endurance running(ER) in minimal versus standard running shoes on the foot’s superficial layer intrinsic muscles and the function of the longitudinal arch.Our hypothesis was that running in minimal shoes would cause hypertrophy in these muscles and lead to higher,stronger,stiffer arches.Methods:The hypothesis was tested using a sample of 33 healthy runners randomized into two groups,a control group shod in traditional running footwear and an experimental group shod in minimal support footwear,whose feet were scanned in an MRI before and after a 12-week training regime.Running kinematics as well as arch stiffness and height were also assessed before and after the treatment period.Results:Analysis of anatomical cross-sectional areas and muscle volumes indicate that the flexor digitomm brevis muscle became larger in both groups by 11%and 21%,respectively,but only the minimally shod runners had significant areal and volumetric increases of the abductor digiti minimi of 18%and 22%,respectively,and significantly increased longitudinal arch stiffness(60%).Conclusion:These results suggest that endurance running in minimal support footwear with 4 mm offset or less makes greater use of the springlike function of the longitudinal arch,thus leading to greater demands on the intrinsic muscles that support the arch,thereby strengthening the foot.展开更多
Barefoot running has been around for millions of years,and it is safe to presume that for most of that time,the practice occasioned little interest.Our ancestors ran barefoot because they had no shoes.When footwear wa...Barefoot running has been around for millions of years,and it is safe to presume that for most of that time,the practice occasioned little interest.Our ancestors ran barefoot because they had no shoes.When footwear was first invented during the last 40,000 years (no doubt at different times and in different places),shoes were by necessity minimal-essentially sandals and moccasins-designed to protect the sole of the foot but lacking any of the sophisticated features and materials present in modem running shoes such as elevated cushioned heels,arch supports,and toe springs.Most of these features were invented in the 1970s,and they quickly became more popular and sophisticated as running underwent a worldwide boom.Today,the vast majority of runners think it is normal to wear cushioned running shoes,and would never dream of running without them.展开更多
Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regul...Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regulates different functions of the cell, such as cellular growth, differentiation, metabolism and motility. RTK s triggers growth factor receptors such as epidermal growth factor, insulin growth factor-1 receptor, platelet derived growth factor receptor, and fibro blast growth factor receptor and vascular endothelial growth factor receptor, thereby initiating and regulating cell growth and proliferation. MAPK/RAS and PI3/AKT pathways are the major pathways of RTK’s function. Dysregulation of these RTK’s and pathways often leads to many diseases such as Noonan Syndrome, Logius Syndrome, CFC syndrome and different types of cancer. Point mutation and over expression of receptors and mutations in Ras leads to 30% of human cancers. Also over expression of different growth factor receptors by RTK too lead to several types of cancers as Glioblastoma, Thyroid cancer, Colon cancer and Non-small cell lung cancer. PTEN mutation in PI3/AKT pathway often leads to carcinoma relative to Thyroid, Skin, Large intestine, eye and Bone. Therefore, these RTK’s often used as targets for cancer therapies. The medical sector uses various types of small molecule tyrosine kinase inhibitors such as ATP competitive inhibitors, Allosteric inhibitors and covalent inhibitors which are known as Afatinib, Crizotinib, Eroltinib, Icotinib, Lepatinib and Lenvatinib in treatment and management of differential carcinomas.展开更多
Background and Purpose: With the unexpectedly rapid increase in the prevalence of types of diabetes worldwide, this chronic disease is no longer being viewed as a systemic health issue, but also treated as the start o...Background and Purpose: With the unexpectedly rapid increase in the prevalence of types of diabetes worldwide, this chronic disease is no longer being viewed as a systemic health issue, but also treated as the start of the deadly disease. As the sixth complication of diabetes, periodontitis is a chronic inflammatory condition that leads directly and indirectly to a severer condition of diabetes via its underlying mechanisms. Interestingly, both diseases are not been fully identified in their bidirectional relationships by researchers. Thus, healthcare agencies must pay appropriate attention. This literature review paper aims to investigate and discuss dentists’ role in modulating environmental and epigenetic determinants in the oral health of diabetic patients based on the bidirectional relationship between these diseases, their prevalence and how treatment of one disease affects the other. Methods: The authors conducted electronic searches in PubMed, Google Scholar, One Search UofT, ScienceDirect, and the National Library of Medicine. The paper also included gray literature from government resources related to the topic. The paper will review the epidemiology, pathogenesis, and epigenetics of both diabetes and periodontal disease and their functions with each other. Results: The literature has consistently shown that diabetes and periodontal disease have responded to the formation and severity of each other. Patients with pre- and diabetes have potentially higher risks of causing periodontal disease and other complications if adequate diagnosis and treatment are not involved timely. The combination of risk factors, including individual, social, environmental, and genetic, play a crucial role in the development of diabetes and the severity of periodontitis. Conclusions: Based on the results, the collaboration between dentists and other healthcare practitioners is inevitable in the overall development of treatment for both diseases. With the proper and updated knowledge, dentists can benefit patients’ overall physical conditions through strategic intervention in diabetes patients.展开更多
Prostate homeostasis and regeneration rely on the proper function of adult stem/progenitor cells(Ousset et al., 2012), which have also been considered as potential cells of origin for prostate cancer(Visvader, 2011) g...Prostate homeostasis and regeneration rely on the proper function of adult stem/progenitor cells(Ousset et al., 2012), which have also been considered as potential cells of origin for prostate cancer(Visvader, 2011) given their key positions in the lineage hierarchy and self-renewal capability. Accumulating evidence reveals the existence of multipotent progenitor cells in both basal and luminal cells.展开更多
Protein phosphorylation plays an important role in physiological processes, such as muscle contraction. Phospho-specific antibodies have become powerful tools to study these processes. Cardiac myosin binding protein-C...Protein phosphorylation plays an important role in physiological processes, such as muscle contraction. Phospho-specific antibodies have become powerful tools to study these processes. Cardiac myosin binding protein-C (cMyBP-C) is one of the proteins that make up the contractile apparatus of cardiomyocytes. Phosphorylation of cMyBP-C is essential for normal cardiac function, since dephosphorylation of this protein leads to its degradation and has been associated with cardiomyopathy. One of the upstream kinases, which phosphorylate cMyBP-C, is protein kinase D (PKD). While studying the role of PKD in cMyBP-C phosphorylation, we tried to analyze phosphorylation of PKD with a phospho-specific PKD-Ser744/748 antibody. Contrary to the expected 115 kDa, a signal was found for a 150-kDa protein. By MALDI-TOF mass spectrometry, we identified this protein to be cMyBP-C. These data were confirmed by immunostaining using the p-PKD-Ser744/748 antibody, which displayed a striated pattern similar to the one observed for a regular cMyBP-C antibody. To our knowledge there are no antibodies commercially available for phosphorylated cMyBP-C. Thus, the p-PKD-Ser744/748 antibody can accelerate research into the role of cMyBP-C phosphorylation in cardiomyocytes.展开更多
Objective： This study examined the anti-adipogenic effects of extracts of Ficus deltoidea var. deltoidia and var. angustifolia, a natural slimming aid, on 3T3-L1 adipocytes. Methods： Methanol and water extracts of l...Objective： This study examined the anti-adipogenic effects of extracts of Ficus deltoidea var. deltoidia and var. angustifolia, a natural slimming aid, on 3T3-L1 adipocytes. Methods： Methanol and water extracts of leaves of the F. deltoidea varieties were analyzed to determine their total flavonoid content （TFC） and total phenolic content （TPC）, respectively. The study was initiated by determining the maximum non-toxic dose （MNTD） of the methanol and water extracts for 3T3-L1 preadipocytes. Possible anti-adipogenic effects were then examined by treating 2-d post confluent 3T3-L1 preadipocytes with either methanol extract or water extract at MNTD and half MNTD （1/2MNTD）, after which the preadipocytces were induced to form mature adipocytes. Visualisation and quantification of lipid content in mature adipocytes were carried out through oil red O staining and measurement of optical density （OD） at 520 nm, respec- tively. Results： The TFCs of the methanol extracts were 1.36 and 1.97 g quercetin equivalents （QE）/100 g dry weight （DW）, while the TPCs of the water extracts were 5.61 and 2.73 g gallic acid equivalents （GAE）/100 g DW for var. deltoidea and var. angustilofia, respectively. The MNTDs determined for methanol and water extracts were （300.0±28.3） and （225.0±21.2） μg/ml, respectively, for var. deltoidea, while much lower MNTDs [（60.0±2.0） IJg/ml for methanol extracts and （8.0＋1.0） μg/ml for water extracts] were recorded for var. angustifolia. Studies revealed that the methanol extracts of both varieties and the water extracts of var. angustifolia at either MNTD or 1/2MNTD significantly inhibited the maturation of preadipocytes. Conclusions： The inhibition of the formation of mature adipocytes indicated that leaf extracts of F. deltoidea could have potential anti-obesity effects.展开更多
Since the discovery of blood circulation and transfusion, there has been an insatiable demand for voluntary blood donations throughout the world. However, gathering blood donors has never been easy because eligible do...Since the discovery of blood circulation and transfusion, there has been an insatiable demand for voluntary blood donations throughout the world. However, gathering blood donors has never been easy because eligible donors constitute only a fraction of the general population and are often reluctant to donate. This is especially challenging in underprivileged countries of sub-Saharan Africa such as Malawi whose nationally run blood transfusion service struggles to maintain hospital blood banks. As a result, hospitals turn to their local communities for directed donations. A retrospective analysis from January 2014 to June 2016 of directed blood donor data from two hospitals in the Kasungu District of Malawi was conducted. The analysis of 2134 donations was carried out with respect to sex, age, hemoglobin concentration, blood group, and presence of transfusion-transmissible infections. On average, donors were 30 years of age and predominately male. Blood group O+ constituted more than half of all directed blood donations. Ultimately, about one third of donations were unable to be utilized for transfusion.展开更多
The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this a...The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this axis,mediated by gut microbiota dysbiosis,impaired intestinal barrier function,and pro-inflammatory signaling,contributes significantly to insulin resistance,hepatic steatosis,and systemic metabolic dysfunction.This review explores the underlying mechanisms by which microbial alterations,increased gut permeability,and inflammatory pathways influence hepatic insulin resistance and glucose metabolism.In addition to established mechanisms,emerging pathways involving neuroendocrine circuits,microbial metabolites,and immune mediators are discussed,offering deeper insight into gut-liver interactions in metabolic disease.The review also outlines therapeutic strategies targeting the gut-liver axis,including microbiota modulation,barrier function enhancement,and anti-inflammatory interventions,emphasizing their potential in advancing diabetes management.A conceptual framework is proposed to integrate these components into a precision medicine approach for metabolic regulation.Key challenges in clinical translation,including patient heterogeneity and the absence of reliable biomarkers to guide treatment decisions are also discussed to inform future research.By linking mechanistic understanding with therapeutic innovation,the review highlights the gut-liver axis as a promising target for personalized diabetes care.展开更多
Primary biliary cholangitis(PBC)is an autoimmune disease characterized by the selective destruction of intrahepatic small bile ducts,primarily by infiltrating lymphocytes,and has limited therapeutic options.A growing ...Primary biliary cholangitis(PBC)is an autoimmune disease characterized by the selective destruction of intrahepatic small bile ducts,primarily by infiltrating lymphocytes,and has limited therapeutic options.A growing body of evidence suggests that nanoparticles encapsulating rapamycin(ImmTOR)can suppress autoreactive lymphocytes and reduce inflammatory cytokine levels in various autoimmune diseases.In a recent study,Yang et al investigated the therapeutic effects of ImmTOR in a mouse model of PBC.ImmTOR treatment reduced the expression and number of CD4+T cells,CD8+T cells,and B cells isolated from the liver and spleen,improved liver inflammation and enzyme levels,and was associated with a concomitant decrease in anti-mitochondrial antibody levels.In this editorial,we highlight the significance of these findings,focusing on the potential mechanisms by which ImmTOR suppresses hepatic autoreactive T cells and reduces anti-mitochondrial antibody levels,ultimately improving liver pa-thology,through pathways such as mammalian target of rapamycin inhibition and autophagy restoration.We also offer a perspective on future research di-rections for PBC in both animal models and in vitro studies.展开更多
Perianal fistulizing Crohn’s disease(PFCD)is a complication of CD that signi-ficantly impacts patients’quality of life,particularly their social and sexual well-being.Despite advances in therapy,its treatment remain...Perianal fistulizing Crohn’s disease(PFCD)is a complication of CD that signi-ficantly impacts patients’quality of life,particularly their social and sexual well-being.Despite advances in therapy,its treatment remains a major challenge in the field of inflammatory bowel disease.The pathogenesis of PFCD involves in-creased production of inflammatory cytokines by infiltrating macrophages and lymphocytes,stimulation of the epithelial-to-mesenchymal transition,activation of myofibroblasts,and elevated levels of matrix metalloproteinases.Mesenchymal stem cells(MSCs)are multipotent stromal cells with self-renewal and differen-tiation capabilities.Evidence from animal models and clinical trials indicates that MSC injection into PFCD lesions suppresses the infiltration of inflammatory cells and cytokines,resulting in complete fistula healing.More recently,MSC-derived extracellular vesicles(EVs)have shown promising results in promoting fistula healing,particularly in cases of refractory or relapsing fistulas.Notably,the activation of macroautophagy(hereafter referred to as autophagy)in MSCs has been shown to accelerate the healing process.This narrative review discusses the mechanisms underlying PFCD pathogenesis,the therapeutic roles of MSCs and their EVs,and the potential role of autophagy upregulation in enhancing MSC function and EV production.展开更多
Diabetes,commonly known for its metabolic effects,also critically affects the enteric nervous system(ENS),which is essential in regulating gastrointestinal(GI)motility,secretion,and absorption.The development of diabe...Diabetes,commonly known for its metabolic effects,also critically affects the enteric nervous system(ENS),which is essential in regulating gastrointestinal(GI)motility,secretion,and absorption.The development of diabetes-induced enteric neuropathy can lead to various GI dysfunctions,such as gastroparesis and irregular bowel habits,primarily due to disruptions in the function of neuronal and glial cells within the ENS,as well as oxidative stress and inflammation.This editorial explores the pathophysiological mechanisms underlying the development of enteric neuropathy in diabetic patients.Additionally,it discusses the latest advances in diagnostic approaches,emphasizing the need for early detection and intervention to mitigate GI complications in diabetic individuals.The editorial also reviews current and emerging therapeutic strategies,focusing on pharmacological treatments,dietary management,and potential neuromodulatory interventions.Ultimately,this editorial highlights the necessity of a multidisciplinary approach in managing enteric neuropathy in diabetes,aiming to enhance patient quality of life and address a frequently overlooked complication of this widespread disease.展开更多
Constipation and fecal impaction are frequent and distressing complaints in pediatric gastroenterology. Especially in neurologically handicapped children, treatment of severe forms of slow-transit constipation (STC) c...Constipation and fecal impaction are frequent and distressing complaints in pediatric gastroenterology. Especially in neurologically handicapped children, treatment of severe forms of slow-transit constipation (STC) can be difficult. In the majority of cases, STC is of unknown etiology. However, in recent years, there is growing evidence that interstitial cells of Cajal (ICCs), which serve as electrical pacemakers and generate spontaneous electrical slow waves in the gastrointestinal tract, might play an important role in the pathophysiology of STC. It remains unclear whether morphological ICC alterations seen in affected patients are based on congenital developmental anomalies, or whether they are a consequence of long-term constipation with secondary damage of the gastrointestinal nervous system. To the best of our knowledge, we present the first case of a patient with histological alterations in ICC morphology who displayed multiple alterations of c-kit at the level of mRNA. The protein encoded by c-kit is the receptor tyrosine kinase Kit (CD117), which is crucial for development and function of ICCs. Therefore, these findings provide a new explanation for congenital alterations of ICC development that result in gastrointestinal motility disorders.展开更多
文摘Agrizim and bayleton,two commonly usedagricultural fungicides in India,wereinvestigated for their genotoxicpotentialities on cultured humanlymphocytes by studying chromosomalaberrations and sister chromatid exchangesin the presence and absence of
文摘N-myc downstream regulated gene 1 (NDRG1), also known as differentiation related gene 1, was previously identified as an up-regulated gene upon cellular differentiation. Even though its sequence along with its expressional pattern in cancer cell lines are evident, the functional aspects concerning cell proliferation, viability, differentiation and cell cycle regulation of NDRG1 remains vague. The aim of the present study was to elucidate the functional role of NDRG1 in human prostate cancer. Our results showed basal levels of NDRG1 expression in PC-3 (poorly differentiated, null p53), DU-145 (moderately differentiated, mutant p53) and LNCaP (well-differentiated, wiled type p53). Nevertheless, NDRG1 sequencing assay disclosed no mutations in the gene. Furthermore, human cDNA of NDRG1 from normal placenta was cloned into a eukaryotic expression vector and transfected into the three cancer cell lines. This resulted in over-expression of NDRG1, which in turn markedly up regulated two differentiation markers of the prostate tissue, p21 and cytokeratin 8/18. Unpredictably, cell cycle progression, cell proliferation and DNA synthesis were unaffected following NDRG1 expression. These results revealed that NDRG1 is functional in prostate cancer cells and able to induce expression of differentiation factors through p53 independent pathway. However, the pathway downstream NDRG1, involving p21 and c8/18, regulating cell cycle progression and DNA synthesis is unfunctional. Loss of sensitivity to p21 cell cycle control may be associated with prostatic cancer behavior. Further studies are required to clarify the intra cellular molecular pathways affecting NDRG1 function in human prostate cancer.
文摘Inactivation of tumor suppressor genes is a key factor in cancer regulation. N-myc downstream regulated gene 1 (NDRG1) is a tumor suppressor gene well known to be involved in carcinogenesis of numerous cancer types. The present study was designed to investigate the role of NDRG1 in human ovarian cancer, using SKOV-3 and SW626 (moderately and well differentiated cancer cells, respectively). Our results revealed that over-expressed NDRG1 significantly up-regulated the differentiation marker p21, in the ovarian cancer cell lines. This regulation led to decrease in cell viability and DNA synthesis rates in SW626 cells (83% and 89.5%, respectively). However, no effect on viability or on DNA synthesis was observed in SKOV-3 NDRG1-transfected cells. These findings prove that NDRG1 is indubitably functional in human ovarian cancer cells, as it up-regulated p21 expression. Nevertheless, this regulation showed differential effect on cell viability and DNA formation thus promoting the perception that downstream regulation of p21 could be inefficient in some cancer cells, a concept that needs to be further explored in order to understand its disability to play as regulator of cell cycle progression.
文摘Diabetic retinopathy(DR)remains a leading cause of vision impairment and blindness among individuals with diabetes,necessitating innovative approaches to screening and management.This editorial explores the transformative potential of artificial intelligence(AI)and machine learning(ML)in revolutionizing DR care.AI and ML technologies have demonstrated remarkable advancements in enhancing the accuracy,efficiency,and accessibility of DR screening,helping to overcome barriers to early detection.These technologies leverage vast datasets to identify patterns and predict disease progression with unprecedented precision,enabling clinicians to make more informed decisions.Furthermore,AI-driven solutions hold promise in personalizing management strategies for DR,incorpo-rating predictive analytics to tailor interventions and optimize treatment path-ways.By automating routine tasks,AI can reduce the burden on healthcare providers,allowing for a more focused allocation of resources towards complex patient care.This review aims to evaluate the current advancements and applic-ations of AI and ML in DR screening,and to discuss the potential of these techno-logies in developing personalized management strategies,ultimately aiming to improve patient outcomes and reduce the global burden of DR.The integration of AI and ML in DR care represents a paradigm shift,offering a glimpse into the future of ophthalmic healthcare.
文摘Gestational diabetes mellitus(GDM)is increasingly recognized not only for its immediate obstetric complications but also for its long-term metabolic consequences in both mothers and their offspring.Traditionally,research has emphasized the roles of pancreaticβ-cell dysfunction and placental dysregulation in GDM.However,emerging evidence highlights the maternal liver as a central metabolic hub during pregnancy coordinating glucose,lipid,and hormonal adaptations essential for fetal development.This review synthesizes current findings on how GDM disrupts the maternal liver’s adaptive roles,transforming it from a metabolic coordinator into a source of maladaptive endocrine,inflammatory,and nutrient signals.It outlines key mechanistic pathways through which maternal hepatic dysfunction may increase offspring susceptibility to non-alcoholic fatty liver disease and type 2 diabetes mellitus.These include hepatokine dysregulation,altered lipid metabolism,impaired insulin signaling,inflammatory and oxidative stress pathways,and epigenetic and transcriptomic reprogramming.In addition,it explores novel axes such as the gut-liver-placenta interplay,bile acid signaling disruptions,endoplasmic reticulum stress responses,and extracellular vesiclemediated communication.By reframing the maternal liver’s role in GDM pathophysiology,this review identifies critical windows for early clinical intervention and highlights the potential for liver-focused strategies to prevent the intergenerational transmission of metabolic disease.
文摘The pathogenesis of insulin resistance is influenced by environmental factors,genetic predispositions,and several medications.Various drugs used to managemultiple ailments have been shown to induce insulin resistance,which could lead to Type II Diabetes mellitus(T2DM).Central to drug-induced insulin resistance is mitochondrial dysfunction.Amongst disturbed pathways in drug-inducedmitochondrial toxicity is mitophagy,a process that removes dysfunctionalmitochondria through the lysosomal pathways to maintain mitochondrial quality.A balancemust always be maintained between mitochondrial dynamics and mitophagy,as any alterations may contribute to the pathogenesis of metabolic diseases such as diabetes mellitus.If damaged mitochondria are not removed,their accumulation leads to increased production of reactive oxygen species(ROS)and release of calcium and cytochrome C,which leads to apoptosis.This review paper focuses on the implications of the mitophagy initiation pathways,such as Adenosine Monophosphate-activated Protein Kinase/Mammalian Target of Rapamycin(AMPK/mTOR),PTEN-induced kinase 1,and Parkin RBR E3 ubiquitin-protein ligase,PINK/Parkin,and the receptor-mediated pathways,such as FUN14 domain containing 1(FUNDC1)and Bcl-2 interacting protein 3(BNIP3/NIX),as a crucial link between drug-induced mitochondrial dysfunction and insulin sensitivity impairment.It also focuses on the implications of mitochondrial dynamics in drug-induced insulin impairments.Pharmacological agents such as simvastatin,clarithromycin,olanzapine,and dexamethasone have been investigated and shown to induce insulin resistance in part through altered mitochondrial function.In this review paper,we further illuminate disturbances in mitophagy and mitochondrial dynamics that could also be pivotal in insulin resistance development as a result of exposure to these drugs.Mitophagy and mitochondrial dynamics remain understudied.Exploring the implications of mitophagy pathways and mitochondrial dynamics on drug-induced insulin resistance could lead to the development of new approaches that can be used to mitigate insulin resistance associated with different classes of pharmacological modalities.
基金supported by grants from the Guangdong Basic and Applied Basic Research Foundation(2021A1515110912)Guangdong Provincial Key Laboratory of Brain Connectome and Behavior(2017B030301017)Shenzhen Key Laboratory of Translational Research for Brain Diseases(ZDSYS20200828154800001).
文摘Microglial functions are linked to Ca2+signaling,with endoplasmic reticulum(ER)calcium stores playing a crucial role.Microglial abnormality is a hallmark of Alzheimer’s disease(AD),but how ER Ca2+receptors regulate microglial functions under physiological and AD conditions remains unclear.We found reduced ryanodine receptor 2(Ryr2)expression in microglia from an AD mouse model.Modulation of RyR2 using S107,a RyR-Calstabin stabilizer,blunted spontaneous Ca2+transients in controls and normalized Ca2+transients in AD mice.S107 enhanced ATP-induced migration and phagocytosis while reducing ramification in control microglia;however,these effects were absent in AD microglia.Our findings indicate that RyR2 stabilization promotes an activation state shift in control microglia,a mechanism impaired in AD.These results highlight the role of ER Ca2+receptors in both homeostatic and AD microglia,providing insights into microglial Ca2+malfunctions in AD.
基金supported by the Charles Phelps Taft Research Center at the University of Cincinnati
文摘Background:This prospective study explored the effects of endurance running(ER) in minimal versus standard running shoes on the foot’s superficial layer intrinsic muscles and the function of the longitudinal arch.Our hypothesis was that running in minimal shoes would cause hypertrophy in these muscles and lead to higher,stronger,stiffer arches.Methods:The hypothesis was tested using a sample of 33 healthy runners randomized into two groups,a control group shod in traditional running footwear and an experimental group shod in minimal support footwear,whose feet were scanned in an MRI before and after a 12-week training regime.Running kinematics as well as arch stiffness and height were also assessed before and after the treatment period.Results:Analysis of anatomical cross-sectional areas and muscle volumes indicate that the flexor digitomm brevis muscle became larger in both groups by 11%and 21%,respectively,but only the minimally shod runners had significant areal and volumetric increases of the abductor digiti minimi of 18%and 22%,respectively,and significantly increased longitudinal arch stiffness(60%).Conclusion:These results suggest that endurance running in minimal support footwear with 4 mm offset or less makes greater use of the springlike function of the longitudinal arch,thus leading to greater demands on the intrinsic muscles that support the arch,thereby strengthening the foot.
文摘Barefoot running has been around for millions of years,and it is safe to presume that for most of that time,the practice occasioned little interest.Our ancestors ran barefoot because they had no shoes.When footwear was first invented during the last 40,000 years (no doubt at different times and in different places),shoes were by necessity minimal-essentially sandals and moccasins-designed to protect the sole of the foot but lacking any of the sophisticated features and materials present in modem running shoes such as elevated cushioned heels,arch supports,and toe springs.Most of these features were invented in the 1970s,and they quickly became more popular and sophisticated as running underwent a worldwide boom.Today,the vast majority of runners think it is normal to wear cushioned running shoes,and would never dream of running without them.
文摘Receptor Tyrosine kinases (RTKs) play a crucial role in the signal transduction pathways at cellular levels. RTK plays a vital role in cellular communication and transmission of signals to the adjacent cells and regulates different functions of the cell, such as cellular growth, differentiation, metabolism and motility. RTK s triggers growth factor receptors such as epidermal growth factor, insulin growth factor-1 receptor, platelet derived growth factor receptor, and fibro blast growth factor receptor and vascular endothelial growth factor receptor, thereby initiating and regulating cell growth and proliferation. MAPK/RAS and PI3/AKT pathways are the major pathways of RTK’s function. Dysregulation of these RTK’s and pathways often leads to many diseases such as Noonan Syndrome, Logius Syndrome, CFC syndrome and different types of cancer. Point mutation and over expression of receptors and mutations in Ras leads to 30% of human cancers. Also over expression of different growth factor receptors by RTK too lead to several types of cancers as Glioblastoma, Thyroid cancer, Colon cancer and Non-small cell lung cancer. PTEN mutation in PI3/AKT pathway often leads to carcinoma relative to Thyroid, Skin, Large intestine, eye and Bone. Therefore, these RTK’s often used as targets for cancer therapies. The medical sector uses various types of small molecule tyrosine kinase inhibitors such as ATP competitive inhibitors, Allosteric inhibitors and covalent inhibitors which are known as Afatinib, Crizotinib, Eroltinib, Icotinib, Lepatinib and Lenvatinib in treatment and management of differential carcinomas.
文摘Background and Purpose: With the unexpectedly rapid increase in the prevalence of types of diabetes worldwide, this chronic disease is no longer being viewed as a systemic health issue, but also treated as the start of the deadly disease. As the sixth complication of diabetes, periodontitis is a chronic inflammatory condition that leads directly and indirectly to a severer condition of diabetes via its underlying mechanisms. Interestingly, both diseases are not been fully identified in their bidirectional relationships by researchers. Thus, healthcare agencies must pay appropriate attention. This literature review paper aims to investigate and discuss dentists’ role in modulating environmental and epigenetic determinants in the oral health of diabetic patients based on the bidirectional relationship between these diseases, their prevalence and how treatment of one disease affects the other. Methods: The authors conducted electronic searches in PubMed, Google Scholar, One Search UofT, ScienceDirect, and the National Library of Medicine. The paper also included gray literature from government resources related to the topic. The paper will review the epidemiology, pathogenesis, and epigenetics of both diabetes and periodontal disease and their functions with each other. Results: The literature has consistently shown that diabetes and periodontal disease have responded to the formation and severity of each other. Patients with pre- and diabetes have potentially higher risks of causing periodontal disease and other complications if adequate diagnosis and treatment are not involved timely. The combination of risk factors, including individual, social, environmental, and genetic, play a crucial role in the development of diabetes and the severity of periodontitis. Conclusions: Based on the results, the collaboration between dentists and other healthcare practitioners is inevitable in the overall development of treatment for both diseases. With the proper and updated knowledge, dentists can benefit patients’ overall physical conditions through strategic intervention in diabetes patients.
基金supported by the grant JCYJ20200109141229255 from Science, Technology and Innovation Commission of Shenzhen Municipalitysupported by grants R01CA171189 and R01CA193455 from the National Cancer Institute, National Institutes of Healthsupported in part by the Emory Integrated Genomics Core, Integrated Cellular Imaging Core Facility, Winship Research Pathology Core, and Transgenic Mouse and Gene Targeting Core of Emory University Winship Cancer Institute and NIH/NCI under award number P30CA138292。
文摘Prostate homeostasis and regeneration rely on the proper function of adult stem/progenitor cells(Ousset et al., 2012), which have also been considered as potential cells of origin for prostate cancer(Visvader, 2011) given their key positions in the lineage hierarchy and self-renewal capability. Accumulating evidence reveals the existence of multipotent progenitor cells in both basal and luminal cells.
文摘Protein phosphorylation plays an important role in physiological processes, such as muscle contraction. Phospho-specific antibodies have become powerful tools to study these processes. Cardiac myosin binding protein-C (cMyBP-C) is one of the proteins that make up the contractile apparatus of cardiomyocytes. Phosphorylation of cMyBP-C is essential for normal cardiac function, since dephosphorylation of this protein leads to its degradation and has been associated with cardiomyopathy. One of the upstream kinases, which phosphorylate cMyBP-C, is protein kinase D (PKD). While studying the role of PKD in cMyBP-C phosphorylation, we tried to analyze phosphorylation of PKD with a phospho-specific PKD-Ser744/748 antibody. Contrary to the expected 115 kDa, a signal was found for a 150-kDa protein. By MALDI-TOF mass spectrometry, we identified this protein to be cMyBP-C. These data were confirmed by immunostaining using the p-PKD-Ser744/748 antibody, which displayed a striated pattern similar to the one observed for a regular cMyBP-C antibody. To our knowledge there are no antibodies commercially available for phosphorylated cMyBP-C. Thus, the p-PKD-Ser744/748 antibody can accelerate research into the role of cMyBP-C phosphorylation in cardiomyocytes.
基金Project supported by the International Medical University （No. BPharm B0108 Res072011）, Malaysia
文摘Objective： This study examined the anti-adipogenic effects of extracts of Ficus deltoidea var. deltoidia and var. angustifolia, a natural slimming aid, on 3T3-L1 adipocytes. Methods： Methanol and water extracts of leaves of the F. deltoidea varieties were analyzed to determine their total flavonoid content （TFC） and total phenolic content （TPC）, respectively. The study was initiated by determining the maximum non-toxic dose （MNTD） of the methanol and water extracts for 3T3-L1 preadipocytes. Possible anti-adipogenic effects were then examined by treating 2-d post confluent 3T3-L1 preadipocytes with either methanol extract or water extract at MNTD and half MNTD （1/2MNTD）, after which the preadipocytces were induced to form mature adipocytes. Visualisation and quantification of lipid content in mature adipocytes were carried out through oil red O staining and measurement of optical density （OD） at 520 nm, respec- tively. Results： The TFCs of the methanol extracts were 1.36 and 1.97 g quercetin equivalents （QE）/100 g dry weight （DW）, while the TPCs of the water extracts were 5.61 and 2.73 g gallic acid equivalents （GAE）/100 g DW for var. deltoidea and var. angustilofia, respectively. The MNTDs determined for methanol and water extracts were （300.0±28.3） and （225.0±21.2） μg/ml, respectively, for var. deltoidea, while much lower MNTDs [（60.0±2.0） IJg/ml for methanol extracts and （8.0＋1.0） μg/ml for water extracts] were recorded for var. angustifolia. Studies revealed that the methanol extracts of both varieties and the water extracts of var. angustifolia at either MNTD or 1/2MNTD significantly inhibited the maturation of preadipocytes. Conclusions： The inhibition of the formation of mature adipocytes indicated that leaf extracts of F. deltoidea could have potential anti-obesity effects.
文摘Since the discovery of blood circulation and transfusion, there has been an insatiable demand for voluntary blood donations throughout the world. However, gathering blood donors has never been easy because eligible donors constitute only a fraction of the general population and are often reluctant to donate. This is especially challenging in underprivileged countries of sub-Saharan Africa such as Malawi whose nationally run blood transfusion service struggles to maintain hospital blood banks. As a result, hospitals turn to their local communities for directed donations. A retrospective analysis from January 2014 to June 2016 of directed blood donor data from two hospitals in the Kasungu District of Malawi was conducted. The analysis of 2134 donations was carried out with respect to sex, age, hemoglobin concentration, blood group, and presence of transfusion-transmissible infections. On average, donors were 30 years of age and predominately male. Blood group O+ constituted more than half of all directed blood donations. Ultimately, about one third of donations were unable to be utilized for transfusion.
文摘The gut-liver axis represents a complex,bidirectional communication network between the gastrointestinal tract and the liver,playing a central role in maintaining metabolic homeostasis.In diabetes,disruption of this axis,mediated by gut microbiota dysbiosis,impaired intestinal barrier function,and pro-inflammatory signaling,contributes significantly to insulin resistance,hepatic steatosis,and systemic metabolic dysfunction.This review explores the underlying mechanisms by which microbial alterations,increased gut permeability,and inflammatory pathways influence hepatic insulin resistance and glucose metabolism.In addition to established mechanisms,emerging pathways involving neuroendocrine circuits,microbial metabolites,and immune mediators are discussed,offering deeper insight into gut-liver interactions in metabolic disease.The review also outlines therapeutic strategies targeting the gut-liver axis,including microbiota modulation,barrier function enhancement,and anti-inflammatory interventions,emphasizing their potential in advancing diabetes management.A conceptual framework is proposed to integrate these components into a precision medicine approach for metabolic regulation.Key challenges in clinical translation,including patient heterogeneity and the absence of reliable biomarkers to guide treatment decisions are also discussed to inform future research.By linking mechanistic understanding with therapeutic innovation,the review highlights the gut-liver axis as a promising target for personalized diabetes care.
文摘Primary biliary cholangitis(PBC)is an autoimmune disease characterized by the selective destruction of intrahepatic small bile ducts,primarily by infiltrating lymphocytes,and has limited therapeutic options.A growing body of evidence suggests that nanoparticles encapsulating rapamycin(ImmTOR)can suppress autoreactive lymphocytes and reduce inflammatory cytokine levels in various autoimmune diseases.In a recent study,Yang et al investigated the therapeutic effects of ImmTOR in a mouse model of PBC.ImmTOR treatment reduced the expression and number of CD4+T cells,CD8+T cells,and B cells isolated from the liver and spleen,improved liver inflammation and enzyme levels,and was associated with a concomitant decrease in anti-mitochondrial antibody levels.In this editorial,we highlight the significance of these findings,focusing on the potential mechanisms by which ImmTOR suppresses hepatic autoreactive T cells and reduces anti-mitochondrial antibody levels,ultimately improving liver pa-thology,through pathways such as mammalian target of rapamycin inhibition and autophagy restoration.We also offer a perspective on future research di-rections for PBC in both animal models and in vitro studies.
文摘Perianal fistulizing Crohn’s disease(PFCD)is a complication of CD that signi-ficantly impacts patients’quality of life,particularly their social and sexual well-being.Despite advances in therapy,its treatment remains a major challenge in the field of inflammatory bowel disease.The pathogenesis of PFCD involves in-creased production of inflammatory cytokines by infiltrating macrophages and lymphocytes,stimulation of the epithelial-to-mesenchymal transition,activation of myofibroblasts,and elevated levels of matrix metalloproteinases.Mesenchymal stem cells(MSCs)are multipotent stromal cells with self-renewal and differen-tiation capabilities.Evidence from animal models and clinical trials indicates that MSC injection into PFCD lesions suppresses the infiltration of inflammatory cells and cytokines,resulting in complete fistula healing.More recently,MSC-derived extracellular vesicles(EVs)have shown promising results in promoting fistula healing,particularly in cases of refractory or relapsing fistulas.Notably,the activation of macroautophagy(hereafter referred to as autophagy)in MSCs has been shown to accelerate the healing process.This narrative review discusses the mechanisms underlying PFCD pathogenesis,the therapeutic roles of MSCs and their EVs,and the potential role of autophagy upregulation in enhancing MSC function and EV production.
文摘Diabetes,commonly known for its metabolic effects,also critically affects the enteric nervous system(ENS),which is essential in regulating gastrointestinal(GI)motility,secretion,and absorption.The development of diabetes-induced enteric neuropathy can lead to various GI dysfunctions,such as gastroparesis and irregular bowel habits,primarily due to disruptions in the function of neuronal and glial cells within the ENS,as well as oxidative stress and inflammation.This editorial explores the pathophysiological mechanisms underlying the development of enteric neuropathy in diabetic patients.Additionally,it discusses the latest advances in diagnostic approaches,emphasizing the need for early detection and intervention to mitigate GI complications in diabetic individuals.The editorial also reviews current and emerging therapeutic strategies,focusing on pharmacological treatments,dietary management,and potential neuromodulatory interventions.Ultimately,this editorial highlights the necessity of a multidisciplinary approach in managing enteric neuropathy in diabetes,aiming to enhance patient quality of life and address a frequently overlooked complication of this widespread disease.
文摘Constipation and fecal impaction are frequent and distressing complaints in pediatric gastroenterology. Especially in neurologically handicapped children, treatment of severe forms of slow-transit constipation (STC) can be difficult. In the majority of cases, STC is of unknown etiology. However, in recent years, there is growing evidence that interstitial cells of Cajal (ICCs), which serve as electrical pacemakers and generate spontaneous electrical slow waves in the gastrointestinal tract, might play an important role in the pathophysiology of STC. It remains unclear whether morphological ICC alterations seen in affected patients are based on congenital developmental anomalies, or whether they are a consequence of long-term constipation with secondary damage of the gastrointestinal nervous system. To the best of our knowledge, we present the first case of a patient with histological alterations in ICC morphology who displayed multiple alterations of c-kit at the level of mRNA. The protein encoded by c-kit is the receptor tyrosine kinase Kit (CD117), which is crucial for development and function of ICCs. Therefore, these findings provide a new explanation for congenital alterations of ICC development that result in gastrointestinal motility disorders.
