K^(+) channel-mediated retarded maturation of interneurons and its role in neurodevelopmental disorders

De novo mutations in genes encoding K^(+)channels are implicated in many severe neurodevelopmental disorders.Specifically,mutations in KCNA2,encoding the Shaker-type voltage-gated K^(+)channel Kv1.2,and KCNJ2,encoding the inwardly rectifying K^(+)channel Kir2.1,associate with focal and generalized epilepsies,brain atrophy,autism,ataxia and hereditary spastic paraplegia(Syrbe et al.,2015;Masnada et al.,2017;Cheng et al.,2021).

Lactate is a potentially harmful substitute for brain glucose fuel:consequences for metabolic restoration of neurotransmission

The metabolite lactate (L-lactate) can be generated and released by diverse brain cells,including neurons,astrocytes,and oligodendrocytes (Kann,2023;Rae et al.,2024).Lactate production usually requires the degradation of glucose (D-glucose)-and glycogen in astrocytes-to pyruvate by glycolysis and subsequent conversion of pyruvate to lactate by the enzyme lactate dehydrogenase(Figure 1A;Dienel,2019;Rae et al.,2024).

In vivo and in vitro study of resorbable magnesium wires for medical implants:Mg purity,surface quality,Zn alloying and polymer coating

Magnesium is an excellent material in terms of biocompatibility and its corrosion products can serve as an active source for new bone formation.However,localized corrosion and H_(2)generation limit the potential of Mg-based implants.Utilizing low-alloyed Mg-Zn wires can strongly reduce problems with large H_(2)bubbles and improve the mechanical properties considerably while maintaining excellent long-term biocompatibility.Acidic pickling and a polymer coating can be effectively used to lower the rate of in vivo degradation.In this work,microstructural,mechanical,and in vitro characterization of 250μm and 300μm extruded wires made from ultra-pure Mg,commercially pure Mg,Mg-0.15Zn,Mg-0.4Zn and Mg-1Zn was performed.Additionally,Mg-0.4Zn wires together with a variant coated with a copolymer of L-lactide andε-caprolactone were tested in vivo on artificially damaged Wistar rat femurs.Based on the observed Mg-induced osteogenesis,polymer-coated Mg wires with a small addition of Zn are a perspective material for bone-support applications,such as cerclage and fixation wires.

Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology

The gastrointestinal tract is the largest reservoir of commensal bacteria in the human body, providing nutrients and space for the survival of microbes while concurrently operating mucosal barriers to confine the microbial population. The epithelial cells linked by tight junctions not only physically separate the microbiota from the lamina propria, but also secrete proinflammatory cytokines and reactive oxygen species in response to pathogen invasion and metabolic stress and serve as a sentinel to the underlying immune cells. Accumulating evidence indicates that commensal bacteria are involved in various physiological functions in the gut and microbial imbalances (dysbiosis) may cause pathology. Commensal bacteria are involved in the regulation of intestinal epithelial cell turnover, promotion of epithelial restitution and reorganization of tight junctions, all of which are pivotal for fortifying barrier function. Recent studies indicate that aberrant bacterial lipopolysaccharide-mediated signaling in gut mucosa may be involved in the pathogenesis of chronic inflammation and carcinogenesis. Our perception of enteric commensals has now changed from one of opportunistic pathogens to active participants in maintaining intestinal homeostasis. This review attempts to explain the dynamic interaction between the intestinal epithelium and commensal bacteria in disease and health status.

Differential role of Hedgehog signaling in human pancreatic(patho-)physiology:An up to date review

Since the discovery of the Hedgehog(Hh)pathway in drosophila melanogaster,our knowledge of the role of Hh in embryonic development,inflammation,and cancerogenesis in humans has dramatically increased over the last decades.This is the case especially concerning the pancreas,however,real therapeutic breakthroughs are missing until now.In general,Hh signaling is essential for pancreatic organogenesis,development,and tissue maturation.In the case of acute pancreatitis,Hh has a protective role,whereas in chronic pancreatitis,Hh interacts with pancreatic stellate cells,leading to destructive parenchym fibrosis and atrophy,as well as to irregular tissue remodeling with potency of initiating cancerogenesis.In vitro and in situ analysis of Hh in pancreatic cancer revealed that the Hh pathway participates in the development of pancreatic precursor lesions and ductal adenocarcinoma including critical interactions with the tumor microenvironment.The application of specific inhibitors of components of the Hh pathway is currently subject of ongoing clinical trials(phases 1 and 2).Furthermore,a combination of Hh pathway inhibitors and established chemotherapeutic drugs could also represent a promising therapeutic approach.In this review,we give a structured survey of the role of the Hh pathway in pancreatic development,pancreatitis,pancreatic carcinogenesis and pancreatic cancer as well as an overview of current clinical trials concerning Hh pathway inhibitors and pancreas cancer.

Modulatory effects of Lactiplantibacillus plantarum on chronic metabolic diseases

The increased global incidence of chronic metabolic diseases,a vital threat to human health and a burden on our healthcare systems,includes a series of clinical metabolic syndromes such as obesity,diabetes,hypertension,and dyslipidemia.One of the well-known probiotic microorganisms,Lactiplantibacillus plantarum plays an important role in promoting human health,including inhibiting the occurrence and development of a variety of chronic metabolic diseases.The present study provides an overview of the preventive and therapeutic effects of L.plantarum on diabetes,obesity,non-alcoholic fatty liver disease,kidney stone disease,and cardiovascular diseases in animal models and human clinical trials.Ingesting L.plantarum demonstrated its ability to reduce inflammatory and oxidative stress levels by regulating the production of cytokines and short-chain fatty acids(SCFAs),the activity of antioxidant enzymes,and the balance of intestinal microbial communities to alleviate the symptoms of chronic metabolic diseases.Furthermore,updated applications and technologies of L.plantarum in food and biopharmaceutical industries are also discussed.Understanding the characteristics and functions of L.plantarum will guide the development of related probiotic products and explore the modulatory benefit of L.plantarum supplementations on the prevention and treatment of multiple chronic metabolic diseases.

Enhancement of intranasalmucosal immunization of mucosal vaccines by ultrasonic treatment

The pathogens of most infectious diseases invade the host through mucosal sites,and immunization with mucosal vaccines is the best means of combating these infectious diseases.Oral delivery and nasal delivery are the most common methods of mucosal vaccination.However,the delivery process is inefficient,and mucosal vaccination is ineffective because the vaccine formulation is easily and rapidly removed and has difficulty in crossing the mucosal surface.In this paper,we investigated whether the mucosal immune response could be enhanced by ultrasound facilitation of nasal mucosal delivery of vaccine preparations.For this purpose,we used manganese dioxide(MnO2)as the vaccine carrier/adjuvant,coated with chitosan oligosaccharide(COS)to enhance mucosal adsorption,and further physically adsorbed model antigen ovalbumin(OVA)to construct a nanoparticulate vaccine formulation MnO2@COS@OVA.Ultrasound treatment was found to promote antigen delivery and recruitment of dendritic cells(DCs)and macrophages as well as T-cell infiltration in nasal mucosal tissues through nasal mucosal immunization studies.With ultrasound assistance,MnO2@COS@OVA particles promoted the maturation of DCs in vitro and in vivo and promoted the production of effector memory T cells in vivo and cytokine secretion by splenocytes in vitro.In particular,ultrasound treatment significantly increased the levels of secretory IgA antibodies in the nasal mucosa and genital tract mucosa of experimental mice.In addition,the experimental data showed that the MnO2@COS@OVA particles had good biocompatibility and caused no significant damage to the nasal mucosal and vital organ tissue.These data suggest that ultrasound treatment can promote the induction of efficient immune responses to mucosal vaccines and provide new ideas for the opening and clinical translation of mucosal vaccines.

Quality Evaluation of Streptocaulon griffithii Hook Based on Fingerprint and Quantitative Analysis of Multiple Components by the QAMS Method

[Objectives]Chromatographic fingerprint analysis technology and quantitative analysis of multi-components by singlemarker(QAMS)were used to identify the authenticity and multi-component quantitative analysis ofStreptocaulon griffithiiHook,which provided experimental reference for the quality evaluation and control ofS.griffithiiHook.[Methods]Method was carried out on Agilent ZORBAX SB-C18(150 mm×4.6 mm,5μm)column with mobile phase composed of methanol-0.2%phosphoric acid solution at a flow rate of 1.0 mL/min in gradient elution mode.The column temperature was maintained at 30℃,the injection volume was 5μL,and the detection wavelengths were set at 230 nm.The HPLC fingerprint ofS.griffithiiHook was established byFingerprint Similarity Evaluation Software of Traditional Chinese Med-i cine(2012 edition),and the quality of 11 batches ofS.griffithiiHook extracts was analyzed.The content of chlorogenic acid,caffeic acid and4-methoxysalicylaldehyde inS.griffithiiHook was determined by QAMS.[Results]Thirteen common peaks were identified in the extract ofS.g riffithiiHook,and three components were identified as chlorogenic acid,caffeic acid and 4-methoxysalicylaldehyde,there was no significant difference between QAMS method and external standard method with chlorogenic acid as reference substance.[Conclusions]The established HPLC method is specific,accurate,stable and reproducible,and it can be used as an effective method for the quality control ofS.griffithii Hook.

Non-Invasive Approach to Early Diagnosis of the Formation of Oncological Neoplasms

The currently developed instrumental approaches for detecting pathological changes in the body have a number of disadvantages. The most important of them is that the equipment is sensitive to the detection of diseases only from a certain threshold level of destructive changes in the body. The present article discusses the possibility of using the new instrumental complex “Bioscope” for early and non-invasive diagnosis of the beginning of the formation of ontological neoplasm’s in the body.

Polyoxidovanadates a new therapeutic alternative for neurodegenerative and aging diseases

Aging is a natural phenomenon characterized by a progressive decline in physiological integrity,leading to a deterioration of cognitive function and increasing the risk of suffering from chronic-degenerative diseases,including cardiovascular diseases,osteoporosis,cancer,diabetes,and neurodegeneration.Aging is considered the major risk factor for Parkinson’s and Alzheimer’s disease develops.Likewise,diabetes and insulin resistance constitute additional risk factors for developing neurodegenerative disorders.Currently,no treatment can effectively reverse these neurodegenerative pathologies.However,some antidiabetic drugs have opened the possibility of being used against neurodegenerative processes.In the previous framework,Vanadium species have demonstrated a notable antidiabetic effect.Our research group evaluated polyoxidovanadates such as decavanadate and metforminium-decavanadate with preventive and corrective activity on neurodegeneration in brain-specific areas from rats with metabolic syndrome.The results suggest that these polyoxidovanadates induce neuronal and cognitive restoration mechanisms.This review aims to describe the therapeutic potential of polyoxidovanadates as insulin-enhancer agents in the brain,constituting a therapeutic alternative for aging and neurodegenerative diseases.

Coumarin and eugenol ameliorate LPS-induced inflammation in RAW 264.7 cells via modulating the NLRP3 inflammasome pathway

Objective:To investigate the underlying mechanism of anti-inflammatory action of coumarin and eugenol in lipopolysaccharide(LPS)-stimulated RAW 264.7 cells.Methods:RAW 264.7 cells were treated with 2.5μg/mL of LPS,50μM of coumarin,and 50μM eugenol for 24 h.The viability of the cells was assessed using MTT assay.The production of nitric oxide was determined using Griess reagent and DCFH-DA was used to measure the production of reactive oxygen species.The protein expression of NLRP3,IL-1β,NF-κB,and cyclooxygenase 2 was assessed using Western blot analysis.Results:Coumarin and eugenol showed anti-inflammatory effects against LPS-induced inflammatory response by ameliorating the expression of NLRP3 inflammasome and NF-κB,which further led to a subsequent reduction in IL-1β,nitric oxide,and reactive oxygen species.Conclusions:Coumarin and eugenol exert their anti-inflammatory activities by modulating the NLRP3 inflammasome pathway and NF-κB.These compounds may have promising therapeutic applications for the treatment of various inflammatory diseases.

Thrombotic complications post liver transplantation:Etiology and management

Liver transplantation(LT)is the life saving therapeutic option for patients with acute and chronic end stage liver disease.This is a routine procedure with excellent outcomes in terms of patient survival and quality of life post LT.Orthotopic LT(OLT)patients require a critical care as they are prone to variety of post-operative vascular,cardiovascular,biliary,pulmonary and abdominal complications.Thrombotic complications(both arterial and venous)are not uncommon post liver transplant surgery.Such vascular problems lead to increased morbidity and mortality in both donor and graft recipient.Although thromboprophylaxis is recommended in general surgery patients,no such standards exist for liver transplant patients.Drastic advancements of surgical and anesthetic procedures have improvised survival rates of patients post OLT.Despite these,haemostatic imbalance leading to thrombotic events post OLT cause significant graft loss and morbidity and even lead to patient’s death.Thus it is extremely important to understand pathophysiology of thrombosis in LT patients and shorten the timing of its diagnosis to avoid morbidity and mortality in both donor and graft recipient.Present review summarizes the current knowledge of vascular complications associated with LT to highlight their impact on short and long-term morbidity and mortality post LT.Also,present report discusses the lacunae existing in the literature regarding the risk factors leading to arterial and venous thrombosis in LT patients.

Growth factor receptors and related signalling pathways as targets for novel treatment strategies of hepatocellular cancer

Growth factors and their corresponding receptors are commonly overexpressed and/or dysregulated in many cancers including hepatocellular cancer （HCC）. Clinical trials indicate that growth factor receptors and their related signalling pathways play important roles in HCC cancer etiology and progression, thus providing rational targets for innovative cancer therapies. A number of strategies including monoclonal antibodies, tyrosine kinase inhibitors （＂small molecule inhibitors＂） and antisense oligonucleotides have already been evaluated for their potency to inhibit the activity and downstream signalling cascades of these receptors in HCC. First clinical trials have also shown that multi-kinase inhibition is an effective novel treatment strategy in HCC. In this respect sorafenib, an inhibitor of Raf-, VEGF- and PDGF-signalling, is the first multi-kinase inhibitor that has been approved by the FDA for the treatment of advanced HCC. Moreover, the serine-threonine kinase of mammalian target of rapamycin （mTOR） upon which the signalling of several growth factor receptors converge plays a central role in cancer cell proliferation, roTOR inhibition of HCC is currently also being studied in preclinical trials. As HCCs represent hypervascularized neoplasms, inhibition of tumour vessel formation via interfering with the VEGF/VEGFR system is another promising approach in HCC treatment. This review will summarize the current status of the various growth factor receptor-based treatment strategies and in view of the multitude of novel targeted approaches, the rationale for combination therapies for advanced HCC treatment will also be taken into account.

Local Proinflammatory Effects of Repeated Skin Exposure to Warfarin, An Anticoagulant Rodenticide in Rats

Objective： To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin. Methods： Rats were exposed to warfarin by applying 10 μg of warfarin‐sodium to 10‐12 cm 2 skin （range 0.8‐1 μg per 1 cm 2 ） for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application. Results： Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury （increased malondialdehyde, MDA, production, evident histo‐morphological changes in epidermis and dermis depicting cell injury and death）. Increased numbers of proliferating cell nuclear antigen （PCNA ＋ ） cells indicated reparative processes in injured skin. Infiltration of CD3 ＋ cells （T lymphocytes） along with the increased production of tumor necrosis factor‐α （TNF‐α） by epidermal cells from warfarin‐treated skin and their co‐stimulatory effect in an in vitro T‐cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin. Conclusion： Presented data have documented tissue damage associated with immune/ inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.

Role of Helicobacter pylori in gastric mucosa-associated lymphoid tissue lymphomas

Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent extranodal marginal zone B-cell lymphoma, originating in acquired MALT that is induced in mucosal barriers as part of a normal adaptive immune response to a chronic immunoinflammatory stimulus, most notably chronic infection by Helicobacter pylori (H. pylori). This antigenic stimulation initially leads to lymphoid hyperplasia; the acquisition of additional genetic aberrations culminates in the activation of intracellular survival pathways, with disease progression due to proliferation and resistance to apoptosis, and the emergence of a malignant clone. There are descriptions of MALT lymphomas affecting practically every organ and system, with a marked geographic variability partially attributable to the epidemiology of the underlying risk factors; nevertheless, the digestive system (and predominantly the stomach) is the most frequently involved location, reflecting the gastrointestinal tract’s unique characteristics of contact with foreign antigens, high mucosal permeability, large extension and intrinsic lymphoid system. While early-stage gastric MALT lymphoma can frequently regress after the therapeutic reversal of the chronic immune stimulus through antibiotic eradication of H. pylori infection, the presence of immortalizing genetic abnormalities, of advanced disease or of eradication-refractoriness requires a more aggressive approach which is, presently, not consensual. The fact that MALT lymphomas are rare neoplasms, with a worldwide incidence of 1-1.5 cases per 105 population, per year, limits the ease of accrual of representative series of patients for robust clinical trials that could sustain informed evidence-based therapeutic decisions to optimize the quality of patient care.

Preventive effect of a pectic polysaccharide of the common cranberry Vaccinium oxycoccos L. on acetic acid-induced colitis in mice

AIM： To study isolation and chemical characterization of pectin derived from the common cranberry Vaccin/um oxycoccos L. （oxycoccusan OP） and the testing of its preventive effect on experimental colitis. METHODS： Mice were administrated orally with OP two days prior to a rectal injection of 5% acetic acid and examined for colonic damage 24 h later. Colonic inflammation was characterized by macroscopical injury and enhanced levels of myeloperoxidase activity measured spectrophotometrically with o-phenylene diamine as the substrate. The mucus contents of the colon were determined by the Alcian blue dye binding method. Vascular permeability was estimated using 4% Evans blue passage after i.p. injection of 0.05 mol/L acetic acid. RESULTS： In the mice treated with OP, colonic macroscopic scores （1.1 ± 0.4 vs 2.7, P 〈 0.01） and the total square area of damage （10 ± 2 vs 21 ± 7, P 〈 0.01） were significantly reduced when compared with the vehicle-treated colitis group. OP was shown to decrease the tissue myeloperoxidase activity in colons （42 ± 11 vs 112 ± 40, P 〈 0.01） and enhance the amount of mucus of colitis mice （0.9 ± 0.1 vs 0.4 ± 0.1, P 〈 0.01）. The level of colonic malondialdehyde was noted to decrease in OP-pretreated mice （3.6 ± 0.7 vs 5.1 ± 0.8, P 〈 0.01）. OP was found to decrease the inflammatory status of mice as was determined by reduction of vascular permeability （161 ± 34 vs 241 ± 21, P 〈 0.01）. Adhesion of peritoneal neutrophils and macrophages was also shown to decrease after administration of OP （141 ± 50 vs 235 ± 37, P 〈 0.05）. CONCLUSION： Thus, a preventive effect of pectin from the common cranberry, namely oxycoccusan OP, on acetic acid-induced colitis in mice was detected. A reduction of neutrophil infiltration and antioxidant action may be implicated in the protective effect of oxycoccusan.

ISCHEMIC PRECONDITIONING RELIEVES ISCHEMIA/REPERFUSION INJURY OF HIPPOCAMPUS NEURONS IN RAT BY INHIBITING p53 AND BAX EXPRESSIONS

Objective To examine whether ischemic preconditioning (IPC) can protect neuron against delayed death in CA1 subfield of hippocampus following reperfusion of a lethal ischemia in rats, and explore the role of p53 and bax in this process. Methods We examined the effect of IPC on delayed neuron death, neuron apoptosis, expressions of p53 and bax gene in the CA1 area of hippocampus in the rats using HE staining, flow cytometry, RT-PCR, and immunohistochemistry technique. Results IPC enhanced the quantity of survival cells in the CA1 region of hippocampus (216±9 cells/0.72 mm2 vs. 30±5 cells/0.72 mm2, P<0.01), decreased the percentages of apoptotic neurons of hippocampus caused by ischemia/reperfusion (2.06%±0.21% vs. 4.27%±0.08%, P<0.01), and weakened the expressions of p53 and bax gene of hippocampus compared with ischemia/reperfusion without IPC. Conclusion IPC can protect the neurons in the CA1 region of hippocampus against apoptosis caused by ische- mia/reperfusion, and this process may be related to the reduced expressions of p53 and bax.

Effects of two medicinal plants Psidium guajava L. (Myrtaceae) and Diospyros mespiliformis L. (Ebenaceae) leaf extracts on rat skeletal muscle cells in primary culture

Crude decoction, aqueous and ethanolic extracts of two medicinal plants （Psidiura guajava and Diospyros raespiliformis）, widely used in the central plateau of Burkina Faso to treat many diseases were evaluated for their antagonistic effects on caffeine induced calcium release from sarcoplasmic reticulum of rat skeletal muscle cells. These different extracts showed a decrease of caffeine induced calcium release in a dose dependent manner. Comparison of the results showed that Psidiura guajava leaf extracts are more active than extracts of Diospyros mespiliformis and that crude decoctions show better inhibitory activity. The observed results could explaine their use as antihypertensive and antidiarrhoeal agents in traditional medicine, by inhibiting intracellular calcium release.

Lead Induced Oxidative Stress: Beneficial Effects of Kombucha Tea

Objective To evaluate the effect of oral administration of Kombucha tea (K-tea) on lead induced oxidative stress. Methods Sprague Dawley rats were administered 1 mL of 3.8% lead acetate solution daily alone or in combination with K-tea orally for 45 d, and the antioxidant status and lipid peroxidation were evaluated. Results Oral administration of lead acetate to rats enhanced lipid peroxidation and release of creatine phosphokinase and decreased levels of reduced glutathione (GSH) and antioxidant enzymes (superoxide dismutase, SOD and glutathione peroxidase, GPx). Lead treatment did not alter humoral immunity, but inhibited DTH response when compared to the control. Lead administration also increased DNA fragmentation in liver. Oral administration of Kombucha tea to rats exposed to lead decreased lipid peroxidation and DNA damage with a concomitant increase in the reduced glutathione level and GPx activity. Kombucha tea supplementation relieved the lead induced immunosuppression to appreciable levels. Conclusion The results suggest that K-tea has potent antioxidant and immunomodulating properties.

Dispersion of ventricular repolarization: Temporal and spatial

Repolarization heterogeneity(RH)is an intrinsic property of ventricular myocardium and the reason for T-wave formation on electrocardiogram(ECG).Exceeding the physiologically based RH level is associated with appearance of life-threatening ventricular arrhythmias and sudden cardiac death.In this regard,an accurate and comprehensive evaluation of the degree of RH parameters is of importance for assessment of heart state and arrhythmic risk.This review is devoted to comprehensive consideration of RH phenomena in terms of electrophysiological processes underlying RH,cardiac electric field formation during ventricular repolarization,as well as clinical significance of RH and its reflection on ECG parameters.The formation of transmural,apicobasal,left-toright and anterior-posterior gradients of action potential durations and end of repolarization times resulting from the heterogenous distribution of repolarizing ion currents and action potential morphology throughout the heart ventricles,and the different sensitivity of myocardial cells in different ventricular regions to the action of pharmacological agents,temperature,frequency of stimulation,etc.,are being discussed.The review is focused on the fact that RH has different aspects–temporal and spatial,global and local;ECG reflection of various RH aspects and their clinical significance are being discussed.Strategies for comprehensive assessment of ventricular RH using different ECG indices reflecting various RH aspects are presented.