Therapeutic Limitations Research Articles

Natural phytochemicals reverting M2 to M1 macrophages: A novel alternative Leishmaniasis therapy.

Leishmaniasis is a tropical parasitic disease caused by the protozoan Leishmania which remains a significant global health concern with diverse clinical manifestations. Transmitted through the bite of an infected sandfly, its progression depends on the interplay between the host immune response and the parasite. The disease outcome is linked to macrophage polarisation into M1 and M2 phenotypes. M1 macrophages are pro-inflammatory and promote parasite clearance, while M2 macrophages support tissue repair and parasite survival by facilitating promastigote entry and intracellular amastigote proliferation. The review focuses on discovering novel phytochemicals that exploit the immunomodulatory properties of macrophages, which can serve as an alternative antileishmanial treatments due to their diverse chemical structures and ability to modulate immune responses. It examines the immunomodulatory effects of phytochemicals that directly or indirectly promote antileishmanial activity by influencing macrophage polarisation and cytokine secretion. They can induce M1 macrophage polarisation to directly combat leishmaniasis or suppress M2 macrophages, thereby exerting indirect antileishmanial activity by influencing the release of M1- and M2-related cytokines. & Discussion: Phytochemicals demonstrate antileishmanial effects through ROS production, M1 activation, and cytokine modulation. They regulate M1/M2-related cytokines and macrophage activity, influencing immune responses. Although their effects may be non-specific, targeted delivery strategies could overcome current therapeutic limitations, positioning phytochemicals as promising candidates for leishmaniasis treatment to counter the limitations of current medications.

Targeting Brain Drug Delivery with Macromolecules Through Receptor-Mediated Transcytosis.

Brain diseases pose significant treatment challenges due to the restrictive nature of the blood-brain barrier (BBB). Recent advances in targeting macromolecules offer promising avenues for overcoming these obstacles through receptor-mediated transcytosis (RMT). We summarize the current progress in targeting brain drug delivery with macromolecules for brain diseases. This exploration details the transport mechanisms across the BBB, focusing on RMT and its use of natural ligands for drug delivery. Furthermore, the review examines macromolecular ligands such as antibodies, peptides, and aptamers that leverage RMT for effective BBB traversal. Advancements in macromolecules-based delivery systems for brain diseases are summarized, emphasizing their therapeutic potential and limitations. Finally, emerging RMT strategies, including viral vectors, exosomes, and boron neutron capture therapy, are discussed for their precision in brain-targeted treatments. This comprehensive overview underscores the potential of RMT-based approaches to revolutionize brain disease therapy.

Cystatin A promotes the antitumor activity of T helper type 1 cells and dendritic cells in murine models of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis due to diagnostic and therapeutic limitations. We previously identified cystatin A (CSTA) as a PDAC biomarker and have conducted the present study to investigate the antitumor effects of CSTA. PDAC murine models were established with genetically modified PAN02 tumor cell lines to evaluate the antitumor immune response. PDAC mouse survival was significantly longer with CSTA, and its antitumor effect was mediated mainly by CD4+ cells and partly by CD8+ cells. We also observed an increased infiltration of CD4+ and CD8+ cells in tumors of mice overexpressing CSTA. Phenotypically, we confirmed higher T helper type 1 (Th1) cell activity and increased frequency and activity of M1 macrophages and dendritic cells (DCs) in CSTA-overexpressing mice. Gene expression analysis highlighted pathways related to interferon gamma (IFN-γ) induction and Th1 lymphocyte activation that were induced by CSTA. Macrophages and DCs shifted toward proinflammatory antitumor phenotypes. Furthermore, activated splenocytes of PDAC model mice expressing CSTA had increased proapoptotic activity. CSTA also promoted the selective migration of CD4+ and CD11c+ immune cells in an in vitro migration assay. In conclusion, CSTA exerts antitumor effects by enhancing Th1-mediated antitumor effects through promotion of DC and M1 macrophage activity, thereby increasing immune cell chemotaxis. CSTA could be a novel therapeutic candidate for PDAC.

Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, the extension of these successes to solid tumors remains limited due to several intrinsic challenges, including antigen heterogeneity and immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview of recent advances in CAR T cell therapy aimed at overcoming these obstacles. We discuss the importance of antigen identification by emphasizing the identification of tumor-specific and tumor-associated antigens and the development of CAR T therapies targeting these antigens. Furthermore, we highlight key structural innovations, including cytokine-armored CARs, protease-regulated CARs, and CARs engineered with chemokine receptors, to enhance tumor infiltration and activity within the immunosuppressive microenvironment. Additionally, novel manufacturing approaches, such as the Sleeping Beauty transposon system, mRNA-based CAR transfection, and in vivo CAR T cell production, are discussed as scalable solution to improve the accessibility of CAR T cell therapies. Finally, we address critical therapeutic limitations, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and suboptimal persistence of CAR T cells. An examination of emerging strategies for countering these limitations reveals that CRISPR-Cas9-mediated genetic modifications and combination therapies utilizing checkpoint inhibitors can improve CAR T cell functionality and durability. By integrating insights from preclinical models, clinical trials, and innovative engineering approaches, this review addresses advances in CAR T cell therapies and their performance in solid tumors.

Cellulose Based Nano-Scaffolds for Targeted Cancer Therapies: Current Status and Future Perspective.

In the last few years, cellulose has garnered much interest for its application in drug delivery, especially in cancer therapy. It has special properties like biocompatibility, biodegradability, high porosity, and water permeability render it a good candidate for developing efficient carriers for anticancer agents. Cellulose based nanomaterials like cellulose nanofibers, bacterial cellulose, cellulose nanocrystals and microcrystalline cellulose as delivery vehicles for targeted drug delivery to cancer cells are reviewed. This review elaborates on the synthesis, functionalization, and application strategies of these nanocarriers, and shows how they facilitate to improve drug stability, bioavailability and targeted delivery to tumor sites. Their possibilities as a tool to overcome the limitations of conventional cancer therapeutics are also discussed. We also explore future directions for improving the efficacy of cellulose based carriers in cancer therapy.

The mechanism of action of indole-3-propionic acid on bone metabolism.

Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.

Repairing muscle with broccoli-derived sulforaphane: A preclinical evaluation for the treatment of mitochondrial myopathies.

Skeletal muscle health relies on the production of adenosine triphosphate (ATP) in the mitochondria. ATP production is accompanied by oxidative phosphorylation, which generates reactive oxygen species (ROS). When there is an imbalance in ROS levels, oxidative stress and subsequent mitochondrial dysfunction, mitochondrial myopathies including sarcopenia, chronic progressive external ophthalmoplegia, and proximal myopathy can result. Such incurable myopathies are characterised by aberrant metabolism, limited ATP production, and muscle atrophy. Broccoli-derived sulforaphane has emerged as a novel treatment for mitochondrial myopathies because of its antioxidant and anti-inflammatory properties. This review discusses preclinical models that reveal sulforaphane's potential therapeutic benefits and limitations in treating mitochondrial myopathies.

Recent advances in research on common targets of neurological and sex hormonal influences on asthma.

Asthma is currently one of the most common of respiratory diseases, severely affecting the lives of patients. With the in-depth study of the role of the nervous system and sex hormones on the development of asthma, it has been found that the nervous system and sex hormones are related to each other in the pathway of asthma. To investigate the effects of sex hormones and the nervous system on the development of asthma. In this review, we searched for a large number of relevant literature to elucidate the unique mechanisms of sex hormones and the nervous system on asthma development, and summarized several common targets in the pathways of sex hormones and the nervous system on asthma. We summarize several common important targets in the pathways of action of sex hormones and the nervous system in asthma, provide new directions and ideas for asthma treatment, and discuss current therapeutic limitations and future possibilities. Finally, the article predicts future applications of several important targets in asthma therapy.

Therapeutic Frontiers in Nanozyme-Based Cancer Treatment: Advances, Challenges, and Future Directions

Nanozymes, artificial nanomaterials mimicking enzyme activity, are at the forefront of innovative cancer therapies, particularly in chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT). Their capacity to selectively generate reactive oxygen species under tumor-specific conditions, including low pH and high H₂O₂ levels, facilitates targeted induction of cancer cell death while minimizing damage to healthy tissues. When integrated with PDT or PTT, nanozymes enhance oxidative stress and promote immunogenic cell death, further amplifying anti-tumor immune responses. Recent advances in single-atom nanozymes and intelligent nanozymes have shown promise in overcoming therapeutic limitations, such as tumor hypoxia and immune suppression while modulating the tumor microenvironment to boost treatment efficacy. Additionally, ongoing preclinical and clinical evaluations highlight the potential of nanozymes to synergistically enhance immunotherapy outcomes. Their advantages over traditional enzymes, such as stability, tunability, cost-effectiveness, and the ability to maintain catalytic activity in hostile environments, position nanozymes as transformative agents in cancer therapy. However, their clinical translation faces significant challenges, including biocompatibility concerns, delivery inefficiencies to tumor sites, and stringent regulatory hurdles, which require comprehensive research and innovative solutions to address. Despite these limitations, advancements in nanozyme design and functionalization continue to pave the way for more effective and safer applications in cancer therapy which will be discussed in detail in this review.Keywords: Cancer therapy, Nanomaterial, Nanozymes, ROS, chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT)

Long-term courses of anxiety disorders

At present there is no comprehensive overview of the long-term development of the clinical picture, disease-associated impairments and neurobiological correlates of anxiety disorders as well as what influence certain risk factors and treatment have on the prognosis. This article presents findings regarding disorder-specific symptoms and disorder-associated changes in the areas of functional level, quality of life, neurocognitive performance and structural brain anatomy over the lifespan. It also reports on how patient-related and environment-related aspects as well as guideline-oriented therapy influence the course of the disorder. Aliterature search was conducted in PubMed on the aspects of individual components. Meta-analyses, longitudinal and cohort studies were included. To illustrate changes over time, the findings were predominantly presented separately for children and adolescents as well as for early and late adulthood. Anxiety disorders primarily exhibit age-associated differences in the symptom profile but also in the areas of functional level and quality of life. Risk factors for an unfavorable course of the disorder were identified particularly for young and middle-aged people; however, the findings indicate that evidence-based psychotherapy or pharmacotherapy also has alasting effect even after termination. For long-term therapeutic success, age-dependent characteristics and limitations as well as prognostically relevant aspects in the diagnostics and treatment of anxiety disorders should be taken into consideration and treatment should be started as soon as possible.

Anti-inflammatory action and intraocular kinetics of bromfenac in anterior uveitis depending on the composition of topical formulation

Purpose: a comparative study of the main characteristics of the anti-inflammatory effect of the ophthalmic dosage form (ODF) of bromfenac — the drug Broxinac and analogues, their local bioavailability, biodistribution and intraocular pharmacokinetics during the inflammatory process in the anterior segment of the rabbit eye.Material and methods. The studies were performed on 40 sexually mature male rabbits of the “Soviet Chinchilla” breed with an experimental model of carrageenan anterior uveitis. The anti-inflammatory and local irritant effect on the cornea, bioavailability and intraocular pharmacokinetics in the anterior chamber humor of ODF - bromfenac drops with various auxiliary components when instilled into the conjunctival sac were determined.Results. Broxinac, containing 0.05 mg/ml benzalkonium chloride as an auxiliary substance, exhibits more pronounced anti-inflammatory properties than existing analogues containing benzalkonium chloride at a concentration of 0.01 mg/ml or not containing it at all. The drug does not cause a local irritant effect when administered every 12 hours for 10 days 1 drop into the conjunctival sac of the eye of an awake rabbit, only minor signs of irritation in the form of closing of the eyelids in some rabbits were noted. When using comparison drugs containing 0.01 mg of the aforementioned preservative, the severity of the local irritant reaction fluctuated in a fairly wide range: from moderate to pronounced. It was established that the dosing form of Broxinac creates high peak concentrations in the anterior chamber humor and vitreous body, which remain within the therapeutic limits for at least 12 hours regardless of the presence of uveitis, with a half-life from the anterior chamber humor, depending on the presence of pathology, from 79 to 89 minutes.Conclusion. The ability of auxiliary components to change the pharmacology of the dosing form is the basis for optimizing the local bioavailability and pharmacodynamics of bromfenac as the active substance of the drug Broxinac. An increase in the concentration of benzalkonium chloride to 0.05 mg / ml (which is 5 times higher than that of the selected analogues) facilitates the passage of bromfenac through the tissue barrier of the eye and prevents presystemic elimination.

Infection-induced trained immunity: a twist in paradigm of innate host defense and generation of immunological memory.

In contrast to adaptive immunity, which relies on memory T and B cells for long-term pathogen-specific responses, trained immunity involves the enhancement of innate immune responses through cellular reprogramming. Experimental evidence from animal models and human studies supports the concept of trained immunity and its potential therapeutic applications in the development of personalized medicine. However, there remains a huge gap in understanding the mechanisms, identifying specific microbial triggers responsible for the induction of trained immunity. This underscores the importance of investigating the potential role of trained immunity in redefining host defense and highlights future research directions. This minireview will provide a comprehensive summary of the new paradigm of trained immunity or innate memory pathways. It will shed light on infection-induced pathways through non-specific stimulation within macrophages and natural killer cells, which will be further elaborated in multiple disease perspectives caused by infectious agents such as bacteria, fungi, and viruses. The article further elaborates on the biochemical and cellular basis of trained immunity and its impact on disease status during recurrent exposures. The review concludes with a perspective segment discussing potential therapeutic benefits, limitations, and future challenges in this area of study. The review also sheds light upon potential risks involved in the induction of trained immunity.

Anti‑proliferative effects of Drynaria fortunei in a model for triple negative breast cancer.

Triple negative breast cancer (TNBC) is characterized by the absence of hormones and growth factor receptors. It is typically responsive to anthracycline/taxol-based conventional chemotherapy. However, major therapeutic limitations include systemic toxicity and acquired resistance to chemotherapeutics. To combat this, nutritional herbs from traditional Chinese medicine (TCM) with limited reported toxicity may represent treatment alternatives for TNBC. Such herbs can effectively target multiple signaling pathways in numerous breast cancer models. The efficacy of various nutritional herbs in a cellular model of TNBC is associated with the downregulation of retinoblastoma (RB) signaling through the cyclin D-CDK4/6-RB axis. Therefore, the present study was designed to examine the effects of Drynaria fortunei (DF) in the same cellular model of TNBC to identify potential mechanistic leads for its efficacy. DF is a nutritional herb that represents a common component of herbal formulations used in TCM. The estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative MDA-MB-231 human breast carcinoma-derived cell line was used as the cellular model for TNBC in the present study. Non-fractionated aqueous extract from the bark of DF represented the test agent. Quantitative end-point biomarkers for the efficacy of DF assessed in the present study included cell cycle progression, RB signaling and caspase 3/7 activity. Treatment with DF at cytostatic concentration induced S phase cell cycle arrest and inhibited RB signaling as evidenced by the downregulated expression of cyclin E, CDK2, E2F1 and RB phosphorylation. DF treatment increased pro-apoptotic caspase 3/7 activity which was inhibited by the pan-caspase inhibitor Z-VAD-FMK. DF treatment also exhibited increased expression of cleaved ADP-ribose) polymerase-1. These data identify potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present TNBC model. The present experiments validated a mechanism-driven experimental approach to identify efficacious nutritional herbs and/or their bioactive constituents as treatment alternatives for TNBC.

Multi-omics insights into the pathogenesis of diabetic cardiomyopathy: epigenetic and metabolic profiles.

Diabetic cardiomyopathy (DbCM), a complex metabolic disease, greatly threatens human health due to therapeutic limitations. Multi-omics approaches facilitate the elucidation of its intrinsic pathological changes. Metabolomics, RNA-seq, proteomics, and assay of transposase-accessible chromatin (ATAC-seq) were utilized to elucidate multidimensional molecular alterations in DbCM. In the heart and plasma of mice with DbCM, metabolomic analysis demonstrated significant differences in branched-chain amino acids (BCAAs) and lipids. Subsequent RNA-seq and proteomics showed that the key genes, including BCKDHB, PPM1K, Cpt1b, Fabp4, Acadm, Acadl, Acadvl, HADH, HADHA, HADHB, Eci1, Eci2, PDK4, and HMGCS2, were aberrantly regulated, contributing to the disorder of BCAAs and fatty acids. ATAC-seq analysis underscored the pivotal role of epigenetic regulation by revealing dynamic shifts in chromatin accessibility and a robust positive correlation with gene expression patterns in diabetic cardiomyopathy mice. Furthermore, motif analysis identified that KLF15 as a critical transcription factor in DbCM, regulating the core genes implicated with BCAAs metabolism. Our research delved into the metabolic alterations and epigenetic landscape and revealed that KLF15 may be a promising candidate for therapeutic intervention in DbCM.

Therapeutic efficacy of chitosan-based hybrid nanomaterials to treat microbial biofilms and their infections - A review.

Antimicrobial resistance, the biggest issue facing the global healthcare sector, quickly emerged and spread due to the frequent use of antibiotics in regular treatments. The investigation of polymer-based nanomaterials as possible antibiofilm treatment agents is prompted by the growing ineffectiveness of conventional therapeutic techniques against these resistant bacteria species. So far, several articles have been published on microbial biofilm eradication using various polymer-based nanomaterials due to their therapeutic efficacy and biocompatibility nature. Despite their potential, a comprehensive review of the chitosan-based hybrid nanomaterials to treat microbial biofilms and their infections is lacking. This review provides a comprehensive investigation of the current state of therapeutic efficacy, various nanoformulations, advantages, limitations, and regulations of chitosan-based hybrid nanomaterials for biofilm treatment. Special attention is given to the application of chitosan-based nanomaterials in wound care, urinary tract infections, and dental biofilms are discussed, highlighting their role in managing biofilm-associated complications. Researchers will be better able to comprehend and develop unique, marketable chitosan-based nanomaterials with increased activity to treat biofilm infections in near future with the aid of this review.

Alloimmune Causes of Recurrent Pregnancy Loss: Cellular Mechanisms and Overview of Therapeutic Approaches.

Recurrent pregnancy loss (RPL) is a complex early pregnancy complication affecting 1-2% of couples and is often linked to immune dysfunction. Aberrations in T and B cell subpopulations, as well as natural killer (NK) cell activity, are particularly influential, with studies showing that abnormal NK cell activation and imbalances in T and B cell subtypes contribute to immune-mediated miscarriage risk. Successful pregnancy requires a tightly regulated balance between pro-inflammatory and anti-inflammatory immune responses. In the early stages, inflammation supports processes such as trophoblast invasion and spiral artery remodeling, but this must be tempered to prevent immune rejection of the fetus. In this review, we explore the underlying immune mechanisms of RPL, focusing on how dysregulated T, B, and NK cell function disrupts maternal tolerance. Specifically, we discuss the essential role of uterine NK cells in the early stages of vascular remodeling in the decidua and regulate the depth of invasion by extravillous trophoblasts. Furthermore, we focus on the delicate Treg dynamics that enable the maintenance of optimal immune homeostasis, where the balance, and not only the quantity of Tregs, is crucial for fostering maternal-fetal tolerance. Other T cell subpopulations, such as Th1, Th2, and Th17 cells, also contribute to immune imbalance, with Th1 and Th17 cells promoting inflammation and potentially harming fetal tolerance, while Th2 cells support immune tolerance. Finally, we show how changes in B cell subpopulations and their functions have been associated with adverse pregnancy outcomes. We further discuss current therapeutic strategies aimed at correcting these immune imbalances, including intravenous immunoglobulin (IVIg), glucocorticoids, and TNF-α inhibitors, examining their efficacy, challenges, and potential side effects. By highlighting both the therapeutic benefits and limitations of these interventions, we aim to offer a balanced perspective on clinical applications for women facing immune-related causes of RPL.

Predictive risk models for COVID-19 patients using the multi-thresholding meta-algorithm

This study aims to develop a Machine Learning model to assess the risks faced by COVID-19 patients in a hospital setting, focusing specifically on predicting the complications leading to Intensive Care Unit (ICU) admission or mortality, which are minority classes compared to the majority class of discharged patients. We operate within a multiclass framework comprising three distinct classes, and address the challenge of dataset imbalance, a common source of model bias. To effectively manage this, we introduce the Multi-Thresholding meta-algorithm (MTh), an innovative output-level methodology that extends traditional thresholding from binary to multiclass classification. This methodology dynamically adjusts class probabilities using misclassification costs, making it highly effective in imbalanced datasets. Our approach is further enhanced by integrating the simplicity, transparency, and effectiveness of Bayesian networks to create a robust predictive model. Using patient admission data, the model accurately identifies key risk and protective factors for COVID-19 outcomes. Our findings indicate that certain patient characteristics, such as high Charlson Index and pre-existing conditions, significantly influence the risk of ICU admission and mortality. Moreover, we introduce an explanatory model that elucidates the interrelationships among these factors, demonstrating the influence of therapeutic limits on the overall risk assessment of COVID-19 patients. Overall, our research provides a significant contribution to the field of Machine Learning by offering a novel solution for multiclass classification in the context of imbalanced datasets. This model not only enhances predictive accuracy but also supports critical decision-making processes in healthcare, potentially improving patient outcomes and optimizing clinical resource allocation.

Abstract 4119428: Monosialoganglioside-containing nanoliposomes protect against acute and chronic ischemic stroke injury

Background: Stroke remains a leading cause of mortality and disability. The narrow temporal window and limited availability of, and eligibility for thrombolytic therapy or endovascular thrombectomy are major therapeutic limitations in treating stroke. Neuroprotective therapies that could be given early to replace or augment these existing therapies are needed to improve stroke outcomes. We showed that monosialoganglioside (GM1) containing nanoliposomes composed of phosphatidylcholine, cholesterol and GM1 (70/25/5% molar ratios, NLGM1) protect against hypoxic injury likely through Nrf2-dependent upregulation of antoxidant enzymes. Aims: To test if post-occlusion NLGM1 treatment could reduce 1) acute stroke injury following middle cerebral artery occlusion (MCAO) and 2) chronic injury following photothrombotic (PT) stroke injury. Methods: 20 week old C57BL/6 mice underwent MCAO for 60 minutes and then injected with saline or NLGM1 (1 or 2 mg IV) prior to reperfusion. Neurologic deficit score and brain infarct % area were measured the next day. Separately, mice underwent PT injury followed by injection of saline or NLGM1 (1 or 2 mg immediately and 2 hours post-injury) and cognitive/behavior tests done 1-90 days post injury. Results: Following MCAO, there was reduced neurologic impairment, infarct volume and brain edema with NLGM1 versus saline control (Fig. 1). Following PT injury, there was reduced neurologic, cognitive and motor impairment from Day 2-90 post-injury with NLGM1 versus saline control (Fig. 2). In both stroke models, there was no difference in efficacy between 1 and 2 mg NLGM1 doses. Conclusions: Treatment of mice with NLGM1 following MCAO or PT stroke injury resulted in improved structural (infarct size, edema) and functional (cognitive, behavior, motor) outcomes in the acute (MCAO) and chronic (PT) timeframes. NLGM1 is a potential novel therapeutic agent for stroke.

Enhanced reno-protective effects of CHIR99021 modified mesenchymal stem cells against rat acute kidney injury model

Introduction: Mesenchymal stem cells of human umbilical cord origin (hucMSCs) appear to be an attractive candidate for cell-based therapies. However, their efficacy requires improvement as poor survival and specific homing to the site of injury are the major barriers to their effective implementation in cell therapy. As Wnt signaling pathway is involved in the development and repair of organs, we adopted a preconditioning strategy of stem cells by using CHIR99021 compound (a Wnt pathway agonist) to potentiate hucMSCs beneficial effects and circumvent their therapeutic limitations. Methods: We treated hucMSCs with 5 µM of CHIR99021 and evaluated the expression levels of genes involved in different biological processes through qRT-PCR. Subsequently, we examined the effectiveness of preconditioned cells (CHIR99021-hucMSCs) in a cisplatin-induced rat acute kidney injury model. Amelioration in tissue injury was evaluated by histopathology, immunohistochemistry and renal functional assessment. Results: In treated groups, we observed preserved renal tissue architecture in terms of lesser epithelial cells necrosis (P ≤ 0.001) and cast formation ( ≤ 0.05). Accelerated proliferation of injured tubular cells (P ≤ 0.001) and low serum creatinine values (P ≤ 0.01) were observed in preconditioned hucMSCs group compared to untreated AKI rats. In addition, administration of preconditioned hucMSCs in kidney injury model offered better restoration of tubular cell membrane β-catenin molecules. Our findings showed that CHIR99021-modified hucMSCs may exhibit better capacity for cell migration and proliferation. Conclusion: The results showed that preconditioning of stem cells with Wnt pathway activators could provide advanced benefits for organ repair, which may contribute to design a more effective therapeutic approach for renal regeneration.

Fecal Microbiota Transplantation: A Systematic Review of Therapeutic Potential, Preparation Techniques, and Delivery Methods Across Medical Conditions

Fecal microbiota transplantation (FMT) is revolutionizing the treatment of gastrointestinal disorders by leveraging the gut microbiome in innovative ways. This systematic review evaluates the clinical effectiveness and safety of FMT across various medical conditions, offering insights into its therapeutic potential and limitations. A comprehensive search of PubMed, Web of Science, Scopus, Embase, and ClinicalTrials.gov from January 2000 to December 2023 identified 97 relevant studies on FMT's efficacy, safety, and microbiome changes after eliminating duplicates. FMT has demonstrated high success rates, particularly in treating recurrent and refractory Clostridium difficile infections (CDI), with up to 90% effectiveness, establishing it as a primary treatment for antibiotic-resistant cases. FMT’s applications are expanding to inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease, as well as metabolic disorders and neuropsychiatric conditions. Remission rates for IBD range from 37-45%, with outcomes influenced by donor characteristics, stool preparation, and disease subtype. with mild, self-limiting side effects such as transient diarrhea and abdominal cramping. However, rare serious adverse events underscore the need for rigorous donor screening and standardized preparation protocols to mitigate risks. FMT’s ability to restore healthy gut flora highlights its promise in both gastrointestinal and systemic disease management. However, further research is essential to establish optimized procedures, standardized guidelines, and long-term safety data to facilitate its integration into mainstream medical practice.