Micro-RNAs as clinical biomarkers and therapeutic targets in breast cancer:Quo vadis?

Breast cancer(BC) is the most frequent type of non skin cancer among women and a major leading cause of cancer-related deaths in Western countries. It is substantial to discover novel biomarkers with diagnostic, prognostic or predictive usefulness as well as therapeutic value for BC. Micro-RNAs(miR NAs) belong to a novel class of endogenous interfering RNAs that play a crucial role in post transcriptional gene silencing through m RNA targeting and, thus, are involved in many biological processes encompassing apoptosis,cell-cycle control, cell proliferation, DNA repair, immunity, metabolism, stress, aging, etc. Mi RNAs exert their action mainly in a tumor suppressive or oncogenic manner. The specific aberrant expression patterns of miR NAs in BC that are detected with the use of highthroughput technologies reflect their key role in cancer initiation, progression, migration, invasion and metastasis. The detection of circulating extracellular miR NAs in plasma of BC patients may provide novel, non-invasive biomarkers in favor of BC diagnosis and prognosis and,at the same time, accumulating evidence has underscored the possible contribution of miR NAs as valuable biomarkers to predict response to chemotherapy or radiotherapy. Data from in vitro and in vivo studies on BC have revealed promising therapeutic approaches via mi RNA delivery and mi RNA inhibition. The purpose of this review is to explore the ontological role of miR NAs in BC etiopathogenesis as well as to highlight their potential, not only as non-invasive circulating biomarkers with diagnostic and prognostic significance, but also as treatment response predictors and therapeutic targets aiding BC management.

Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Rose Hip Powder That Contains the Natural Amount of Shells and Seeds Alleviates Pain in Osteoarthritis of the Dominant Hand—A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Clinical Trial

Aim: A standardized preparation of seeds and shells of selected sub-species of Rosa canina L, trade name Hyben Vital, reduces discomfort from osteoarthritis of the knee and hip. This study aims to investigate the impact of the same rose-hip powder (RHP) on discomfort and the consumption of rescue medication, in patients with osteoarthritis of the hand. Methods: The double blind, placebo-controlled, crossover trial included 30 patients with osteoarthritis of the dominant hand. Patients were randomly allocated to treatment with either five gram encapsulated RHP or placebo, for three months (Phase 1), after which they switched to the corresponding treatment for a further three months period (Phase 2). Before entering the study, after 3 weeks and following three months of each of the study phases, scores for pain, stiffness and general feeling of discomfort were evaluated using a 10 step categorical scale, focusing on 16 different daily activities of the hand. The consumption of rescue medication was also calculated at the beginning and at the end of each study phase. Data are based on the intention to treat. Results: At the end of Phase 1, 90% of patients in the group receiving RHP first (group A), showed a reduction in pain, as compared to 36% in the group B initially given placebo (p 0.029). In line with this observation, stiffness and the general feeling of discomfort from the disease declined during RHP treatment (p 0.032). In group A, symptom reduction was still indicated by the study subjects 3 weeks after the switch to placebo. The consumption of rescue medication such as paracetamol, codeine and tramadol also declined significantly in group A when compared to group B (p 0.013). Conclusion: The present data suggest that administration of RHP, containing seeds and shells can reduce symptoms of osteoarthritis of the hand and consumption of rescue medication.

Changes in the gut mycobiome in pediatric patients in relation to the clinical activity of Crohn's disease

BACKGROUND Numerous studies have shown that in Crohn’s disease(CD),the gut microbiota is of great importance in the induction and maintenance of inflammation in the gastrointestinal tract.Until recently,studies have focused almost exclusively on bacteria in the gut.Lately,more attention has been paid to the role of intestinal fungi.AIM To study the gut mycobiome analysis of pediatric patients with CD(in different stages of disease activity)compared to healthy children.METHODS Fecal samples were collected from patients:With active,newly diagnosed CD(n=50);active but previously diagnosed and treated CD(n=16);non-active CD and who were in clinical remission(n=39)and from healthy volunteers(n=40).Fungal DNA was isolated from the samples.Next,next generation sequencing(MiSeq,Illumina)was performed.The composition of mycobiota was correlated with clinical and blood parameters.RESULTS Candida spp.were overrepresented in CD patients,while in the control group,the most abundant genus was Saccharomyces.In CD patients,the percentage of Malassezia was almost twice that of the control(P<0.05).In active CD patients,we documented a higher abundance of Debaryomyces hansenii(D.hansenii)compared to the non-active CD and control(P<0.05)groups.Moreover,statistically significant changes in the abundance of Mycosphaerella,Rhodotorula,and Microidium were observed.The analyses at the species level and linear discriminant analysis showed that in each group it was possible to distinguish a specific species characteristic of a given patient population.Moreover,we have documented statistically significant correlations between:D.hansenii and patient age(negative);C.zeylanoides and patient age(positive);C.dubliniensis and calprotectin(positive);C.sake and calprotectin(positive);and C.tropicalis and pediatric CD activity index(PCDAI)(positive).CONCLUSION Mycobiome changes in CD patients,and the positive correlation of some species with calprotectin or PCDAI,give strong evidence that fungi may be of key importance in the development of CD.

Cholesteryl ester storage disease of clinical and genetic characterisation: A case report and review of literature

BACKGROUND Cholesteryl ester storage disease(CESD)is a rare genetic disease.Its symptoms and severity are highly variable.CESD is a systemic disease that can lead to the accumulation of fat and inflammation in the liver,as well as gastrointestinal and cardiovascular disease.The majority of patients require liver transplantation due to decompensated cirrhosis.Enzyme replacement therapy has been approved based on a randomized trial.Our study aims to clinically and genetically evaluate two siblings with CESD who underwent liver transplantation,as well as their first-degree family members.CASE SUMMARY The siblings were compound heterozygous for the missense variant in LIPA exon 8,c.894G>A,(p.Gln298Gln)and a single base pair deletion,c.482del(p.Asn161Ilefs*19).Analyses of single nucleotide polymorphisms showed variants with an increased risk of fatty liver disease and fibrosis for both patients.Clinically,both patients show signs of recurrence of CESD in the liver after transplantation and additional gastrointestinal and cardiovascular signs of CESD.Three family members who were LIPA heterozygous had a lysosomal acid lipase activity below the reference value.One of these carriers,a seven-year-old boy,was found to have severe dyslipidemia and was subsequently treated with statins.CONCLUSION Our study underlines that CESD is a multi-organ disease,the progression of which may occur post-liver transplantation.Our findings underline the need for monitoring of complications and assessment of possible further treatment.

Clinical and Biochemical Evaluation of Facial Acanthosis Nigricans

Background: Acanthosis nigricans is a well known cause of facial melanosis in Iraqi males and usually it is a part of ordinary acanthosis nigricans. It is commonly associated with many metabolic derangements. Objectives: To evaluate cases of acanthosis nigricans of the face for all metabolic disturbances including fasting blood sugar, fasting serum insulin, total cholesterol, triglyceride, growth hormone and serum leptin. Patients and Methods: Twenty seven cases of acanthosis nigricans of the face were included in this case descriptive, clinical and biochemical study. This was conducted in Department of Dermatology-Baghdad Teaching Hospital and Department of Clinical Biochemistry, College of Medicine, Baghdad, Iraq during the period from November 2012-August 2014. It consisted of 26 males and one female, their ages ranged from 16 - 58 (39 ± 4.9) years. The diagnosis was established by clinical and histopathological evaluation. Sharquie’s ANSI scoring of acanthosis nigricans of face was carried out for all patients, also body mass index was assessed. Biochemical evaluation was carried out for all patients including total cholesterol, triglyceride, fasting blood sugar and insulin, insulin resistance, growth hormone and leptin enzyme immunoassay. Twenty seven healthy control non obese individuals with comparable ages and gender were assessed for all tests. Results: Biochemical results showed that fasting blood glucose, fasting serum insulin, insulin resistance, fasting serum triglyceride, total cholesterol, growth hormone and serum leptin were statistically significantly high in patients with acanthosis nigricans of the face in comparison with control individuals and all were positively correlated with the scoring of acanthosis nigricans of the face apart from high density lipoprotein was negatively correlated. Conclusion: Acanthosis nigricans of the face is a good marker for the associated metabolic diseases and these metabolic changes were statistically significantly correlated with the severity of acanthosis nigricans.

Red cell distribution width/platelet ratio estimates the 3-year risk of decompensation in Metabolic Dysfunction-Associated Steatotic Liver Disease-induced cirrhosis

BACKGROUND For compensated advanced chronic liver disease(cACLD)patients,the first decompensation represents a dramatically worsening prognostic event.Based on the first decompensation event(DE),the transition to decompensated advanced chronic liver disease(dACLD)can occur through two modalities referred to as acute decompensation(AD)and non-AD(NAD),respectively.Clinically Significant Portal Hypertension(CSPH)is considered the strongest predictor of decompensation in these patients.However,due to its invasiveness and costs,CSPH is almost never evaluated in clinical practice.Therefore,recognizing noninvasively predicting tools still have more appeal across healthcare systems.The red cell distribution width to platelet ratio(RPR)has been reported to be an indicator of hepatic fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD).However,its predictive role for the decompensation has never been explored.AIM In this observational study,we investigated the clinical usage of RPR in predicting DEs in MASLD-related cACLD patients.METHODS Fourty controls and 150 MASLD-cACLD patients were consecutively enrolled and followed up(FUP)semiannually for 3 years.At baseline,biochemical,clinical,and Liver Stiffness Measurement(LSM),Child-Pugh(CP),Model for End-Stage Liver Disease(MELD),aspartate aminotransferase/platelet count ratio index(APRI),Fibrosis-4(FIB-4),Albumin-Bilirubin(ALBI),ALBI-FIB-4,and RPR were collected.During FUP,DEs(timing and modaities)were recorded.CSPH was assessed at the baseline and on DE occurrence according to the available Clinical Practice Guidelines.RESULTS Of 150 MASLD-related cACLD patients,43(28.6%)progressed to dACLD at a median time of 28.9 months(29 NAD and 14 AD).Baseline RPR values were significantly higher in cACLD in comparison to controls,as well as MELD,CP,APRI,FIB-4,ALBI,ALBI-FIB-4,and LSM in dACLD-progressing compared to cACLD individuals[all P<0.0001,except for FIB-4(P:0.007)and ALBI(P:0.011)].Receiving operator curve analysis revealed RPR>0.472 and>0.894 as the best cut-offs in the prediction respectively of 3-year first DE,as well as its superiority compared to the other non-invasive tools examined.RPR(P:0.02)and the presence of baseline-CSPH(P:0.04)were significantly and independently associated with the DE.Patients presenting baseline-CSPH and RPR>0.472 showed higher risk of decompensation(P:0.0023).CONCLUSION Altogether these findings suggest the RPR as a valid and potentially applicable non-invasive tool in the prediction of timing and modalities of decompensation in MASLD-related cACLD patients.

Effect of Dendrobium nobile powder combined with conventional therapy on mild to moderate fatty liver

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)encompasses a variety of liver conditions impacting individuals who consume minimal or no alcohol.Recently,traditional Chinese medicine has been gradually used to treat mild to moderate fatty liver,among which Dendrobium nobile Lindl.powder has been affirmed by many doctors and patients to be effective.However,there is limited research on combining this treatment with standard therapies for mild to moderate NAFLD.AIM To survey the effect of combining Dendrobium nobile Lindl.powder with standard treatment on liver function and lipid metabolism disorder in patients with mild to moderate NAFLD.METHODS Eighty patients with mild to moderate NAFLD participated in this retrospective study,classified into two groups:The observation group(n=40)and the control group(n=40).In November 2020 and November 2022,the study was conducted at People’s Hospital of Chongqing Liang Jiang New Area.The control group received standard treatment,while the observation group received Dendrobium nobile Lindl.powder based on the control group.The study compared differences in traditional Chinese medicine clinical syndrome scores,liver fibrosis treatment,liver function indicators,lipid levels,and serum inflammatory factor levels before and after treatment,and we calculated the incidence of adverse reactions for both groups.RESULTS The total effective rate was 97.50%in the observation group and 72.5%in the control group.After 8 weeks of treatment,the main and secondary symptom scores remarkably decreased,especially in the observation group(P<0.05),and there was a significant reduction in the serum levels of hyaluronic acid(HA),laminin(LN),human rocollagen III(PC III),and collagen type IV(CIV).The levels of HA,LN,PC III,and CIV were significantly lower in the observation group(P<0.05).After 8 weeks,both groups indicated remarkable improvements in liver function and blood lipid levels,with the observation group having even lower levels(P<0.05).Serum levels of interleukin-1β,tumor necrosis factor-α,and interleukin-8 also dropped significantly.The observation group had a lower rate of adverse reactions(5.00%)compared to the control group(22.50%).CONCLUSION Adding Dendrobium nobile Lindl.powder to standard treatment has been found to remarkably improve symptoms and reduce inflammation in patients with mild to moderate fatty liver disease.It also enhances hepatic function and lipid profile,ameliorates liver fibrosis indices,and lowers the risk of side effects.Consequently,this therapeutic protocol shows promise for clinical implementation and dissemination.

Lacidipine,thiamine pyrophosphate and their combination on the ocular ischemic syndrome induced by bilateral common carotid artery ligation

AIM:To investigate the effect of lacidipine,thiamine pyrophosphate(TPP)and the combination of lacidipine and TPP against oxidative and inflammatory eye damage induced by bilateral common carotid artery ligation in rats.METHODS:Male albino Wistar rats were categorized as those who underwent sham surgery(SG),right and left common carotid cross-clamping and unclamping procedure(CCU),lacidipine+CCU(LCCU),TPP+CCU(TCCU),and combination of lacidipine and TPP(LTC)+CCU(LTCCU).One hour before anesthesia,the LCCU(n=6)received lacidipine(4 mg/kg,orally)and the TCCU(n=6)received TPP(20 mg/kg,intraperitoneally).The SG(n=6)and CCU(n=6)received the same volume of distilled water from the same route.After anesthesia(60 mg/kg ketamine,intraperitoneally),the necks of the rats were opened in the midline.Ischemia was created for 10min by placing clips on the right and left common carotid arteries.Rats in the SG only underwent subcutaneous incision.After 10min,the clips were removed and reperfusion was achieved for six days.Then,the animals were euthanized(120 mg/kg ketamine,intraperitoneally)and the levels of oxidant,antioxidant and proinflammatory cytokines in the eye tissues were determined.The retinal tissue of the eye was also examined histopathologically.RESULTS:Lacidipine,TPP,and LTC significantly prevent the increase in malondialdehyde,tumor necrosis factoralpha,interleukin-1β(IL-1β),and IL-6 levels,decrease in total glutathione levels,superoxide dismutase and catalase activities and histopathological retinal damage in eye tissue induced by bilateral common carotid artery ligation in rats.The impact of these drugs on protection is determined to be LTC>lacidipine>TPP.CONCLUSION:As a result of the study,it is concluded that LTC may be more effective than lacidipine and TPP alone in treating ocular ischemic syndrome.

The Combined Effect of Lumenato and Ceramide in the Protection of Collagen Damage Induced by Neutrophils in Normal Human Dermal Fibroblasts

Introduction: Collagen is the primary structural protein fibroblasts produce in the skin’s extracellular matrix. Infiltration of neutrophils into the epidermis and dermis by exposure to UV causes collagen damage and contributes to photoaging. Methods: To study the combined effect of Lumenato and ceramide in preventing collagen-1 damage induced by phagocytes, we used co-cultures of normal human dermal fibroblasts (fibroblasts) and activated human neutrophils. The present study aimed to determine the protective effect of the combination of Lumenato and ceramide on fibroblast collagen-1 damage induced by neutrophils. Results: Lumenato (in the range of 6.5 - 208 μg/ml) or ceramide (in the range of 0.1 - 50 μM) inhibited the production of superoxides and MPO by TNFα-stimulated neutrophils, as well as the production of NO by LPS-stimulated macrophages in a dose-dependent manner. The combinations of Lumenato and ceramide, in low concentrations, caused synergistic prevention of fibroblasts’ collagen-1 damage induced by TNFα-activated neutrophils, detected by fluorescence immunostaining and WB analysis. MPO activity in the supernatants of the co-cultures was also synergistically inhibited. Adding Lumenato or ceramide singly or in combinations in these low concentrations to the fibroblast cultures did not affect the expression of collagen-1. The combinations of Lumenato or ceramide in these concentrations also caused a synergistic inhibition of NO production by activated macrophages. Conclusions: The results suggest that combining low concentrations of Lumenato and ceramide results in synergistic protection against fibroblasts’ collagen-1 damage induced by neutrophils, thus indicating their possible potential for enhanced skin health.

The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory

Background:The dysregulation of Isocitrate dehydrogenase(IDH)and the subsequent production of 2-Hydroxyglutrate(2HG)may alter the expression of epigenetic proteins in Grade 4 astrocytoma.The interplay mechanism between IDH,O-6-methylguanine-DNA methyltransferase(MGMT)-promoter methylation,and protein methyltransferase proteins-5(PRMT5)activity,with tumor progression has never been described.Methods:A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors.Both groups were tested for MGMT-promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis.Inter-cohort statistical significance was evaluated.Results:Both IDH-mutant WHO grade 4 astrocytomas(n=22,64.7%)and IDH-wildtype glioblastomas(n=12,35.3%)had upregulated PRMT5 gene expression except in one case.Out of the 22 IDH-mutant tumors,10(45.5%)tumors showed MGMT-promoter methylation and 12(54.5%)tumors had unmethylated MGMT.All IDH-wildtype tumors had unmethylated MGMT.There was a statistically significant relationship between MGMT-promoter methylation and IDH in G4 astrocytoma(p-value=0.006).Statistically significant differences in progression-free survival(PFS)were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide(TMZ)or TMZ plus other chemotherapies,regardless of their IDH or MGMT-methylation status(p-value=0.0014).Specifically,IDH-mutant tumors that had upregulated PRMT5 activity and MGMT-promoter methylation,who received only TMZ,have exhibited longer PFS.Conclusions:The relationship between PRMT5,MGMT-promoter,and IDH is not tridirectional.However,accumulation of D2-hydroxyglutarate(2-HG),which partially activates 2-OG-dependent deoxygenase,may not affect their activities.In IDH-wildtype glioblastomas,the 2HG-2OG pathway is typically inactive,leading to PRMT5 upregulation.TMZ alone,compared to TMZ-plus,can increase PFS in upregulated PRMT5 tumors.Thus,using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.

Impact of umbelliprenin-containing niosome nanoparticles on VEGF-A and CTGF genes expression in retinal pigment epithelium cells

AIM:To investigate the impact of niosome nanoparticles carrying umbelliprenin(UMB),an anti-angiogenic and anti-inflammatory plant compound,on the expression of vascular endothelial growth factor(VEGF-A)and connective tissue growth factor(CTGF)genes in a human retinal pigment epithelium(RPE)-like retina-derived cell line.METHODS:UMB-containing niosomes were created,optimized,and characterized.RPE-like cells were treated with free UMB and UMB-containing niosomes.The IC_(50)values of the treatments were determined using an MTT assay.Gene expression of VEGF-A and CTGF was evaluated using real-time polymerase chain reaction after RNA extraction and cDNA synthesis.Niosomes’characteristics,including drug entrapment efficiency,size,dispersion index,and zeta potential were assessed.Free UMB had an IC_(50)of 96.2μg/mL,while UMB-containing niosomes had an IC_(50)of 25μg/mL.RESULTS:Treatment with UMB-containing niosomes and free UMB resulted in a significant reduction in VEGF-A expression compared to control cells(P=0.001).Additionally,UMB-containing niosomes demonstrated a significant reduction in CTGF expression compared to control cells(P=0.05).However,there was no significant reduction in the expression of both genes in cells treated with free UMB.CONCLUSION:Both free UMB and niosome-encapsulated UMB inhibits VEGF-A and CTGF genes expression.However,the latter demonstrates significantly greater efficacy,potentially due to the lower UMB dosage and gradual delivery.These findings have implications for anti-angiogenesis therapeutic approaches targeting age-related macular degeneration.

Anti-corisin immunotherapy:therapeutic perspective for reducing the risk of developing COVID-19 coagulopathy?

Corisin,a 19 amino acid proapoptotic peptide derived from the lung microbiota(i.e.,by Staphylococci),is implicated in the pathogenesis of acute lung injury and exacerbation of pulmonary fibrosis.Recent evidence also suggests that this molecule may have a role in lung thrombosis,as its concentration correlates with a prothrombotic state.It has also been demonstrated that corisin inhibition by using monoclonal antibodies is effective inhibiting pulmonary fibrosis and venous thrombosis in patients with coronavirus disease 2019(COVID-19).Further studies should hence be planned to verify whether anti-corisin immunotherapy could become a reliable therapeutic perspective against the risk of developing COVID-19 coagulopathy.

Dose-response effect of pre-exercise carbohydrates under muscle glycogen unavailability:Insights from McArdle disease

Background:This study aimed to determine the effect of different carbohydrate(CHO)doses on exercise capacity in patients with McArdle disease—the paradigm of“exercise intolerance”,characterized by complete muscle glycogen unavailability—and to determine whether higher exogenous glucose levels affect metabolic responses at the McArdle muscle cell(in vitro)level.Methods:Patients with McArdle disease(n=8)and healthy controls(n=9)underwent a 12-min submaximal cycling constant-load bout followed by a maximal ramp test 15 min after ingesting a non-caloric placebo.In a randomized,double-blinded,cross-over design,patients repeated the tests after consuming either 75 g or 150 g of CHO(glucose:fructose=2:1).Cardiorespiratory,biochemical,perceptual,and electromyographic(EMG)variables were assessed.Additionally,glucose uptake and lactate appearance were studied in vitro in wild-type and McArdle mouse myotubes cultured with increasing glucose concentrations(0.35,1.00,4.50,and 10.00 g/L).Results:Compared with controls,patients showed the“classical”second-wind phenomenon(after prior disproportionate tachycardia,myalgia,and excess electromyographic activity during submaximal exercise,all p<0.05)and an impaired endurance exercise capacity(-51%ventilatory threshold and55%peak power output,both p<0.001).Regardless of the CHO dose(p<0.05 for both doses compared with the placebo),CHO intake increased blood glucose and lactate levels,decreased fat oxidation rates,and attenuated the second wind in the patients.However,only the higher dose increased ventilatory threshold(+27%,p=0.010)and peak power output(+18%,p=0.007).In vitro analyses revealed no differences in lactate levels across glucose concentrations in wild-type myotubes,whereas a doseresponse effect was observed in McArdle myotubes.Conclusion:CHO intake exerts beneficial effects on exercise capacity in McArdle disease,a condition associated with total muscle glycogen unavailability.Some of these benefits are dose dependent.

A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms

Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer(CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors.The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site(Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2(CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α(PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase(PI3K) expression, Ak strain transforming phosphorylation,m TOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation.These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.

我们应该怎样利用新抗凝剂治疗急性肺栓塞?

由于大多数的治疗都增加了出血并发症的风险,因此急性肺栓塞（pulmonary embolism,PE）患者的治疗成为临床医生面临的一大挑战。80%的PE患者具有可识别的诱发因素,

An insight into the diagnosis and pathogenesis of hepatitis C virus infection

This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus(HCV)infection over the last few decades.The information based on published literature provides an update on these two aspects of HCV.HCV infection,previously called blood transmitted non-A,non-B infection,is prevalent globally and poses a serious public health problem worldwide.The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction(PCR)technique.Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles.Moreover,multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes.In contrast to previous methods,the newly developed assays are not only fast and eco-nomic,but also resolve the problem of the window period as well as differentiate present from past infection.HCV is a non-cytopathic virus,thus,its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress,insulin resistance and hepatic steatosis.Both innate and adaptive immunity play an important role in HCV pathogenesis.Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins,HCV-quasispecies and several metabolic factors regulating liver metabolism.HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.

C-reactive protein,procalcitonin,interleukin-6,vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancer

AIM:The current study was to determine the serum/pLasma levels of VEGF,IL-6,malondialdehyde (MDA),nitric oxide (NO),PCT and CRP in gastric carcinoma and correlation with the stages of the disease and accompanying infection. METHODS:We examined the levels of serum VEGF,IL-6, PCT,CRP and plasma MDA,NO in 42 preoperative gastric cancer patients and 23 healthy subjects.There were infection anamneses that had no definite origin in 19 cancer patients. RESULTS:The VEGF levels (mean±SD; pg/mL) were 478.05±178.29 and 473.85±131.24 in gastric cancer patients with and without infection,respectively,and these values were not significantly different (P>0.05).The levels of VEGF, CRP,PCT,It-6,MDA and NO in cancer patients were significantly higher than those in healthy controls and the levels of CRP,PCT,It-6,MDA and NO were statistically increased in infection group when compared with non- infection group (P<0.001). CONCLUSION:Although serum VEGF concentrations were increased in gastric cancer,this increase might not be related to infection.CRP,PCT,IL-6,MDA and NO have obvious drawbacks in the diagnosis of infections in cancer patients. These markers may not help to identify infections in the primary evaluation of cancer patients and hence to avoid unnecessary antibiotic treatments as well as hospitalization. According to the results of this study,IL-6,MDA,NO and especially VEGF can be used as useful parameters to diagnose and grade gastric cancer.

Prognostic significance of red blood cell distribution width in gastrointestinal disorders

The red blood cell distribution width(RDW) is a routinely measured and automatically reported blood parameter,which reflects the degree of anisocytosis. Recently,the baseline RDW was found to have clinical significance for assessing clinical outcome and severity of various pathological conditions including cardiovascular diseases,sepsis,cancers,leukemia,renal dysfunction and respiratory diseases. A myriad of factors,most of which ill-defined,have an impact on the red cell population dynamics(i.e.,production,maturation and turnover). A delay in the red blood cell clearance in pathological conditions represents one of the leading determinants of increased anisocytosis. Further study of RDW may reveal new insight into inflammation mechanisms. In this review,we specifically discuss the current literature about the association of RDW in various disease conditions involving the gastrointestinal and hepatobiliary systems. We also present some of the related measurements for their value in predicting clinical outcomes in such conditions. According to our data,RDW was found to be a valuable prognostic index in gastrointestinal disorders along with additional inflammatory biomarkers(i.e.,C reactive protein,erythrocyte sedimentation rate,and platelet count) and current disease severity indices used in clinical practice.

Advances in nutritional therapy in inflammatory boweldiseases:Review

Inflammatory bowel diseases(IBD), including ulcerative colitis and Crohn's disease are chronic, life-long, and relapsing diseases of the gastrointestinal tract. Currently, there are no complete cure possibilities, but combined pharmacological and nutritional therapy may induce remission of the disease. Malnutrition and specific nutritional deficiencies are frequent among IBD patients, so the majority of them need nutritional treatment, which not only improves the state of nutrition of the patients but has strong anti-inflammatory activity as well. Moreover, some nutrients, from early stages of life are suspected as triggering factors in the etiopathogenesis of IBD. Both parenteral and enteral nutrition is used in IBD therapy, but their practical utility in different populations and in different countries is not clearly established, and there are sometimes conflicting theories concerning the role of nutrition in IBD. This review presents the actual data from research studies on the influence of nutrition on the etiopathogenesis of IBD and the latest findings regarding its mechanisms of action. The use of both parenteral and enteral nutrition as therapeutic methods in induction and maintenance therapy in IBD treatment is also extensively discussed. Comparison of the latest research data, scientific theories concerning the role of nutrition in IBD, and different opinions about them are also presented and discussed. Additionally, some potential future perspectives for nutritional therapy are highlighted.