Exploring the role of Müller cells-derived exosomes in diabetic retinopathy.

Exosomes are nanosized vesicles that have been reported as cargo-delivering vehicles between cells. Müller cells play a crucial role in the pathogenesis of diabetic retinopathy (DR). Activated Müller cells in the diabetic retina mediate disruption of barrier integrity and neovascularization. Endothelial cells constitute the inner blood-retinal barrier (BRB). Herein, we aim to evaluate the effect of Müller cell-derived exosomes on endothelial cell viability and barrier function under normal and hyperglycemic conditions. Müller cell-derived exosomes were isolated and characterized using Western blotting, nanoparticle tracking, and electron microscopy. The uptake of Müller cells-derived exosomes by the human retinal endothelial cells (HRECs) was monitored by labeling exosomes with PKH67. Endothelial cell vitality after treatment by exosomes under normo- and hypoglycemic conditions was checked by MTT assay and Western blot for apoptotic proteins. The barrier function of HRECs was evaluated by analysis of ZO-1 and transcellular electrical resistance (TER) using ECIS. Additionally, intracellular Ca+2 in HRECs was assessed by spectrofluorimetry. Analysis of the isolated exosomes showed a non-significant change in the number of exosomes isolated from both normal and hyperglycemic condition media, however, the average size of exosomes isolated from the hyperglycemic group showed a significant rise when compared to that of the normoglycemic group. Müller cells derived exosomes from hyperglycemic condition media markedly reduced HRECs cell count, increased caspase-3 and Annexin V, decreased ZO-1 levels and TER, and increased intracellular Ca+ when compared to other groups. However, treatment of HRECs under hyperglycemia with normo-glycemic Müller cells-derived exosomes significantly decreased cell death, preserved cellular integrity and barrier function, and reduced intracellular Ca+2. Collectively, Müller cell-derived exosomes play a remarkable role in the pathological changes associated with hyperglycemia-induced inner barrier dysfunction in DR. Further in vivo research will help in understanding the role of exosomes as therapeutic targets and/or delivery systems for DR.

Pramipexole protects against diabetic neuropathy: Effect on oxidative stress, TLR4/IRAK-1/TRAF-6/NF-κB and downstream inflammatory mediators.

BACKGROUND: Diabetic neuropathy (DN) is a serious microvascular complication and a major cause of morbidity and mortality in diabetes mellitus. It is characterized by neurodegeneration of terminal sensory nerve fibers with subsequent pain, loss of sensation, and paresthesia, thus compromising the quality of life of diabetic patients. It is considered the leading cause of non-traumatic amputations worldwide, reflecting the insufficiency of current therapies. Pramipexole (PPX) is a dopamine receptor agonist used for the treatment of Parkinson's disease. The current study aims to investigate the potential neuroprotective effect of PPX in an experimental model of DN. METHODS: Sprague Dawley rats were randomly assigned into five groups: normal control, Normal + PPX (1 mg/kg) group, STZ control, STZ + PPX (0.25 and 1 mg/kg/day for eight weeks). The neuroprotective effect of PPX in rats was evaluated in terms of sciatic nerve histological alterations, oxidative stress, and protein expression of TLR4/MyD88/IRAK-1/TRAF-6/NF-κB axis and downstream inflammatory mediators. RESULTS: PPX administration ameliorated histopathological signs of neuronal inflammation and apoptosis. Additionally, PPX attenuated STZ-induced sciatic nerve oxidative stress and downregulated neural tissue expression of TLR4, MyD88, IRAK-1, TRAF-6, NF-κB and downstream mediators (TNF-α, IL-1ß and ICAM-1). CONCLUSION: Collectively, the current study sheds light on PPX as a potential protective medication to alleviate neuropathy progression in diabetic patients. PPX neuroprotective effect can be attributed to modulating TLR4/ MyD88/IRAK-1/TRAF-6/ NF-κB axis signaling in nerve tissues with subsequent attenuation of oxidative stress and inflammation.

Preparation and Characterization of Novel Polyelectrolyte Liposomes Using Chitosan Succinate Layered over Chitosomes: A Potential Strategy for Colon Cancer Treatment.

Chitosan succinate is distinguished by its ability to shield the loaded drug from the acidic environment, localize and keep the drug at the colon site, and release the drug over an extended time at basic pH. The current study attempts to develop polyelectrolyte liposomes (PEL), using chitosan and chitosan succinate (CSSC), as a carrier for liposomal-assisted colon target delivery of 5 fluorouracil (5FU). The central composite design was used to obtain an optimized formulation of 5FU-chitosomes. The chitosan-coated liposomes (chitosomes) were prepared by thin lipid film hydration technique. After that, the optimized formulation was coated with CSSC, which has several carboxylic (COOH) groups that produce an anionic charge that interacts with the cation NH2 in chitosan. The prepared 5FU-chitosomes formulations were evaluated for entrapment efficiency % (EE%), particle size, and in vitro drug release. The optimized 5FU-chitosomes formulation was examined for particle size, zeta potential, in vitro release, and mucoadhesive properties in comparison with the equivalent 5FU-liposomes and 5FU-PEL. The prepared 5FU-chitosomes exhibited high EE%, small particle size, low polydispersity index, and prolonged drug release. PEL significantly limited the drug release at acidic pH due to the deprotonation of carboxylate ions in CSSC, which resulted in strong repulsive forces, significant swelling, and prolonged drug release. According to a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, PEL treatment significantly decreased the viability of HT-29 cells. When compared to 5FU-liposome and 5FU-chitosome, the in vivo pharmacokinetics characteristics of 5FU-PEL significantly (p < 0.05) improved. The findings show that PEL enhances 5FU permeability, which permits high drug concentrations to enter cells and inhibits the growth of colon cancer cells. Based on the current research, PEL may be used as a liposomal-assisted colon-specific delivery.

Nifuroxazide repurposing for protection from diabetes-induced retinal injury in rats: Implication of oxidative stress and JAK/STAT3 axis.

The prevalence of diabetes mellitus (DM) is alarmingly increasing worldwide. Diabetic retinopathy (DR) is a prevailing DM microvascular complication, representing the major cause of blindness in working-age population. Inflammation is a crucial player in DR pathogenesis. JAK/STAT3 axis is a pleotropic cascade that modulates diverse inflammatory events. Nifuroxazide (Nifu) is a commonly used oral antibiotic with reported JAK/STAT3 inhibition activity. The present study investigated the potential protective effect of Nifu against diabetes-induced retinal injury. Effect of Nifu on oxidative stress, JAK/STAT3 axis and downstream inflammatory mediators has been also studied. Diabetes was induced in Sprague Dawley rats by single intraperitoneal injection of streptozotocin (50 mg/kg). Animals were assigned into four groups: normal, Nifu control, DM, and DM + Nifu. Nifu was orally administrated at 25 mg/kg/day for 8 weeks. The effects of Nifu on oxidative stress, JAK/STAT3 axis proteins, inflammatory factors, tight junction proteins, histological, and ultrastructural alterations were evaluated using spectrophotometry, gene and protein analyses, and histological studies. Nifu administration to diabetic rats attenuated histopathological and signs of retinal injury. Additionally, Nifu attenuated retinal oxidative stress, inhibited JAK and STAT3 phosphorylation, augmented the expression of STAT3 signaling inhibitor SOCS3, dampened the expression of transcription factor of inflammation NF-κB, and inflammatory cytokine TNF-α. Collectively, the current study indicated that Nifu alleviated DR progression in diabetic rats, suggesting beneficial retino-protective effect. This can be attributed to blocking JAK/STAT3 axis in retinal tissues with subsequent amelioration of oxidative stress and inflammation.

The Possible Mechanisms of Cu and Zn in the Treatment and Prevention of HIV and COVID-19 Viral Infection.

Due to their unique properties and their potential therapeutic and prophylactic applications, heavy metals have attracted the interest of many researchers, especially during the outbreak of COVID-19. Indeed, zinc (Zn) and copper (Cu) have been widely used during viral infections. Zn has been reported to prevent excessive inflammatory response and cytokine storm, improve the response of the virus to Type I interferon (IFN-1), and enhance the production of IFN-a to counteract the antagonistic effect of SARS-CoV-2 virus protein on IFN. Additionally, Zn has been found to promote the proliferation and differentiation of T and B lymphocytes, thereby improving immune function, inhibiting RNA-dependent RNA polymerase (RdRp) in SARS- CoV-2 reducing the viral replication and stabilizing the cell membrane by preventing the proteolytic processing of viral polyprotein and proteases enzymes. Interestingly, Zn deficiency has been correlated with enhanced SARS-CoV-2 viral entry through interaction between the ACE2 receptor and viral spike protein. Along with zinc, Cu possesses strong virucidal capabilities and is known to be effective at neutralizing a variety of infectious viruses, including the poliovirus, influenza virus, HIV type 1, and other enveloped or nonenveloped, single- or double-stranded DNA and RNA viruses. Cu-related antiviral action has been linked to different pathways. First, it may result in permanent damage to the viral membrane, envelopes, and genetic material of viruses. Second, Cu produces reactive oxygen species to take advantage of the redox signaling mechanism to eradicate the virus. The present review focused on Zn and Cu in the treatment and prevention of viral infection. Moreover, the application of metals such as Cu and gold in nanotechnology for the development of antiviral therapies and vaccines has been also discussed.

Ginger Oil Nanoemulsion Formulation Augments Its Antiproliferative Effect in Ehrlich Solid Tumor Model.

Cancer is a disease that is characterized by uncontrolled cell proliferation. Breast cancer is the most prevalent cancer among women. Ginger oil is a natural cancer fighter and anti-oxidant. However, the minimal absorption of ginger oil from the gastrointestinal tract accounts for its limited medicinal efficacy. The present study was designed to evaluate the efficacy of a nanoemulsion preparation of ginger oil on its oral bioavailability and in vivo anti-cancer efficacy. Ginger oil nanoemulsion was prepared by a high-pressure homogenization technique using different surfactants (Tween 20, 40, and 80). The prepared formulations were evaluated for droplet size, polydispersity index (PDI), zeta potential (ZP), pH, viscosity, and stability by calculating the creaming index percentage. The best formulation was evaluated for shape by TEM. The antitumor activity of the best nano-formulation was determined in comparison with the free oil using the in vivo Ehrlich solid tumor (EST) model. The prepared ginger oil nanoemulsion formulations exhibited acceptable droplet size in the range from 56.67 ± 3.10 nm to 357.17 ± 3.62 nm. A PDI of less than 0.5 indicates the homogeneity of size distribution. The oil globules possessed a negative charge ranging from -12.33 ± 1.01 to -39.33 ± 0.96 mV. The pH and viscosity were in the acceptable range. The TEM image of the best formulation appeared to be spherical with a small size. The ginger oil nanoemulsion reduced in vivo tumor volume and weight, extended animals' life span, and ameliorated liver and kidney function in EST-bearing mice. These effects were superior to using free ginger oil. Collectively, the present study demonstrated that the ginger oil nanoemulsion improved oral absorption with a subsequent enhancement of its anti-proliferative efficacy in vivo, suggesting a nano-formulation of ginger oil for better therapeutic outcomes in breast cancer patients.

Punicalagin's Protective Effects on Parkinson's Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway.

Parkinson's disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl2), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl2), G4 (SI + MnCl2), G5 (SI + PUN), G6 (MnCl2 + PUN), and G7 (SI + PUN + MnCl2). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl2, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl2. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3ß/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl2. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN's mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3ß/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2.

Multilineage Differentiating Stress Enduring (Muse) Cells: A New Era of Stem Cell-Based Therapy.

Stem cell transplantation has recently demonstrated a significant therapeutic efficacy in various diseases. Multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant endogenous pluripotent stem cells that were first reported in 2010. Muse cells can be found in the peripheral blood, bone marrow and connective tissue of nearly all body organs. Under basal conditions, they constantly move from the bone marrow to peripheral blood to supply various body organs. However, this rate greatly changes even within the same individual based on physical status and the presence of injury or illness. Muse cells can differentiate into all three-germ-layers, producing tissue-compatible cells with few errors, minimal immune rejection and without forming teratomas. They can also endure hostile environments, supporting their survival in damaged/injured tissues. Additionally, Muse cells express receptors for sphingosine-1-phosphate (S1P), which is a protein produced by damaged/injured tissues. Through the S1P-S1PR2 axis, circulating Muse cells can preferentially migrate to damaged sites following transplantation. In addition, Muse cells possess a unique immune privilege system, facilitating their use without the need for long-term immunosuppressant treatment or human leucocyte antigen matching. Moreover, they exhibit anti-inflammatory, anti-apoptotic and tissue-protective effects. These characteristics circumvent all challenges experienced with mesenchymal stem cells and induced pluripotent stem cells and encourage the wide application of Muse cells in clinical practice. Indeed, Muse cells have the potential to break through the limitations of current cell-based therapies, and many clinical trials have been conducted, applying intravenously administered Muse cells in stroke, myocardial infarction, neurological disorders and acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection. Herein, we aim to highlight the unique biological properties of Muse cells and to elucidate the advantageous difference between Muse cells and other types of stem cells. Finally, we shed light on their current therapeutic applications and the major obstacles to their clinical implementation from laboratory to clinic.

Enhanced Skin Permeation and Controlled Release of ß-Sitosterol Using Cubosomes Encrusted with Dissolving Microneedles for the Management of Alopecia.

The use of synthetic medication for treating alopecia is restricted because of systemic exposure and related negative effects. Beta-sitosterol (ß-ST), a natural chemical, has lately been studied for its potential to promote hair development. The cubosomes with dissolving microneedles (CUBs-MND) created in this study may be a useful starting point for the creation of a sophisticated dermal delivery system for ß-ST. Cubosomes (CUBs) were prepared by the emulsification method, using glyceryl monooleate (GMO) as a lipid polymer. CUBs were loaded with dissolving microneedles (MND) fabricated with HA and a PVP-K90 matrix. An ex vivo skin permeation study and an in vivo hair growth efficacy test of ß-ST were performed with both CUB and CUB-MND. The average particle size of the CUBs was determined to be 173.67 ± 0.52 nm, with a low polydispersity index (0.3) and a high zeta potential value that prevents the aggregate formation of dispersed particles. When compared to CUBs alone, CUBs-MND displayed higher permeating levels of ß-ST at all-time points. In the animals from the CUB-MND group, significant hair development was observed. According to the results of the current investigation, CUBs that integrate dissolving microneedles of ß-ST are superior in terms of transdermal skin penetration and activity for the treatment of alopecia.

Exosomes in COVID-19 infection: Focus on role in diagnosis, pathogenesis, immunity, and clinical trials.

Since the end of 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread as a new strain of coronavirus disease (COVID-19) and progressed as a global pandemic. Exosomes are membrane-bound vesicles released from almost all cells and are crucially involved in cell-cell communication. Interestingly, COVID-19 viral particles produce exosomes that moderate communication between infected and uninfected cells. Hence, there is growing evidence highlighting the crucial implications of exosomes in COVID-19 infection, transmission, intercellular spread, and reinfection. On the other hand, clinical trials have demonstrated mesenchymal stem cell-derived exosomes as a promising therapeutic strategy for severely affected COVID-19 patients. Also, convalescent plasma-derived exosomes have been proposed for multiple efficacies in COVID-19 patients. Furthermore, messenger RNAs (mRNA)-loaded exosomes were superior to mRNA-loaded lipid nanoparticles as a delivery system. Hence, exosomes can be used to safely induce SARS-CoV-2 immunity via their loading with mRNAs encoding immunogenic forms of SARS-CoV-2 spike and nucleocapsid proteins. Moreover, exosomes can be used as a nano-delivery system for microRNA to alleviate cytokine storm and prevent the progression of organ failure in COVID-19 patients. The present review summarizes state of the art concerning the role of exosomes in COVID-19 infection and accompanying organ complications as well as the potential use of exosomes in COVID-19 diagnosis, treatment, drug delivery, and vaccination. The review also sheds the light on the common biogenic pathway between the SARS-CoV-2 virus and exosomes. Additionally, the latest and current clinical trials using exosomes for COVID-19 infection are summarized.

Optimization and In Vitro Characterization of Telmisartan Loaded Sodium Alginate Beads and Its In Vivo Efficacy Investigation in Hypertensive Induced Animal Model.

BACKGROUND: Antihypertensive drug telmisartan (TEL) belongs to BCS class II, which is characterized by low water solubility and, consequently, low oral bioavailability. Gastroretentive systems may overcome the problems associated with low solubility of TEL and incomplete absorption by localizing the drug release in the stomach. The purpose of this study was to prepare TEL-loaded, oil-entrapped, floating alginate beads with the intent of enhancing the oral bioavailability of TEL for the treatment of hypertension. METHODS: For the formulation and optimization of seventeen formulations of TEL-loaded oil-entrapped floating alginate beads, a central composite design was utilized. The concentration of sodium alginate (X1), the concentration of cross-linker (X2), and the concentration of sesame oil (X3) served as independent variables, whereas the entrapment efficiency (Y1), in vitro buoyancy (Y2), and drug release Q6h (Y3) served as dependent variables. Using the emulsion gelation method and calcium chloride as the cross-linking agent, different formulations of TEL alginate beads were produced. All formulations were evaluated for their entrapment efficiency percentage, in vitro buoyancy, and in vitro drug release. The optimal formulation of TEL alginate beads was prepared with and without oil and evaluated for entrapment efficiency percentage, in vitro buoyancy, swelling ratio, average size, and in vitro drug release. Using scanning electron microscopes, the surface morphology was determined. Using IR spectroscopy, the compatibility between the ingredients was determined. In vivo evaluation of the optimized formulation in comparison to the free TEL was done in hypertension-induced rats, and the systolic blood pressure and all pharmacokinetic parameters were measured. RESULTS: The prepared beads exhibited a high entrapment efficiency percentage, in vitro buoyancy, and prolonged drug release. TEL was compatible with other ingredients, as approved by IR spectroscopy. The prepared TEL beads were spherical, as shown by the SEM. The relative bioavailability of TEL-loaded oil-entrapped beads was 222.52%, which was higher than that of the pure TEL suspension. The prepared TEL beads formulation exhibited a higher antihypertensive effect for a prolonged time compared to pure TEL suspension. CONCLUSIONS: It can be concluded that this innovative delivery method of TEL-loaded oil-entrapped beads is a promising tool for enhancing drug solubility and, thus, oral bioavailability and therapeutic efficacy, resulting in enhanced patient compliance. Furthermore, the in vivo study confirmed the formulation's extended anti-hypertensive activity in animal models.

The Implication of Mechanistic Approaches and the Role of the Microbiome in Polycystic Ovary Syndrome (PCOS): A Review.

As a complex endocrine and metabolic condition, polycystic ovarian syndrome (PCOS) affects women's reproductive health. These common symptoms include hirsutism, hyperandrogenism, ovulatory dysfunction, irregular menstruation, and infertility. No one knows what causes it or how to stop it yet. Alterations in gut microbiota composition and disruptions in secondary bile acid production appear to play a causative role in developing PCOS. PCOS pathophysiology and phenotypes are tightly related to both enteric and vaginal bacteria. Patients with PCOS exhibit changed microbiome compositions and decreased microbial diversity. Intestinal microorganisms also alter PCOS patient phenotypes by upregulating or downregulating hormone release, gut-brain mediators, and metabolite synthesis. The human body's gut microbiota, also known as the "second genome," can interact with the environment to improve metabolic and immunological function. Inflammation is connected to PCOS and may be caused by dysbiosis in the gut microbiome. This review sheds light on the recently discovered connections between gut microbiota and insulin resistance (IR) and the potential mechanisms of PCOS. This study also describes metabolomic studies to obtain a clear view of PCOS and ways to tackle it.

The Combined Anti-Tumor Efficacy of Bioactive Hydroxyapatite Nanoparticles Loaded with Altretamine.

In the current study, the combined anti-tumor efficacy of bioactive hydroxyapatite nano- particles (HA-NPs) loaded with altretamine (ALT) was evaluated. The well-known fact that HA has great biological compatibility was confirmed through the findings of the hemolytic experiments and a maximum IC50 value seen in the MTT testing. The preparation of HA-NPs was performed using the chemical precipitation process. An in vitro release investigation was conducted, and the results demonstrated the sustained drug release of the altretamine-loaded hydroxyapatite nanoparticles (ALT-HA-NPs). Studies using the JURKAT E6.1 cell lines MTT assay, and cell uptake, as well as in vivo pharmacokinetic tests using Wistar rats demonstrated that the ALT-HA-NPs were easily absorbed by the cells. A putative synergism between the action of the Ca2+ ions and the anticancer drug obtained from the carrier was indicated by the fact that the ALT-HA-NPs displayed cytotoxicity comparable to the free ALT at 1/10th of the ALT concentration. It has been suggested that a rise in intracellular Ca2+ ions causes cells to undergo apoptosis. Ehrlich's ascites model in Balb/c mice showed comparable synergistic efficacy in a tumor regression trial. While the ALT-HA-NPs were able to shrink the tumor size by six times, the free ALT was only able to reduce the tumor volume by half.

Vitamin K2 (MK-7) Intercepts Keap-1/Nrf-2/HO-1 Pathway and Hinders Inflammatory/Apoptotic Signaling and Liver Aging in Naturally Aging Rat.

Aging is a naturally occurring physiological process with a deleterious impact on various body organs and humans' well-being. The aging population is increasing worldwide, which imposes the need for the exploration of nutritional options that can intercept the impact of the aging processed on various body organs. Vitamin K2 (VK2) is a fat-soluble vitamin with emerging evidence on its therapeutic merits. In the current study, natural aging induced a significant liver deterioration with a disrupted Keap-1/Nrf-2/HO-1 axis and increased COX-2, iNOS and TNF-α expression and apoptotic and fibrotic changes. VK2 administration, on the other hand, improved the biochemical indices of liver function (total protein, albumin, ALT and AST); the suppressed hepatic expression of Keap-1 and increased the hepatic expression of Nrf-2 with a parallel increase in the hepatic activity of HO-1. Subsequently, the liver content and hepatic expression of TNF-α, COX-2 and iNOS were significantly retracted. In context, the liver content and hepatic expression of the fibrotic biomarkers TGFß and TIMP significantly retracted as well. Moreover, the TUNEL assay confirmed the retraction of liver apoptotic changes. Of notice, electron transmission microscope examination confirmed the preservation of mitochondrial functions and preservation of the ultra-microscopical structures. In conclusion, the VK2-mediated interception of aging-induced Keap-1/Nrf-2/HO-1 signaling suppressed the hepatic contents of inflammatory and fibrotic biomarkers, as well as apoptotic changes with preservation of the hepatic architectural and functional status. VK2 can be presumed to be an effective nutritional supplement to the aging population to spare the liver, amongst other body organs, against aging-induced deleterious injury.

Decoding Diabetes Biomarkers and Related Molecular Mechanisms by Using Machine Learning, Text Mining, and Gene Expression Analysis.

The molecular basis of diabetes mellitus is yet to be fully elucidated. We aimed to identify the most frequently reported and differential expressed genes (DEGs) in diabetes by using bioinformatics approaches. Text mining was used to screen 40,225 article abstracts from diabetes literature. These studies highlighted 5939 diabetes-related genes spread across 22 human chromosomes, with 112 genes mentioned in more than 50 studies. Among these genes, HNF4A, PPARA, VEGFA, TCF7L2, HLA-DRB1, PPARG, NOS3, KCNJ11, PRKAA2, and HNF1A were mentioned in more than 200 articles. These genes are correlated with the regulation of glycogen and polysaccharide, adipogenesis, AGE/RAGE, and macrophage differentiation. Three datasets (44 patients and 57 controls) were subjected to gene expression analysis. The analysis revealed 135 significant DEGs, of which CEACAM6, ENPP4, HDAC5, HPCAL1, PARVG, STYXL1, VPS28, ZBTB33, ZFP37 and CCDC58 were the top 10 DEGs. These genes were enriched in aerobic respiration, T-cell antigen receptor pathway, tricarboxylic acid metabolic process, vitamin D receptor pathway, toll-like receptor signaling, and endoplasmic reticulum (ER) unfolded protein response. The results of text mining and gene expression analyses used as attribute values for machine learning (ML) analysis. The decision tree, extra-tree regressor and random forest algorithms were used in ML analysis to identify unique markers that could be used as diabetes diagnosis tools. These algorithms produced prediction models with accuracy ranges from 0.6364 to 0.88 and overall confidence interval (CI) of 95%. There were 39 biomarkers that could distinguish diabetic and non-diabetic patients, 12 of which were repeated multiple times. The majority of these genes are associated with stress response, signalling regulation, locomotion, cell motility, growth, and muscle adaptation. Machine learning algorithms highlighted the use of the HLA-DQB1 gene as a biomarker for diabetes early detection. Our data mining and gene expression analysis have provided useful information about potential biomarkers in diabetes.