Modifying platelets at their birth: anti-thrombotic therapy without haemorrhage.

Cardiovascular disease is a leading cause of death. The current approach to the prevention of arterial thrombosis in cardiovascular disease is dependent on the use of therapies which inhibit the activation of platelets. Predictably these are associated with an increased risk of haemorrhage which causes significant morbidity. The thrombotic potential of an activated platelet is modifiable; being determined before thrombopoiesis. Increased megakaryocyte ploidy is associated with larger and more active platelets carrying an increased risk of thrombosis. The reduction in the ploidy of megakaryocytes is therefore a novel area of therapeutic interest for reducing thrombosis. We propose a new therapeutic approach for the prevention and treatment of thrombosis by targeting the reduction in ploidy of megakaryocytes. We examine the role of a receptor mediated event causing megakaryocytes to increase ploidy, the potential for targeting the molecular mechanisms underpinning megakaryocyte endomitosis and the existence of two separate regulatory pathways to maintain haemostasis by altering the thrombotic potential of platelets as targets for novel therapeutic approaches producing haemostatically competent platelets which are not prothrombotic.

Association between gut microbiota and pan-dermatological diseases: a bidirectional Mendelian randomization research.

Background: Gut microbiota has been associated with dermatological problems in earlier observational studies. However, it is unclear whether gut microbiota has a causal function in dermatological diseases. Methods: Thirteen dermatological diseases were the subject of bidirectional Mendelian randomization (MR) research aimed at identifying potential causal links between gut microbiota and these diseases. Summary statistics for the Genome-Wide Association Study (GWAS) of gut microbiota and dermatological diseases were obtained from public datasets. With the goal of evaluating the causal estimates, five acknowledged MR approaches were utilized along with multiple testing corrections, with inverse variance weighted (IVW) regression serving as the main methodology. Regarding the taxa that were causally linked with dermatological diseases in the forward MR analysis, reverse MR was performed. A series of sensitivity analyses were conducted to test the robustness of the causal estimates. Results: The combined results of the five MR methods and sensitivity analysis showed 94 suggestive and five significant causal relationships. In particular, the genus Eubacterium_fissicatena_group increased the risk of developing psoriasis vulgaris (odds ratio [OR] = 1.32, pFDR = 4.36 × 10-3), family Bacteroidaceae (OR = 2.25, pFDR = 4.39 × 10-3), genus Allisonella (OR = 1.42, pFDR = 1.29 × 10-2), and genus Bacteroides (OR = 2.25, pFDR = 1.29 × 10-2) increased the risk of developing acne; and the genus Intestinibacter increased the risk of urticaria (OR = 1.30, pFDR = 9.13 × 10-3). A reverse MR study revealed insufficient evidence for a significant causal relationship. In addition, there was no discernible horizontal pleiotropy or heterogeneity. Conclusion: This study provides novel insights into the causality of gut microbiota in dermatological diseases and therapeutic or preventive paradigms for cutaneous conditions.

From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies.

In the dynamic landscape of targeted therapeutics, drug discovery has pivoted towards understanding underlying disease mechanisms, placing a strong emphasis on molecular perturbations and target identification. This paradigm shift, crucial for drug discovery, is underpinned by big data, a transformative force in the current era. Omics data, characterized by its heterogeneity and enormity, has ushered biological and biomedical research into the big data domain. Acknowledging the significance of integrating diverse omics data strata, known as multi-omics studies, researchers delve into the intricate interrelationships among various omics layers. This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes. The sheer volume of data generated necessitates sophisticated informatics techniques, with machine-learning (ML) algorithms emerging as robust tools. These datasets not only refine disease classification but also enhance diagnostics and foster the development of targeted therapeutic strategies. Through the integration of high-throughput data, the review focuses on targeting and modeling multiple disease-regulated networks, validating interactions with multiple targets, and enhancing therapeutic potential using network pharmacology approaches. Ultimately, this exploration aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.

Noncoding RNA landscape and their emerging roles as biomarkers and therapeutic targets in meningioma.

Meningiomas are among the most prevalent primary CNS tumors in adults, accounting for nearly 38% of all brain neoplasms. The World Health Organization (WHO) grade assigned to meningiomas guides medical care in patients and is primarily based on tumor histology and malignancy potential. Although often considered benign, meningiomas with complicated histology, limited accessibility for surgical resection, and/or higher malignancy potential (WHO grade 2 and WHO grade 3) are harder to combat, resulting in significant morbidity. With limited treatment options and no systemic therapies, it is imperative to understand meningioma tumorigenesis at the molecular level and identify novel therapeutic targets. The last decade witnessed considerable progress in understanding the noncoding RNA landscape of meningioma, with microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) emerging as molecular entities of interest. This review aims to highlight the commonly dysregulated miRNAs and lncRNAs in meningioma and their correlation with meningioma progression, malignancy, recurrence, and radioresistance. The role of "key" miRNAs as biomarkers and their therapeutic potential has also been reviewed in detail. Furthermore, current and emerging therapeutic modalities for meningioma have been discussed, with emphasis on the need to identify and subsequently employ clinically relevant miRNAs and lncRNAs as novel therapeutic targets and biomarkers.

Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action.

Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals ( O 2 - $$ {{\mathrm{O}}_2}^{-} $$ ) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto-oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs-based therapeutic strategies could be made to thwart cancers.

Lactate transporter MCT1 in hepatic stellate cells promotes fibrotic collagen expression in nonalcoholic steatohepatitis.

Circulating lactate is a fuel source for liver metabolism but may exacerbate metabolic diseases such as nonalcoholic steatohepatitis (NASH). Indeed, haploinsufficiency of lactate transporter monocarboxylate transporter 1 (MCT1) in mice reportedly promotes resistance to hepatic steatosis and inflammation. Here, we used adeno-associated virus (AAV) vectors to deliver thyroxin binding globulin (TBG)-Cre or lecithin-retinol acyltransferase (Lrat)-Cre to MCT1fl/fl mice on a choline-deficient, high-fat NASH diet to deplete hepatocyte or stellate cell MCT1, respectively. Stellate cell MCT1KO (AAV-Lrat-Cre) attenuated liver type 1 collagen protein expression and caused a downward trend in trichrome staining. MCT1 depletion in cultured human LX2 stellate cells also diminished collagen 1 protein expression. Tetra-ethylenglycol-cholesterol (Chol)-conjugated siRNAs, which enter all hepatic cell types, and hepatocyte-selective tri-N-acetyl galactosamine (GN)-conjugated siRNAs were then used to evaluate MCT1 function in a genetically obese NASH mouse model. MCT1 silencing by Chol-siRNA decreased liver collagen 1 levels, while hepatocyte-selective MCT1 depletion by AAV-TBG-Cre or by GN-siRNA unexpectedly increased collagen 1 and total fibrosis without effect on triglyceride accumulation. These findings demonstrate that stellate cell lactate transporter MCT1 significantly contributes to liver fibrosis through increased collagen 1 protein expression in vitro and in vivo, while hepatocyte MCT1 appears not to be an attractive therapeutic target for NASH.

Lipid-Based Nanoparticles as Oral Drug Delivery Systems: Overcoming Poor Gastrointestinal Absorption and Enhancing Bioavailability of Peptide and Protein Therapeutics.

Delivery and formulation of oral peptide and protein therapeutics have always been a challenge for the pharmaceutical industry. The oral bioavailability of peptide and protein therapeutics mainly relies on their gastrointestinal solubility and permeability which are affected by their poor membrane penetration, high molecular weight and proteolytic (chemical and enzymatic) degradation resulting in limited delivery and therapeutic efficacy. The present review article highlights the challenges and limitations of oral delivery of peptide and protein therapeutics focusing on the application, potential and importance of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as lipid-based drug delivery systems (LBDDSs) and their advantages and drawbacks. LBDDSs, due to their lipid-based matrix can encapsulate both lipophilic and hydrophilic drugs, and by reducing the first-pass effect and avoiding proteolytic degradation offer improved drug stability, dissolution rate, absorption, bioavailability and controlled drug release. Furthermore, their small size, high surface area and surface modification increase their mucosal adhesion, tissue-targeted distribution, physiological function and half-life. Properties such as simple preparation, high-scale manufacturing, biodegradability, biocompatibility, prolonged half-life, lower toxicity, lower adverse effects, lipid-based structure, higher drug encapsulation rate and various drug release profile compared to other similar carrier systems makes LBDDSs a promising drug delivery system (DDS). Nevertheless, undesired physicochemical features of peptide and protein drug development and discovery such as plasma stability, membrane permeability and circulation half-life remain a serious challenge which should be addressed in future.

Potential Applications of Mitochondrial Therapy with a Focus on Parkinson's Disease and Mitochondrial Transplantation.

Purpose: Both aging and neurodegenerative illnesses are thought to be influenced by mitochondrial malfunction and free radical formation. Deformities of the energy metabolism, mitochondrial genome polymorphisms, nuclear DNA genetic abnormalities associated with mitochondria, modifications of mitochondrial fusion or fission, variations in shape and size, variations in transit, modified mobility of mitochondria, transcription defects, and the emergence of misfolded proteins associated with mitochondria are all linked to Parkinson's disease. Methods: This review is a condensed compilation of data from research that has been published between the years of 2014 and 2022, using search engines like Google Scholar, PubMed, and Scopus. Results: Mitochondrial transplantation is a one-of-a-kind treatment for mitochondrial diseases and deficits in mitochondrial biogenesis. The replacement of malfunctioning mitochondria with transplanted viable mitochondria using innovative methodologies has shown promising outcomes as a cure for Parkinson's, involving tissue sparing coupled with enhanced energy generation and lower oxidative damage. Numerous mitochondria-targeted therapies, including mitochondrial gene therapy, redox therapy, and others, have been investigated for their effectiveness and potency. Conclusion: The development of innovative therapeutics for mitochondria-directed treatments in Parkinson's disease may be aided by optimizing mitochondrial dynamics. Many neurological diseases have been studied in animal and cellular models, and it has been found that mitochondrial maintenance can slow the death of neuronal cells. It has been hypothesized that drug therapies for neurodegenerative diseases that focus on mitochondrial dysfunction will help to delay the onset of neuronal dysfunction.

The clinical manifestations and molecular pathogenesis of radiation fibrosis.

Advances in radiation techniques have enabled the precise delivery of higher doses of radiotherapy to tumours, while sparing surrounding healthy tissues. Consequently, the incidence of radiation toxicities has declined, and will likely continue to improve as radiotherapy further evolves. Nonetheless, ionizing radiation elicits tissue-specific toxicities that gradually develop into radiation-induced fibrosis, a common long-term side-effect of radiotherapy. Radiation fibrosis is characterized by an aberrant wound repair process, which promotes the deposition of extensive scar tissue, clinically manifesting as a loss of elasticity, tissue thickening, and organ-specific functional consequences. In addition to improving the existing technologies and guidelines directing the administration of radiotherapy, understanding the pathogenesis underlying radiation fibrosis is essential for the success of cancer treatments. This review integrates the principles for radiotherapy dosimetry to minimize off-target effects, the tissue-specific clinical manifestations, the key cellular and molecular drivers of radiation fibrosis, and emerging therapeutic opportunities for both prevention and treatment.

Anti-PD-1 chimeric antigen receptor T cells efficiently target SIV-infected CD4+ T cells in germinal centers.

Programmed cell death protein 1 (PD-1) is an immune checkpoint marker commonly expressed on memory T cells and enriched in latently HIV-infected CD4+ T cells. We engineered an anti-PD-1 chimeric antigen receptor (CAR) to assess the impact of PD-1 depletion on viral reservoirs and rebound dynamics in SIVmac239-infected rhesus macaques (RMs). Adoptive transfer of anti-PD-1 CAR T cells was done in 2 SIV-naive and 4 SIV-infected RMs on antiretroviral therapy (ART). In 3 of 6 RMs, anti-PD-1 CAR T cells expanded and persisted for up to 100 days concomitant with the depletion of PD-1+ memory T cells in blood and tissues, including lymph node CD4+ follicular helper T (TFH) cells. Loss of TFH cells was associated with depletion of detectable SIV RNA from the germinal center (GC). However, following CAR T infusion and ART interruption, there was a marked increase in SIV replication in extrafollicular portions of lymph nodes, a 2-log higher plasma viremia relative to controls, and accelerated disease progression associated with the depletion of CD8+ memory T cells. These data indicate anti-PD-1 CAR T cells depleted PD-1+ T cells, including GC TFH cells, and eradicated SIV from this immunological sanctuary.

Identification of miRNAs that target Fcγ receptor-mediated phagocytosis during macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19-related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor-mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B, the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A, the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic-based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.

Virtual Reality in Acute and Chronic Pain Medicine: An Updated Review.

PURPOSE OF REVIEW: This review critically analyzes the recent literature on virtual reality's (VR) use in acute and chronic pain management, offering insights into its efficacy, applications, and limitations. RECENT FINDINGS: Recent studies, including meta-analyses and randomized controlled trials, have demonstrated VR's effectiveness in reducing pain intensity in various acute pain scenarios, such as procedural/acute pain and in chronic pain conditions. The role of factors such as immersion and presence in enhancing VR's efficacy has been emphasized. Further benefits have been identified in the use of VR for assessment as well as symptom gathering through conversational avatars. However, studies are limited, and strong conclusions will require further investigation. VR is emerging as a promising non-pharmacological intervention in pain management for acute and chronic pain. However, its long-term efficacy, particularly in chronic pain management, remains an area requiring further research. Key findings highlight that VR programs vary in efficacy depending on the specificity of the origin of pain.

Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

Quantum Dots in Cancer Theranostics: A Thorough Review of Recent Advancements in Bioimaging, Tracking, and Therapy across Various Cancer Types.

Quantum dots (QDs) have attracted considerable interest due to their potential applications and economic viability in various industrial sectors, such as communications, displays, and solar cells. This fascination originates from the quantum size effect-induced remarkable optical properties exhibited by QDs. In recent years, significant progress has been made in producing QDs devoid of cadmium, known to be toxic to cells and living organisms. These QDs have generated considerable interest in bioimaging due to their potential for targeting molecules and cells. There is a developing need for diagnostics and therapy at the individual molecule and single-cell level in the medical field. As a result, the application of QDs in the medical industry is gaining momentum. This study provides an overview of the most recent developments in applying QDs for diagnostic and therapeutic purposes, also known as theranostics. It emphasizes specifically the use of QDs in cancer therapy.

The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape.

Epstein-Barr virus (EBV) is a pathogen known to cause a number of malignancies, often taking years for them to develop after primary infection. EBV-associated gastric cancer (EBVaGC) is one such malignancy, and is an immunologically, molecularly and pathologically distinct entity from EBV-negative gastric cancer (EBVnGC). In comparison with EBVnGCs, EBVaGCs overexpress a number of immune regulatory genes to help form an immunosuppressive tumor microenvironment (TME), have improved prognosis, and overall have an "immune-hot" phenotype. This review provides an overview of the histopathology, clinical features and clinical outcomes of EBVaGCs. We also summarize the differences between the TMEs of EBVaGCs and EBVnGCs, which includes significant differences in cell composition and immune infiltration. A list of available EBVaGC and EBVnGC gene expression datasets and computational tools are also provided within this review. Finally, an overview is provided of the various chemo- and immuno-therapeutics available in treating gastric cancers (GCs), with a focus on EBVaGCs.

Immune Homeostasis Maintenance Through Advanced Immune Therapeutics to Target Atherosclerosis.

Atherosclerosis remains the leading cause of coronary heart disease (CHD) with enormous health and societal tolls. Traditional drug development approaches have been focused on small molecule-based compounds that aim to lower plasma lipids and reduce systemic inflammation, two primary causes of atherosclerosis. However, despite the widely available lipid-lowering and anti-inflammatory small compounds and biologic agents, CHD prevalence still remains high. Based on recent advances revealing disrupted immune homeostasis during atherosclerosis pathogenesis, novel strategies aimed at rejuvenating immune homeostasis with engineered immune leukocytes are being developed. This chapter aims to assess basic and translational efforts on these emerging strategies for the effective development of atherosclerosis treatment, as well as key challenges in this important translational field.

Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.

Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.