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Group B Streptococcus (GBS) remains the leading bacterial cause of invasive neonatal disease, resulting in substantial morbidity and mortality. New therapeutic approaches beyond antibacterial treatment to prevent neonatal disease outcomes are urgent. One significant limitation in studying GBS disease and progression is the lack of non-invasive technologies for longitudinal studies. Here, we develop and compare three bioluminescent GBS strains for in vivo pathogenic analysis. Bioluminescence is based on the luxABCDE operon on a replicative vector (luxGBS-CC17), and the red-shifted firefly luciferase on a replicative vector (fflucGBS-CC17) or integrated in the genome (glucGBS-CC17). We show that luxGBS-CC17 is suitable for in vitro analysis but does not produce a significant bioluminescent signal in infected pups. In contrast, the fflucGBS-CC17 results in a strong bioluminescent signal proportional to the organ colonisation level. However, the stability of the replicative vector depends on the route of infection, especially when pups acquire the bacteria from infected vaginal mucosa. Stable chromosomal integration of luciferase in glucGBS-CC17 leads to significant bioluminescence in both haematological and vertical infection models associated with high systemic colonisation. These strains will allow the preclinical evaluation of treatment efficacy against GBS invasive disease using whole-mouse bioluminescence imaging. [ABSTRACT FROM AUTHOR]

Despite significant advancements in ocular drug delivery, challenges persist in treating posterior segment diseases like macular edema (ME) and age-related macular degeneration (AMD). Suprachoroidal (SC) injections are a promising new method for targeted drug delivery to the posterior segment of the eye, providing direct access to the choroid and retina while minimizing systemic exposure and side effects. This review examines the anatomical and physiological foundations of the SC space; evaluates delivery devices such as microcatheters, hypodermic needles, and microneedles; and discusses pharmacokinetic principles. Additionally, advancements in gene delivery through SC injections are explored, emphasizing their potential to transform ocular disease management. This review also highlights clinical applications in treating macular edema, diabetic macular edema, age-related macular degeneration, choroidal melanoma, and glaucoma. Overall, SC injections are emerging as a promising novel route for administering ophthalmic treatments, with high bioavailability, reduced systemic exposure, and favorable safety profiles. Key therapeutic agents such as triamcinolone acetonide, dexamethasone, AAV-based gene therapy, and axitinib have shown promise. The field of suprachoroidal injection is progressing rapidly, and this review article, while attempting to encapsulate most of the published preclinical and clinical studies, mainly focuses on those that are published within 2023 and 2024. [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis is a neglected tropical disease caused by the extracellular protozoan parasite Trypanosoma brucei, and targeted for eradication by 2030. The COVID-19 pandemic contributed to the lengthening of the proposed time frame for eliminating human African trypanosomiasis as control programs were interrupted. Armed with extensive antigenic variation and the depletion of the B cell population during an infectious cycle, attempts to develop a vaccine have remained unachievable. With the absence of a vaccine, control of the disease has relied heavily on intensive screening measures and the use of drugs. The chemotherapeutics previously available for disease management were plagued by issues such as toxicity, resistance, and difficulty in administration. The approval of the latest and first oral drug, fexinidazole, is a major chemotherapeutic achievement for the treatment of human African trypanosomiasis in the past few decades. Timely and accurate diagnosis is essential for effective treatment, while poor compliance and resistance remain outstanding challenges. Drug discovery is on-going, and herein we review the recent advances in anti-trypanosomal drug discovery, including novel potential drug targets. The numerous challenges associated with disease eradication will also be addressed. [ABSTRACT FROM AUTHOR]

Skin conditions are a significant cause of fatal and nonfatal disease burdens globally, ranging from mild irritations to debilitating diseases. Oxidative stress, which is an imbalance between reactive oxygen species and the cells' ability to repair damage, is implicated in various skin diseases. Antioxidants have been studied for their potential benefits in dermatologic health, but the evidence is limited and conflicting. Herein, we conducted a systematic review of controlled trials, meta-analyses, and Cochrane review articles to evaluate the current evidence on the utility of antioxidant supplementation for adjunct prevention and treatment of skin disease and to provide a comprehensive assessment of their role in promoting dermatologic health. The Cochrane Library, PubMed, EMBASE, and Epistemonikos databases were queried. Eligibility criteria included (1) primary focus on nanoparticle utility for skin cancer; (2) includes measurable outcomes data with robust comparators; (3) includes a number of human subjects or cell-line types, where applicable; (4) English language; and (5) archived as full-text journal articles. A total of 55 articles met the eligibility criteria for the present review. Qualitative analysis revealed that topical and oral antioxidant supplementation has demonstrated preliminary efficacy in reducing sunburns, depigmentation, and photoaging. Dietary exogenous antioxidants (namely vitamins A, C, and E) have shown chemopreventive effects against skin cancer. Antioxidant supplementation has also shown efficacy in treating non-cancer dermatoses, including rosacea, psoriasis, atopic dermatitis, and acne vulgaris. While further studies are needed to validate these findings on a larger scale, antioxidant supplementation holds promise for improving skin health and preventing skin diseases. [ABSTRACT FROM AUTHOR]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients. [ABSTRACT FROM AUTHOR]

The role of mechanical signals in the proper functioning of organisms is increasingly recognised, and every cell senses physical forces and responds to them. These forces are generated both from outside the cell or via the sophisticated force-generation machinery of the cell, the cytoskeleton. All regions of the cell are connected via mechanical linkages, enabling the whole cell to function as a mechanical system. In this Review, we define some of the key concepts of how this machinery functions, highlighting the critical requirement for mechanosensory proteins, and conceptualise the coupling of mechanical linkages to mechanochemical switches that enables forces to be converted into biological signals. These mechanical couplings provide a mechanism for how mechanical crosstalk might coordinate the entire cell, its neighbours, extending into whole collections of cells, in tissues and in organs, and ultimately in the coordination and operation of entire organisms. Consequently, many diseases manifest through defects in this machinery, which we map onto schematics of the mechanical linkages within a cell. This mapping approach paves the way for the identification of additional linkages between mechanosignalling pathways and so might identify treatments for diseases, where mechanical connections are affected by mutations or where individual force-regulated components are defective. [ABSTRACT FROM AUTHOR]

Background: Intestinal inflammation is considered to be an important characteristic of ulcerative colitis (UC) and the current medical treatments for UC are usually proposed to suppress abnormal intestinal immune responses. Pulsatilla decoction (PD), a traditional Chinese medicine, is frequently used in UC treatments in Asian countries; however, the mechanism of the action of PD remains unclear. In the present study, the mechanism of the action of PD was elucidated in the dextran sulfate sodium (DSS)-induced colitis mouse model, a model to mimic UC. Methods: Murine colitis was evaluated by comparing the disease activity index score. The intestinal inflammation was examined by histology analyses. The leukocyte infiltration in the colonic tissues was examined by immunohistochemistry analyses. The cytokines level in colonic tissues was examined by Multi-Plex immunoassay. The epithelial proliferation was evaluated by histological analyses. Immunofluorescence double staining was used to examine the expression of MMP-7 in the immune cells. Results: In the DSS-induced colitis mouse model, administration of PD attenuated the intestinal inflammation, with a marked decrease in colonic infiltration of innate immune cells. Immunohistochemical analyses further showed that matrix metalloproteinase-7 (MMP-7) expressed by the infiltrating leukocytes, including neutrophils and macrophages was inhibited by PD treatment. PD increases the cytokine level of IL-6 in colonic tissues. Conclusion: PD suppresses intestinal inflammation, with a marked decrease in colonic infiltration of innate immune cells, through decreasing MMP-7 expression. [ABSTRACT FROM AUTHOR]

The need for new therapeutic approaches for triple-negative breast cancer is a clinically relevant problem that needs to be solved. Using a multi-targeting approach to enhance cancer cell uptake, we synthesized a new family of ruthenium(II) organometallic complexes envisaging simultaneous active and passive targeting, using biotin and polylactide (PLA), respectively. All compounds with the general formula, [Ru(η5-CpR)(P)(2,2′-bipy-4,4′-PLA-biotin)][CF3SO3], where R is -H or -CH3 and P is P(C6H5)3, P(C6H4F)3 or P(C6H4OCH3)3, were tested against triple-negative breast cancer cells MDA-MB-231 showing IC50 values between 2.3–14.6 µM, much better than cisplatin, a classical chemotherapeutic drug, in the same experimental conditions. We selected compound 1 (where R is H and P is P(C6H5)3), for further studies as it was the one showing the best biological effect. In a competitive assay with biotin, we showed that cell uptake via SMVT receptors seems to be the main transport route into the cells for this compound, validating the strategy of including biotin in the design of the compound. The effects of the compound on the hallmarks of cancer show that the compound leads to apoptosis, interferes with proliferation by affecting the formation of cell colonies in a dose-dependent manner and disrupts the cell cytoskeleton. Preliminary in vivo assays in N: NIH(S)II-nu/nu mice show that the concentrations of compound 1 used in this experiment (maximum 4 mg/kg) are safe to use in vivo, although some signs of liver toxicity are already found. In addition, the new compound shows a tendency to control tumor growth, although not significantly. In sum, we showed that compound 1 shows promising anti-cancer effects, bringing a new avenue for triple-negative breast cancer therapy. [ABSTRACT FROM AUTHOR]

The increasingly appreciated prevalence of complicated stressor‐to‐phenotype associations in human disease requires a greater understanding of how specific stressors affect systems or interactome properties. Many currently untreatable diseases arise due to variations in, and through a combination of, multiple stressors of genetic, epigenetic, and environmental nature. Unfortunately, how such stressors lead to a specific disease phenotype or inflict a vulnerability to some cells and tissues but not others remains largely unknown and unsatisfactorily addressed. Analysis of cell‐ and tissue‐specific interactome networks may shed light on organization of biological systems and subsequently to disease vulnerabilities. However, deriving human interactomes across different cell and disease contexts remains a challenge. To this end, this opinion article links stressor‐induced protein interactome network perturbations to the formation of pathologic scaffolds termed epichaperomes, revealing a viable and reproducible experimental solution to obtaining rigorous context‐dependent interactomes. This article presents our views on how a specialized 'omics platform called epichaperomics may complement and enhance the currently available conventional approaches and aid the scientific community in defining, understanding, and ultimately controlling interactome networks of complex diseases such as Alzheimer's disease. Ultimately, this approach may aid the transition from a limited single‐alteration perspective in disease to a comprehensive network‐based mindset, which we posit will result in precision medicine paradigms for disease diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Recently, immunotherapy has been served as the treatment of choice for various human pathophysiologies, including inflammatory diseases and cancer. Though most of the current approaches target the lymphoid compartment, macrophages intimately implicated in the induction or resolution of inflammation have rationally gained their place into the therapeutics arena. In this review, I discuss the past and novel ground‐breaking strategies focusing on macrophages in different human diseases and highlight the current challenges and considerations underlying their translational potentials. [ABSTRACT FROM AUTHOR]

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases. [ABSTRACT FROM AUTHOR]

Laminopathies are a group of rare disorders due to mutation in LMNA gene. Depending on the mutation, they may affect striated muscles, adipose tissues, nerves or are multisystemic with various accelerated ageing syndromes. Although the diverse pathomechanisms responsible for laminopathies are not fully understood, several therapeutic approaches have been evaluated in patient cells or animal models, ranging from gene therapies to cell and drug therapies. This review is focused on these therapies with a strong focus on striated muscle laminopathies and premature ageing syndromes. [ABSTRACT FROM AUTHOR]