Fecal microbiome extract downregulates the expression of key proteins at the interface between airway remodelling and lung cancer pathogenesis in vitro.

Lung cancer (LC) is the leading cause of cancer-related mortality, and it is caused by many factors including cigarette smoking. Despite numerous treatment strategies for LC, its five-year survival is still poor (<20 %), attributable to treatment resistance and lack of early diagnosis and intervention. Importantly, LC incidence is higher in patients affected by chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disorder (COPD), and LC shares with other CRDs common pathophysiological features including chronic inflammation, oxidative stress, cellular senescence, and airway remodelling. Remodelling is a complex process resulting from the aberrant activation of tissue repair secondary to chronic inflammation, oxidative stress, and tissue damage observed in the airways of CRD patients, and it is characterized by irreversible airway structural and functional alterations, concomitantly with tissue fibrosis, epithelial-to-mesenchymal transition (EMT), excessive collagen deposition, and thickening of the basement membrane. Many processes involved in remodelling, particularly EMT, are also fundamental for LC pathogenesis, highlighting a potential connection between CRDs and LC. This provides rationale for the development of novel treatment strategies aimed at targeting components of the remodelling pathways. In this study, we tested the in vitro therapeutic activity of rat fecal microbiome extract (FME) on A549 human lung adenocarcinoma cells. We show that treatment with FME significantly downregulates the expression of six proteins whose function is at the forefront between airway remodelling and LC development: Snail, SPARC, MUC-1, Osteopontin, MMP-2, and HIF-1α. The results of this study, if confirmed by further investigations, provide proof-of-concept for a novel approach in the treatment of LC, focused on tackling the airway remodelling mechanisms underlying the increased susceptibility to develop LC observed in CRD patients.

The link between Alzheimer's disease and stroke: A detrimental synergism.

Being age-related disorders, both Alzheimer's disease (AD) and stroke share multiple risk factors, such as hypertension, smoking, diabetes, and apolipoprotein E (APOE) Ɛ4 genotype, and coexist in patients. Accumulation of amyloid-ß plaques and neurofibrillary tangled impair cognitive potential, leading to AD. Blocked blood flow in the neuronal tissues, causes neurodegeneration and cell death in stroke. AD is commonly characterized by cerebral amyloid angiopathy, which significantly elevates the risk of hemorrhagic stroke. Patients with AD and stroke have been both reported to exhibit greater cognitive impairment, followed by multiple pathophysiological mechanisms shared between the two. The manuscript aims to elucidate the relationship between AD and stroke, as well as the common pathways and risk factors while understanding the preventive therapies that might limit the negative impacts of this correlation, with diagnostic modalities and current AD treatments. The authors provide a comprehensive review of the link and aid the healthcare professionals to identify suitable targets and risk factors, that may retard cognitive decline and neurodegeneration in patients. However, more intricate research is required in this regard and an interdisciplinary approach that would target both the vascular and neurodegenerative factors would improve the quality of life in AD patients.

Role of MMP-9 and NF-κB in Diabetic Retinopathy: Progression and Potential Role of Bioflavonoids in the Mitigation of Diabetic Retinopathy.

"Diabetes mellitus" is a chronic metabolic disorder manifested by elevated blood glucose levels, primarily due to insufficient insulin production or resistance to insulin. Long-term diabetes results in persistent complications like retinopathy, cardiomyopathy, nephropathy, and neuropathy, causing significant health risks. The most alarming microvascular consequence allied with diabetes is "diabetic retinopathy," distinguished by the proliferation of anomalous blood vessels in the eye, mainly in the retina, resulting in visual impairment, diabetic macular edema, and retinal detachment if left untreated. According to estimates, 27.0% of people with diabetes worldwide have retinopathy, which leads to 0.4 million blindness cases. It is believed that mitochondrial damage and the production of inflammatory mediators are the early indicators of diabetic retinopathy before any histological changes occur in the retina. Moreover, it is evident that augmented oxidative stress in the retina further initiates the NF-κB/MMP-9 downstream signaling pathway. Interestingly, these downstream regulators, Nuclear Factor Kappa B [NF- kB] and matrix metalloproteinases 9 [MMP-9], have been recognized as important regulators of the inception and advancement of diabetic retinopathy. This diabetes and oxidative stress-induced MMP-9 are believed to regulate various cellular functions, including angiogenesis and apoptosis, causing blood-retinal barrier breakdown and tight junction protein degradation that further leads to diabetic retinopathy. Thus, there is an emergency need for the treatment of diabetic retinopathy. Emerging treatment options include anti-VEGF, laser treatment, and eye surgery, but these have certain limitations. This comprehensive review explores the mechanisms of MMP-9 and NF-kB involvement in diabetic retinopathy and bioflavonoids' therapeutic potential and mechanisms of action in inhibiting MMP-9 activity and suppressing NF-kB-mediated inflammation. Clinical evidence supporting the use of bioflavonoids in mitigating diabetic complications and future perspectives are also examined.

Impact of Bioactive Compounds in the Management of Various Inflammatory Diseases.

Inflammation is an individual's physiological response to a sequence of physical, chemical, or infectious stressors acting mainly to provide localized protection. Although inflammation is a protective and thus beneficial process, its excess or prolonged action can be harmful to the body. An increasing number of the population worldwide are changing their lifestyles, which leads to a rise in inflammatory diseases, such as atherosclerosis, angina pectoris, myocardial infarction, ulcerative colitis, cancer, and many more. Their treatment is based majorly on the pharmacological approach. However, natural products or bioactive compounds are of great significance in inflammation therapy because they show minimum side effects and maximum bioavailability. Therefore, it is critical to investigate bioactive substances that can modify target functions associated with oxidative stress defense and might be used to achieve various health benefits. This review accentuates the essence of bioactive chemicals used in the treatment of inflammation and other inflammatory illnesses. These bioactive compounds can be of any origin, such as plants, animals, bacteria, fungi, marine invertebrates, etc. Bioactive compounds derived from plant sources, such as glycyrrhizin, lignans, lycopene, resveratrol, indoles, and phenolic and polyphenolic compounds, work mainly by reducing oxidative stress and thereby preventing various inflammatory disorders. A large diversity of these anti-inflammatory bioactive compounds has also been discovered in marine environments, giving rise to an increase in the interest of various scientists in marine invertebrates and microbes. The vast diversity of microbes found in the marine environment represents an enormous supply to extract novel compounds, such as from bacteria, cyanobacteria, fungi, algae, microalgae, tiny invertebrates, etc. In the present review, an attempt has been made to summarize such novel bioactive compounds that help prevent inflammatory responses via different mechanisms of action.

Revolutionizing pediatric neuroblastoma treatment: unraveling new molecular targets for precision interventions.

Neuroblastoma (NB) is the most frequent solid tumor in pediatric cases, contributing to around 15% of childhood cancer-related deaths. The wide-ranging genetic, morphological, and clinical diversity within NB complicates the success of current treatment methods. Acquiring an in-depth understanding of genetic alterations implicated in the development of NB is essential for creating safer and more efficient therapies for this severe condition. Several molecular signatures are being studied as potential targets for developing new treatments for NB patients. In this article, we have examined the molecular factors and genetic irregularities, including those within insulin gene enhancer binding protein 1 (ISL1), dihydropyrimidinase-like 3 (DPYSL3), receptor tyrosine kinase-like orphan receptor 1 (ROR1) and murine double minute 2-tumor protein 53 (MDM2-P53) that play an essential role in the development of NB. A thorough summary of the molecular targeted treatments currently being studied in pre-clinical and clinical trials has been described. Recent studies of immunotherapeutic agents used in NB are also studied in this article. Moreover, we explore potential future directions to discover new targets and treatments to enhance existing therapies and ultimately improve treatment outcomes and survival rates for NB patients.

Revolutionizing lung health: Exploring the latest breakthroughs and future prospects of synbiotic nanostructures in lung diseases.

The escalating prevalence of lung diseases underscores the need for innovative therapies. Dysbiosis in human body microbiome has emerged as a significant factor in these diseases, indicating a potential role for synbiotics in restoring microbial equilibrium. However, effective delivery of synbiotics to the target site remains challenging. Here, we aim to explore suitable nanoparticles for encapsulating synbiotics tailored for applications in lung diseases. Nanoencapsulation has emerged as a prominent strategy to address the delivery challenges of synbiotics in this context. Through a comprehensive review, we assess the potential of nanoparticles in facilitating synbiotic delivery and their structural adaptability for this purpose. Our review reveals that nanoparticles such as nanocellulose, starch, and chitosan exhibit high potential for synbiotic encapsulation. These offer flexibility in structure design and synthesis, making them promising candidates for addressing delivery challenges in lung diseases. Furthermore, our analysis highlights that synbiotics, when compared to probiotics alone, demonstrate superior anti-inflammatory, antioxidant, antibacterial and anticancer activities. This review underscores the promising role of nanoparticle-encapsulated synbiotics as a targeted and effective therapeutic approach for lung diseases, contributing valuable insights into the potential of nanomedicine in revolutionizing treatment strategies for respiratory conditions, ultimately paving the way for future advancements in this field.

Computational insights into KRAS G12C inhibition: exploring possible repurposing of Azacitidine and Ribavirin.

Kirsten rat sarcoma (KRAS) stands out as the most prevalent mutated oncogene, playing a crucial role in the initiation and progression of various cancer types, including colorectal, lung and pancreatic cancer. The oncogenic modifications of KRAS are intricately linked to tumor development and are identified in 22% of cancer patients. This has spurred the necessity to explore inhibition mechanisms, with the aim of investigating and repurposing existing drugs for diagnosing cancers dependent on KRAS G12C In this investigation, 26 nucleoside-based drugs were collected from literature to assess their effectiveness against KRAS G12C. The study incorporates in-silico molecular simulations and molecular docking examinations of these nucleoside-derived drugs with the KRAS G12C protein using Protein Data Bank (PDB) ID: 5V71. The docking outcomes indicated that two drugs, Azacitidine and Ribavirin, exhibited substantial binding affinities of -8.7 and -8.3 kcal/mol, respectively. These drugs demonstrated stability in binding to the active site of the protein during simulation studies. Root mean square deviation (RMSD) analyses indicated that the complexes closely adhered to an equilibrium RMSD value ranging from 0.17 to 0.2 nm. Additionally, % occupancies, bond angles and the length of hydrogen bonds were calculated. These findings suggest that Azacitidine and Ribavirin may potentially serve as candidates for repurposing in individuals with KRAS-dependent cancers.Communicated by Ramaswamy H. Sarma.

Boswellic Acids: A Critical Appraisal of Their Therapeutic and Nutritional Benefits in Chronic Inflammatory Diseases.

BACKGROUND: In the last few decades, it has been largely perceived that the factors affecting the immune system and its varying pathways lead to the pathological progression of inflammation and inflammatory conditions. Chronic inflammation also contributes to common diseases, such as diabetes mellitus, ischemic heart disease, cancer, chronic renal inflammatory disease, non-alcoholic fatty hepat-ic disease, autoimmune diseases and neurodegenerative diseases. OBJECTIVE: Interestingly, plant sources and secondary metabolites from plants have been increasingly employed in managing acute and chronic inflammatory diseases for centuries. Boswellic acids are pentacyclic triterpenoidal moieties obtained from the oleo gum resin of different Boswellia species. METHODS: Detailed data was collected revealing the anti-inflammatory potential of Boswellic acids through various databases. RESULT: These are pharmacologically active agents that possess promising anti-inflammatory, anti-arthritic, antirheumatic, anti-diarrheal, anti-hyperlipidemic, anti-asthmatic, anti-cancer, and anti-microbial effects. CONCLUSION: Boswellic acids have been in use since ancient times primarily to treat acute and chronic inflammatory diseases. This review discusses the various mechanisms underlying the inflammatory process and the necessity of such natural products as a medication to treat inflammatory diseases. In addition, a discussion has also been extended to understand the primary targets involved in inflammation. The review further explores the therapeutic potential of boswellic acids in.

Understanding the Therapeutic Approaches for Neuroprotection.

The term "neurodegenerative disorders" refers to a group of illnesses in which deterioration of nerve structure and function is a prominent feature. Cognitive capacities such as memory and decision-making deteriorate as a result of neuronal damage. The primary difficulty that remains is safeguarding neurons since they do not proliferate or regenerate spontaneously and are therefore not substituted by the body after they have been damaged. Millions of individuals throughout the world suffer from neurodegenerative diseases. Various pathways lead to neurodegeneration, including endoplasmic reticulum stress, calcium ion overload, mitochondrial dysfunction, reactive oxygen species generation, and apoptosis. Although different treatments and therapies are available for neuroprotection after a brain injury or damage, the obstacles are inextricably connected. Several studies have revealed the pathogenic effects of hypothermia, different breathed gases, stem cell treatments, mitochondrial transplantation, multi-pharmacological therapy, and other therapies that have improved neurological recovery and survival outcomes after brain damage. The present review highlights the use of therapeutic approaches that can be targeted to develop and understand significant therapies for treating neurodegenerative diseases.

Understanding the promising role of antibody drug conjugates in breast and ovarian cancer.

A nascent category of anticancer therapeutic drugs called antibody-drug conjugates (ADCs) relate selectivity of aimed therapy using chemotherapeutic medicines with high cytotoxic power. Progressive linker technology led to the advancement of more efficacious and safer treatments. It offers neoteric as well as encouraging therapeutic strategies for treating cancer. ADCs selectively administer a medication by targeting antigens which are abundantly articulated on the membrane surface of tumor cells. Tumor-specific antigens are differently expressed in breast and ovarian cancers and can be utilized to direct ADCs. Compared to conventional chemotherapeutic drugs, this approach enables optimal tumor targeting while minimizing systemic damage. A cleavable linker improves the ADCs because it allows the toxic payload to be distributed to nearby cells that do not express the target protein, operating on assorted tumors with dissimilar cell aggregation. Presently fifteen ADCs are being studied in breast and ovarian carcinoma preclinically, and assortment of few have already undergone promising early-phase clinical trial testing. Furthermore, Phase I and II studies are investigating a wide variety of ADCs, and preliminary findings are encouraging. An expanding sum of ADCs will probably become feasible therapeutic choices as solo agents or in conjunction with chemotherapeutic agents. This review accentuates the most recent preclinical findings, pharmacodynamics, and upcoming applications of ADCs in breast and ovarian carcinoma.

BIN1 in the Pursuit of Ousting the Alzheimer's Reign: Impact on Amyloid and Tau Neuropathology.

Alzheimer's disease contributes to 60-70% of all dementia cases in the general population. Belonging to the BIN1/amphiphysin/RVS167 (BAR) superfamily, the bridging integrator (BIN1) has been identified to impact two major pathological hallmarks in Alzheimer's disease (AD), i.e., amyloid beta (Aß) and tau accumulation. Aß accumulation is found to increase by BIN1 knockdown in cortical neurons in late-onset AD, due to BACE1 accumulation at enlarged early endosomes. Two BIN1 mutants, KR and PL, were identified to exhibit Aß accumulation. Furthermore, BIN1 deficiency by BIN1-related polymorphisms impairs the interaction with tau, thus elevating tau phosphorylation, altering synapse structure and tau function. Even though the precise role of BIN1 in the neuronal tissue needs further investigation, the authors aim to throw light on the potential of BIN1 and unfold its implications on tau and Aß pathology, to aid AD researchers across the globe to examine BIN1, as an appropriate target gene for disease management.

Interplay of Gut Microbiota in Polycystic Ovarian Syndrome: Role of Gut Microbiota, Mechanistic Pathways and Potential Treatment Strategies.

Polycystic Ovarian Syndrome (PCOS) comprises a set of symptoms that pose significant risk factors for various diseases, including type 2 diabetes, cardiovascular disease, and cancer. Effective and safe methods to treat all the pathological symptoms of PCOS are not available. The gut microbiota has been shown to play an essential role in PCOS incidence and progression. Many dietary plants, prebiotics, and probiotics have been reported to ameliorate PCOS. Gut microbiota shows its effects in PCOS via a number of mechanistic pathways including maintenance of homeostasis, regulation of lipid and blood glucose levels. The effect of gut microbiota on PCOS has been widely reported in animal models but there are only a few reports of human studies. Increasing the diversity of gut microbiota, and up-regulating PCOS ameliorating gut microbiota are some of the ways through which prebiotics, probiotics, and polyphenols work. We present a comprehensive review on polyphenols from natural origin, probiotics, and fecal microbiota therapy that may be used to treat PCOS by modifying the gut microbiota.

Spermidine as a promising anticancer agent: Recent advances and newer insights on its molecular mechanisms.

Spermidine is a naturally occurring polyamine compound found in semen. It is also found in several plant sources and boasts a remarkable biological profile, particularly with regards to its anticancer properties. Spermidine specifically interferes with the tumour cell cycle, resulting in the inhibition of tumor cell proliferation and suppression of tumor growth. Moreover, it also triggers autophagy by regulating key oncologic pathways. The increased intake of polyamines, such as spermidine, can suppress oncogenesis and slow the growth of tumors due to its role in anticancer immunosurveillance and regulation of polyamine metabolism. Spermidine/spermine N-1-acetyltransferase (SSAT) plays a critical role in polyamine homeostasis and serves as a diagnostic marker in human cancers. Chemically modified derivatives of spermidine hold great potential for prognostic, diagnostic, and therapeutic applications against various malignancies. This review discusses in detail the recent findings that support the anticancer mechanisms of spermidine and its molecular physiology.

Microbiota dysbiosis and myasthenia gravis: Do all roads lead to Rome?

Dysregulated immune system with a failure to recognize self from non-self-antigens is one of the common pathogeneses seen in autoimmune diseases. The complex interplay of genetic and environmental factors is important for the occurrence and development of the disease. Among the environmental factors, disturbed gut microbiota (gut dysbiosis) has recently attracted particular attention, especially with advancement in human microbiome research. Although the alterations in microbiota have been seen in various autoimmune diseases, including those of nervous system, there is paucity of information on neuromuscular system diseases. Myasthenia gravis (MG) is one such rare autoimmune disease of neuromuscular junction, and is caused by generation of pathogenic autoantibodies to components of the postsynaptic muscle endplate. In the recent years, accumulating evidences have endorsed the key role of host microbiota, particularly those of gut, in the pathogenesis of MG. Differential microbiota composition, characterized by increased abundance of Fusobacteria, Bacteroidetes, and Proteobacteria, and decreased abundance of Actinobacteria and Firmicutes, has been seen in MG patients in comparison to healthy subjects. Disturbance of microbiota composition, particularly reduced ratio of Firmicutes/Bacteroidetes, alter the gut permeability, subsequently triggering the immunological response. Resultant reduction in levels of short chain fatty acids (SCFAs) is another factor contributing to the immunological response in MG patients. Modulation of gut microbiota via intervention of probiotics, prebiotics, synbiotics, postbiotics (metabiotics), and fecal microbiota transplantation (FMT) is considered to be the futuristic approach for the management of MG. This review summarizes the role of gut microbiota and their metabolites (postbiotics) in the progression of MG. Also, various bacteriotherapeutic approaches involving gut microbiota are discussed for the prevention of MG progression.

Polymeric micelles as potent islet amyloid inhibitors: Current advances and future perspectives.

Diabetes mellitus (DM) has become one of the most prevalent diseases across the globe, mainly because of the inability of existing treatment strategies to target its root cause (i.e., pancreatic ß cell damage). Polymeric micelles (PMs) have gained attention as a treatment option for DM by targeting misfolded islet amyloid polypeptide protein (IAPP), which is common in more than 90% of DM patients. Such misfolding could result from either oxidative stress or mutation in the gene encoding IAPP. In this review, we discuss progress in the designing of PMs to halt islet amyloidosis along with their mechanism and dynamics of interactions with IAPP. We also discuss the clinical challenges associated with the translation of PMs as anti-islet amyloidogenic agents.

Recent Developments in the Study of the Microenvironment of Cancer and Drug Delivery.

Cancer is characterized by disrupted molecular variables caused by cells that deviate from regular signal transduction. The uncontrolled segment of such cancerous cells annihilates most of the tissues that contact them. Gene therapy, immunotherapy, and nanotechnology advancements have resulted in novel strategies for anticancer drug delivery. Furthermore, diverse dispersion of nanoparticles in normal stroma cells adversely affects the healthy cells and disrupts the crosstalk of tumour stroma. It can contribute to cancer cell progression inhibition and, conversely, to acquired resistance, enabling cancer cell metastasis and proliferation. The tumour's microenvironment is critical in controlling the dispersion and physiological activities of nano-chemotherapeutics which is one of the targeted drug therapy. As it is one of the methods of treating cancer that involves the use of medications or other substances to specifically target and kill off certain subsets of malignant cells. A targeted therapy may be administered alone or in addition to more conventional methods of care like surgery, chemotherapy, or radiation treatment. The tumour microenvironment, stromatogenesis, barriers and advancement in the drug delivery system across tumour tissue are summarised in this review.

Quality by Design (QbD) Based Method for Estimation of Xanthohumol in Bulk and Solid Lipid Nanoparticles and Validation.

The analytical quality by design (AQbD) approach is utilized for developing and validating the simple, sensitive, cost-effective reverse-phase high performance liquid chromatographic method for the estimation of xanthohumol (XH) in bulk and nanoformulations. The Box-Behnken design (BBD) is applied for method optimization. The mobile phase ratio, pH and flow rate were selected as independent variables, whereas retention time, peak area, peak height, tailing factor, and theoretical plates were selected as dependent variables. The chromatogram of XH obtained under optimized conditions has given optimum conditions such as retention time (5.392 min), peak area (1,226,737 mAU), peak height (90,121 AU), tailing factor (0.991) and theoretical plates (4446.667), which are contoured in the predicted values shown by BBD. Validation of the method has been performed according to ICH Q2(R1) recommendations, using optimized conditions for linearity, limit of detection (LOD) and limit of quantification (LOQ), accuracy, precision, robustness and system suitability. All the values of validation parameters lie within the acceptable limits prescribed by ICH. Therefore, the developed and validated method of XH by the AQbD approach can be applied for the estimation of XH in bulk and various nanoformulations.

Chitosan modified 5-fluorouracil nanostructured lipid carriers for treatment of diabetic retinopathy in rats: A new dimension to an anticancer drug.

Diabetic retinopathy (DR) is one of the chronic complications of diabetes. It includes retinal blood vessels' damage. If untreated, it leads to loss of vision. The existing treatment strategies for DR are expensive, invasive, and need expertise during administration. Hence, there is a need to develop a non-invasive topical formulation that can penetrate deep to the posterior segment of retina and treat the damaged retinal vessels. In addition, it should also provide sustained release. In recent years, novel drug delivery systems (NDDS) have been explored for treating DR and found successful. In this study, chitosan (CS) modified 5-Fluorouracil Nanostructured Lipid Carriers (CS-5-FU-NLCs) were prepared by modified melt emulsification-ultrasonication method and optimized by Box-Behnken Design. The size, polydispersity index, zeta potential and entrapment efficiency of CS-5-FU-NLCs were 163.2 ± 2.3 nm, 0.28 ± 1.52, 21.4 ± 0.5 mV and 85.0 ± 0.2 %, respectively. The in vitro drug release and ex vivo permeation study confirmed higher and sustained drug release in CS-5-FU-NLCs as compared to 5-FU solution. HET-CAM Model ensured the non-irritant nature of CS-5-FU-NLCs. In vivo ocular studies of CS-5-FU-NLCs confirmed antiangiogenic effect of 5-FU by CAM model and diabetic retinopathy induced rat model, indicating successful delivery of 5-FU to the retina.