Regeneration of the heart:f rom molecular mechanisms to clinical therapeutics

Heart injury such as myocardial infarction leads to cardiomyocyte loss,fibrotic tissue deposition,and scar formation.These changes reduce cardiac contractility,resulting in heart failure,which causes a huge public health burden.Military personnel,compared with civilians,is exposed to more stress,a risk factor for heart diseases,making cardiovascular health management and treatment innovation an important topic for military medicine.So far,medical intervention can slow down cardiovascular disease progression,but not yet induce heart regeneration.In the past decades,studies have focused on mechanisms underlying the regenerative capability of the heart and applicable approaches to reverse heart injury.Insights have emerged from studies in animal models and early clinical trials.Clinical interventions show the potential to reduce scar formation and enhance cardiomyocyte proliferation that counteracts the pathogenesis of heart disease.In this review,we discuss the signaling events controlling the regeneration of heart tissue and summarize current therapeutic approaches to promote heart regeneration after injury.

Advances in Zika virus vaccines and therapeutics:A systematic review

Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.

A novel approach to Parkinson's disease treatment with a potentially dual-acting therapeutic agent that targetsα-synuclein aggregation and neuron death

Parkinson's disease(PD),a prevalent neurodegenerative disorder,is chara cterized by the loss of dopaminergic neurons and the aggregation ofα-synuclein protein into Lewy bodies.While the current standards of therapy have been successful in providing some symptom relief,they fail to address the underlying pathophysiology of PD and as a result,they have no effect on disease progression.

Lactate:a prospective target for therapeutic intervention in psychiatric disease

Although antipsychotics that act via monoaminergic neurotransmitter modulation have considera ble therapeutic effect,they cannot completely relieve clinical symptoms in patients suffering from psychiatric disorde rs.This may be attributed to the limited range of neurotransmitters that are regulated by psychotropic drugs.Recent findings indicate the need for investigation of psychotropic medications that target less-studied neurotransmitte rs.Among these candidate neurotransmitters,lactate is developing from being a waste metabolite to a glial-neuronal signaling molecule in recent years.Previous studies have suggested that cerebral lactate levels change considerably in numerous psychiatric illnesses;animal experiments have also shown that the supply of exogenous la ctate exerts an antidepressant effect.In this review,we have described how medications targeting newer neurotransmitte rs offer promise in psychiatric diseases;we have also summarized the advances in the use of lactate(and its corresponding signaling pathways)as a signaling molecule.In addition,we have described the alterations in brain lactate levels in depression,anxiety,bipolar disorder,and schizophrenia and have indicated the challenges that need to be overcome before brain lactate can be used as a therapeutic target in psychopharmacology.

Bile acids,gut microbiota,and therapeutic insights in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a prevalent and aggressive liver malignancy.The interplay between bile acids(BAs)and the gut microbiota has emerged as a critical factor in HCC development and progression.Under normal conditions,BA metabolism is tightly regulated through a bidirectional interplay between gut microorganisms and BAs.The gut microbiota plays a critical role in BA metabolism,and BAs are endogenous signaling molecules that help maintain liver and intestinal homeostasis.Of note,dysbiotic changes in the gut microbiota during pathogenesis and cancer development can disrupt BA homeostasis,thereby leading to liver inflammation and fibrosis,and ultimately contributing to HCC development.Therefore,understanding the intricate interplay between BAs and the gut microbiota is crucial for elucidating the mechanisms underlying hepatocarcinogenesis.In this review,we comprehensively explore the roles and functions of BA metabolism,with a focus on the interactions between BAs and gut microorganisms in HCC.Additionally,therapeutic strategies targeting BA metabolism and the gut microbiota are discussed,including the use of BA agonists/antagonists,probiotic/prebiotic and dietary interventions,fecal microbiota transplantation,and engineered bacteria.In summary,understanding the complex BA-microbiota crosstalk can provide valuable insights into HCC development and facilitate the development of innovative therapeutic approaches for liver malignancy.

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

The spread of tuberculosis(TB),especially multidrug-resistant TB and extensively drug-resistant TB,has strongly motivated the research and development of new anti-TB drugs.New strategies to facilitate drug combinations,including pharmacokinetics-guided dose optimization and toxicology studies of first-and second-line anti-TB drugs have also been introduced and recommended.Liquid chromatography-mass spectrometry(LC-MS)has arguably become the gold standard in the analysis of both endo-and exo-genous compounds.This technique has been applied successfully not only for therapeutic drug monitoring(TDM)but also for pharmacometabolomics analysis.TDM improves the effectiveness of treatment,reduces adverse drug reactions,and the likelihood of drug resistance development in TB patients by determining dosage regimens that produce concentrations within the therapeutic target window.Based on TDM,the dose would be optimized individually to achieve favorable outcomes.Pharmacometabolomics is essential in generating and validating hypotheses regarding the metabolism of anti-TB drugs,aiding in the discovery of potential biomarkers for TB diagnostics,treatment monitoring,and outcome evaluation.This article highlighted the current progresses in TDM of anti-TB drugs based on LC-MS bioassay in the last two decades.Besides,we discussed the advantages and disadvantages of this technique in practical use.The pressing need for non-invasive sampling approaches and stability studies of anti-TB drugs was highlighted.Lastly,we provided perspectives on the prospects of combining LC-MS-based TDM and pharmacometabolomics with other advanced strategies(pharmacometrics,drug and vaccine developments,machine learning/artificial intelligence,among others)to encapsulate in an all-inclusive approach to improve treatment outcomes of TB patients.

Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

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

Metabolic dysfunction-associated steatotic liver disease:Navigating terminological evolution,diagnostic frontiers and therapeutic horizon-an editorial exploration

Metabolic dysfunction-associated steatotic liver disease(MASLD),once known as non-alcoholic fatty liver disease(NAFLD),represents a spectrum of liver disorders characterized by lipid accumulation within hepatocytes.The redefinition of NAFLD in 2023 marked a significant reposition in terminology,emphasizing a broader understanding of liver steatosis and its associated risks.MASLD is now recognized as a major risk factor for liver cirrhosis,hepatocellular carcinoma,and systemic complications such as cardiovascular diseases or systemic inflammation.Diagnostic challenges arise,particularly in identifying MASLD in lean individuals,necessitating updated diagnostic protocols and investing in non-invasive diagnostic tools.Therapeutically,there is an urgent need for effective treatments targeting MASLD,with emerging pharmacological options focusing on,among others,carbohydrate and lipid metabolism.Additionally,understanding the roles of bile acid metabolism,the microbiome,and dietary interventions in MASLD pathogenesis and management holds promise for innovative therapeutic approaches.There is a strong need to emphasize the importance of collaborative efforts in understanding,diagnosing,and managing MASLD to improve physicians’approaches and patient outcomes.

Clinical and Therapeutic Aspects of Migraine in Brazzaville

Introduction: Migraine is the most common primary headache, and can cause significant disability. There are two types, migraine without aura and migraine with aura. The diagnosis of migraine is essentially clinical. Worldwide prevalence was estimated at 11.6% in 2009. In Africa, it is estimated at 10.4%. Objective: To describe the clinical and therapeutic aspects of migraine in Brazzaville. Patients and Methods: This was a door-to-door cross-sectional study conducted from 1st May to 1 st July 2018 in the city of Brazzaville. Subjects over 18 with clearly expressed consent were included. The questionnaire covered demographic characteristics, diagnostic criteria for migraine according to the IHS, treatments taken. The degree of disability was determined using the Migraine Disability Assessment Scale (MIDAS). Statistical analysis was performed using SPSS 22.0 for MAC. Results: Of the 1017 subjects interviewed in this study, 115 (39.9%) had migraine, including 73 women (63.47%) and 42 men (36.52%). In the group of migraine sufferers, the number of cases of definite migraine was 61 (53.04%) and that of probable migraine 54 (46.95%). For 81 migraine sufferers (70.43%), stress was the triggering factor. The frequency of attacks was weekly and monthly for 30 (26.1%) and 19 (16.5%) sufferers respectively. The location of the migraine was unilateral in 38% of cases and tilted in 24.3%. The intensity of the attack was described as moderate and severe in 41.7% and 57.4% of subjects respectively. Phonophobia/photophobia accompanied the migraine in 65.2% of cases. One hundred and eight subjects were treated. Of these, 106 (98.1%) were on medication. Eleven (10.37%) had received a medical prescription, and ninety-seven (89.8%) were self-medicating. Five and three subjects were under the care of a general practitioner and a neurologist respectively. Conclusion: Migraine is a frequent pathology in Brazzaville. Its preponderance among young people and women calls for the implementation of effective prevention strategies for these already vulnerable social groups. The form without aura was the most common type. Visual aura was the most common type. Headache-related symptoms were dominated by phonophotophobia, followed by nausea and vomiting. Almost all migraine sufferers were self-medicating, and very few were under the care of a doctor. First-line analgesics and NSAIDs were the mainstay of treatment.

Lin28 as a therapeutic target for central nervous system regeneration and repair

Axon disconnection in the central nervous system(CNS) usually causes signal transduction failure and severe functional deficits in patients with neurological disorders. Currently, there is no cure for patients with CNS axon injury and they usually suffer from life-long neurological defects(e.g., paralysis, loss of sensory function, and autonomic dysfunction) and life-threatening complications(e.g., autonomic dysreflexia).

Perspectives for delivery of therapeutics by extravasation of biodegradable microspheres in the brain

Development of therapeutics for brain diseases has remained challenging,in particular due to the difficulty of passing the blood-brain barrier.As a result,the current arsenal of therapeutics targeting the brain is limited to small,lipid-soluble drugs and there is a lack of options for treating neuroblastomas,Alzheimer’s disease,and many other devastating pathologies.Despite the advances in strategies for crossing the blood-brain barrier such as the use of nanoparticles(Hersh et al.,2022;Duan et al.,2023),such delivery systems have not yet reached clinical practice.Therefore,novel platforms for the transport of therapeutics across the blood-brain barrier remain highly desired.This specifically holds for large molecules such as monoclonal antibodies and recombinant proteins,as well as nucleotide-based therapeutics and cell therapies.Research efforts in this field are increasing exponentially,with thousands of publications in the last few years.

Results of selective decontamination with oral neomycin and metronidazole for major colorectal surgery in Australia:A cohort study

Objective The role of selective decontamination with oral antibiotics(OABs)and mechanical bowel preparation(MBP)prior to elective colorectal surgery is still widely debated.The objective of this study was to compare the outcomes of selective decontamination with neomycin,metronidazole and MBP compared to those of decontamination with MBP alone or with no preparation.Methods Selective decontamination with neomycin and metronidazole combined with bowel preparation was introduced prior to elective colorectal surgery as part of an enhanced recovery after surgery program at Westmead Hospital,a major Australian tertiary referral hospital,between June 2017 and January 2023.Comparisons between short-term outcomes of OAB+MBP and MBP/no preparation were made using prospectively collected data on length of stay(LOS),readmission,mortality within 30 days,anastomotic leakage(AL),surgical site infection(SSI),urinary tract infection,deep venous thrombosis and/or pulmonary embolism,pneumonia,and ileus.Follow-up was limited to hospital stays and subsequent presentations within the health district within thirty days of surgery.The Mann-Whitney U test was used to analyse continuous data,and the chi-square test was used for categorical data.Univariate and multivariate regression modelling was performed to identify risk factors associated with an increased likelihood of SSI and AL.Results Patients with oral neomycin and metronidazole combined with bowel preparation had reduced superficial SSI(2.7%vs.7.6%,p=0.043)and overall complications(32.7%vs.44.6%,p=0.020),particularly Clavien-Dindo 1 complications(7.3%vs.16.5%,p=0.009).However,the differences in AL(2.7%vs.4.5%,p=0.369)and organ/space SSI(1.3%vs.3.7%,p=0.327)were not statistically significant.The median LOS(6 d vs.6 d,p=0.370)was not different between the groups.Conclusion Selective decontamination with neomycin and metronidazole reduces the risk of SSIs and overall complications.There was a trend to toward a lower AL,but this difference was not statistically significant.

Role of peripheral amyloid-β aggregates in Alzheimer’s disease: mechanistic, diagnostic, and therapeutic implications

Compelling evidence demonstrates that the levels of peripheral amyloid-β(Aβ)fluctuate in Alzheimer’s disease(AD)patients.Moreover,Aβdeposits have been identified in peripheral tissues.However,the relevance of peripheral Aβ(misfolded or not)in pathological situations,and the temporal appearance of these pathological fluctuations,are not well understood.The presence of misfolded Aβin peripheral compartments raises concerns on potential inter-individual transmissions considering the well-reported prion-like properties of this disease-associated protein.The latter is supported by multiple reports demonstrating that Aβmisfolding can be transmitted between humans and experimental animals through multiple routes of exposure.In this mini-review,we discuss the potential implications of peripheral,disease-associated Aβin disease mechanisms,as well as in diagnostic and therapeutic approaches.

Eradication Treatment of Helicobacter pylori Infection: Evaluation of Therapeutic Strategies in N’Djamena

Background: Helicobacter pylori (Hp) infection is the most widespread bacterial infection in the world. The infection is generally acquired in childhood, but can persist into adulthood. Eradication therapy has undergone several modifications. The aim of this study was to evaluate the different therapeutic strategies used in the eradication of Helicobacter pylori infection in the Centre Hospitalier Universitaire La Reference Nationale of N’Djaména. Patients and Methods: This was a prospective, descriptive analytical study spread over one year, from September 2021 to September 2022. Patients at least 15 years of age presenting with dyspeptic symptoms, seen consecutively in a hepato-gastroenterology consultation and with a positive stool test for H. pylori infection, were included in the study. Equally, 1/3 of patients were treated with dual or triple therapy. The remaining third received quadritherapy. Results: A total of 268 patients were included in the study (mean age 38.40 ± 14.66 with extremes of 16 and 80 years). Males predominated in 58% of cases. Overall therapeutic efficacy was 88.9%. According to different therapeutic strategies, efficacy was 90.75% for dual therapy with PPI (Rabeprazole) and Amoxicillin. On the other hand, efficacy was 87% and 88.88% for PPI-based triple therapy and dual antibiotic therapy, and for PPI-based quadruple therapy and triple antibiotic therapy. Conclusion: H. pylori infection is a common disease in Chad. Dual therapy with rabeprazole combined with a high dose of amoxicillin over a period of at least two weeks showed similar if not better efficacy than triple or quadruple therapy.

Lecanemab Unveiled:Exploring Alzheimer’s Treatment Advancements,Assessing Strengths,Limitations,and Its Therapeutic Landscape Position

In the ever-evolving landscape of Alzheimer’s treatment,lecanemab(Leqembi)has emerged as a promising drug.Unlike conventional therapies that merely alleviate symptoms,lecanemab is a humanized monoclonal antibody with a distinct focus.It targets protofibrils,insoluble fibrils,amyloid oligomers,and soluble amyloid-beta protofibrils,which are known to be especially damaging to neurons,with high accuracy.

In vivo direct neuronal conversion as a therapeutic strategy for ischemic stroke

Stroke causes neuronal loss,which ultimately results in persistent neurological dysfunction.Globally,stroke was the third-leading cause of death and disability combined in all ages in 2019,after neonatal disorders and ischemic heart disease.In that year,there were 12.2 million incident strokes,101 million prevalent strokes,and 143 million disability-adjusted life-years due to stroke.

Prognostic significance of SOX2 for chemotherapeutic patients with oral squamous cell carcinoma

Oral squamous cell carcinoma(OSCC)is the most common oral cancers worldwide,accounting for over 90%of all oral malignancies[1].Despite encouraging improvements in therapeutic approaches,including surgical resection,chemotherapy,and radiotherapy,the five-year overall survival rate of OSCC has not been improved significantly over the past decades,mainly due to the high ratio of tumor recurrence and metastasis.

MicroRNA-451a is a candidate biomarker and therapeutic target for major depressive disorder

Background Increasing evidence supports the role of microRNAs(miRNAs)in major depressive disorder(MDD),but the pathophysiological mechanism remains elusive.Aims To explore the mechanism of microRNA-451a(miR-451a)in the pathology and behaviours of depression.Methods Abnormal miRNAs such as miR-451a reported previously in the serum of patients with MDD were screened and then confirmed in a mouse model of depression induced by chronic restraint stress(CRS).Eight-week-old male C57BL/6 mice had miR-451a overexpression in the medial prefrontal cortex(mPFC)via adeno-associated virus serotype 9 vectors encoding a pri-mmu-miR-451a-GFP fusion protein followed by behavioural and pathological analyses.Finally,molecular biological experiments were conducted to investigate the potential mechanism of miR-451a against depression.Results The serum levels of miRNA-451awere significantly lower in patients with MDD,with a negative correlation with the Hamilton Depression Scale scores.Additionally,a negative association between serum miR-451a and behavioural despair or anhedonia was observed in CRS mice.Notably,miR-451a expression was significantly downregulated in the mPFC of CRS-susceptible mice.Overexpressing miR-451a in the mPFC reversed the loss of dendritic spines and the depression-like phenotype of CRS mice.Mechanistically,miR-451a could inhibit CRS-induced corticotropin-releasing factor receptor 1 expression via targeting transcription factor 2,subsequently protecting dendritic spine plasticity.Conclusions Together,these results highlighted miR-451a as a candidate biomarker and therapeutic target for MDD.

SETD2 in cancer:functions,molecular mechanisms,and therapeutic regimens

In recent years,the histone methyltransferase SET domain containing 2(SETD2)has garnered significant attention for its involvement in carcinogenesis.Herein we aim to summarize the research advances regarding SETD2 in tumors,elucidate the role in global epigenetic regulation,highlight potential therapeutic regimens for patients with SETD2 deficiency,and outline future research directions.

Biological,pathological,and multifaceted therapeutic functions of exosomes to target cancer

Exosomes,small tiny vesicle contains a large number of intracellular particles that employ to cause various diseases and prevent several pathological events as well in the human body.It is considered a“double-edged sword”,and depending on its biological source,the action of exosomes varies under physiological conditions.Also,the isolation and characterization of the exosomes should be performed accurately and the methodology also will vary depending on the exosome source.Moreover,the uptake of exosomes from the recipients’cells is a vital and initial step for all the physiological actions.There are different mechanisms present in the exosomes’cellular uptake to deliver their cargo to acceptor cells.Once the exosomal uptake takes place,it releases the intracellular particles that leads to activate the physiological response.Even though exosomes have lavish functions,there are some challenges associated with every step of their preparation to bring potential therapeutic efficacy.So,overcoming the pitfalls would give a desired quantity of exosomes with high purity.