Hope on the Horizon: Promising Therapies for Steatotic Liver Disease.

Steatotic liver disease (SLD) is a highly prevalent chronic liver disease with significant challenges for global health. The pathophysiology of SLD involves an interplay among genetic, endocrine, and metabolic factors. Successful management of SLD entails accurate diagnosis and disease monitoring through noninvasive methods such as advanced imaging techniques and biomarkers. Many emerging pharmacotherapies for SLD are now in the pipeline, which target different pathways like collagen turnover, fibrogenesis, inflammation, and metabolism. The recent approval of resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has been a milestone in addressing the unmet medical need for an efficacious SLD treatment. Finally, the potential of personalized medicine approaches and interdisciplinary cooperation in improving patient outcomes and reducing disease burden should be strongly pursued. SIGNIFICANCE STATEMENT: The healthcare burden due to steatotic liver disease (SLD) is enormous. This perspective sheds light on the recent advances in understanding the pathophysiology and diagnosis of SLD as well as promising drug development approaches.

Adrenoceptor Desensitization: Current Understanding of Mechanisms.

G-protein coupled receptors (GPCRs) transduce a wide range of extracellular signals. They are key players in the majority of biologic functions including vision, olfaction, chemotaxis, and immunity. However, as essential as most of them are to body function and homeostasis, overactivation of GPCRs has been implicated in many pathologic diseases such as cancer, asthma, and heart failure (HF). Therefore, an important feature of G protein signaling systems is the ability to control GPCR responsiveness, and one key process to control overstimulation involves initiating receptor desensitization. A number of steps are appreciated in the desensitization process, including cell surface receptor phosphorylation, internalization, and downregulation. Rapid or short-term desensitization occurs within minutes and involves receptor phosphorylation via the action of intracellular protein kinases, the binding of ß-arrestins, and the consequent uncoupling of GPCRs from their cognate heterotrimeric G proteins. On the other hand, long-term desensitization occurs over hours to days and involves receptor downregulation or a decrease in cell surface receptor protein level. Of the proteins involved in this biologic phenomenon, ß-arrestins play a particularly significant role in both short- and long-term desensitization mechanisms. In addition, ß-arrestins are involved in the phenomenon of biased agonism, where the biased ligand preferentially activates one of several downstream signaling pathways, leading to altered cellular responses. In this context, this review discusses the different patterns of desensitization of the α 1-, α 2- and the ß adrenoceptors and highlights the role of ß-arrestins in regulating physiologic responsiveness through desensitization and biased agonism. SIGNIFICANCE STATEMENT: A sophisticated network of proteins orchestrates the molecular regulation of GPCR activity. Adrenoceptors are GPCRs that play vast roles in many physiological processes. Without tightly controlled desensitization of these receptors, homeostatic imbalance may ensue, thus precipitating various diseases. Here, we critically appraise the mechanisms implicated in adrenoceptor desensitization. A better understanding of these mechanisms helps identify new druggable targets within the GPCR desensitization machinery and opens exciting therapeutic fronts in the treatment of several pathologies.

Polymer nanotherapeutics: A promising approach toward microglial inhibition in neurodegenerative diseases.

Nanoparticles (NPs) that target multiple transport mechanisms facilitate targeted delivery of active therapeutic agents to the central nervous system (CNS) and improve therapeutic transport and efficacy across the blood-brain barrier (BBB). CNS nanotherapeutics mostly target neurons and endothelial cells, however, microglial immune cells are the first line of defense against neuronal damage and brain infections. Through triggering release of inflammatory cytokines, chemokines and proteases, microglia can however precipitate neurological damage-a significant factor in neurodegenerative diseases. Thus, microglial inhibitory agents are attracting much attention among those researching and developing novel treatments for neurodegenerative disorders. The most established inhibitors of microglia investigated to date are resveratrol, curcumin, quercetin, and minocycline. Thus, there is great interest in developing novel agents that can bypass or easily cross the BBB. One such approach is the use of modified-nanocarriers as, or for, delivery of, therapeutic agents to the brain and wider CNS. For microglial inhibition, polymeric NPs are the preferred vehicles for choice. Here, we summarize the immunologic and neuroinflammatory role of microglia, established microglia inhibitor agents, challenges of CNS drug delivery, and the nanotherapeutics explored for microglia inhibition to date. We also discuss applications of the currently considered "most useful" polymeric NPs for microglial-inhibitor drug delivery in CNS-related diseases.

C-peptide in diabetes: A player in a dual hormone disorder?

C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications.

A comprehensive review of online resources for microRNA-diseases associations: the state of the art.

MicroRNAs (miRNAs) as small 19- to 24-nucleotide noncoding RNAs regulate several mRNA targets and signaling pathways. Therefore, miRNAs are considered key regulators in cellular pathways as well as various pathologies. There is substantial interest in the relationship between disease and miRNAs, which made that one of the important research topics. Interestingly, miRNAs emerged as an attractive approach for clinical application, not only as biomarkers for diagnosis and prognosis or in the prediction of therapy response but also as therapeutic tools. For these purposes, the identification of crucial miRNAs in disease is very important. Databases provided valuable experimental and computational miRNAs-disease information in an accessible and comprehensive manner, such as miRNA target genes, miRNA related in signaling pathways and miRNA involvement in various diseases. In this review, we summarized miRNAs-disease databases in two main categories based on the general or specific diseases. In these databases, researchers could search diseases to identify critical miRNAs and developed that for clinical applications. In another way, by searching particular miRNAs, they could recognize in which disease these miRNAs would be dysregulated. Despite the significant development that has been done in these databases, there are still some limitations, such as not being updated and not providing uniform and detailed information that should be resolved in future databases. This survey can be helpful as a comprehensive reference for choosing a suitable database by researchers and as a guideline for comparing the features and limitations of the database by developer or designer. Short abstract We summarized miRNAs-disease databases that researchers could search disease to identify critical miRNAs and developed that for clinical applications. This survey can help choose a suitable database for researchers.

Prevalence and molecular characterization of colistin resistance in Pseudomonas aeruginosa isolates: insights from a study in Ardabil hospitals.

BACKGROUND: Pseudomonas aeruginosa is a common cause of nosocomial infections. However, the emergence of multidrug-resistant strains has complicated the treatment of P. aeruginosa infections. While polymyxins have been the mainstay for treatment, there is a global increase in resistance to these antibiotics. Therefore, our study aimed to determine the prevalence and molecular details of colistin resistance in P. aeruginosa clinical isolates collected between June 2019 and May 2023, as well as the genetic linkage of colistin-resistant P. aeruginosa isolates. RESULTS: The resistance rate to colistin was 9% (n = 18) among P. aeruginosa isolates. All 18 colistin-resistant isolates were biofilm producers and carried genes associated with biofilm formation. Furthermore, the presence of genes encoding efflux pumps, TCSs, and outer membrane porin was observed in all colistin-resistant P. aeruginosa strains, while the mcr-1 gene was not detected. Amino acid substitutions were identified only in the PmrB protein of multidrug- and colistin-resistant strains. The expression levels of mexA, mexC, mexE, mexY, phoP, and pmrA genes in the 18 colistin-resistant P. aeruginosa strains were as follows: 88.8%, 94.4%, 11.1%, 83.3%, 83.3%, and 38.8%, respectively. Additionally, down-regulation of the oprD gene was observed in 44.4% of colistin-resistant P. aeruginosa strains. CONCLUSION: This study reports the emergence of colistin resistance with various mechanisms among P. aeruginosa strains in Ardabil hospitals. We recommend avoiding unnecessary use of colistin to prevent potential future increases in colistin resistance.

Omega-3 fatty acids and endothelial function: A GRADE-assessed systematic review and meta-analysis.

INTRODUCTION: N-3 polyunsaturated fatty acids (PUFAs) supplementation has been reported to have an impact on flow-mediated dilatation (FMD), a conventionally used clinical technique for estimating endothelial dysfunction. However, its proven effects on endothelial function are unclear. This systematic review and meta-analysis were conducted to evaluate the effects of n-3 PUFAs supplementation on FMD of the brachial artery. METHOD: This study was performed following the PRISMA guidelines. To identify eligible RCTs, a systematic search was completed in PubMed/Medline, Scopus and Web of Science using relevant keywords. A fixed- or random-effects model was utilized to estimate the weighted mean difference (WMD) and 95% confidence interval (95% CI). RESULTS: Thirty-two studies (with 35 arms) were included in this meta-analysis, involving 2385 subjects with intervention duration ranging from 4 to 48 weeks. The pooled meta-analysis demonstrated a significant effect of omega-3 on FMD (WMD = 0.8%, 95% CI = 0.3-1.3, p = .001) and heterogeneity was significant (I2 = 82.5%, p < .001). CONCLUSION: We found that n-3 PUFA supplementation improves endothelial function as estimated by flow-mediated dilatation of the brachial artery.

Whether and Why Do We Need a Vaccine Against Atherosclerosis? Can We Expect It Anytime Soon?

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of premature death. Lipid disorders, particularly elevated serum low-density lipoprotein cholesterol (LDL-C), contribute significantly to ASCVD. The risk of developing ASCVD is influenced by the duration of exposure to elevated LDL-C concentrations (cholesterol-years concept). Implementing lipid-lowering treatments based on the principles of "the earlier the better," "the lower the better," and "the longer the better" has been shown to reduce cardiovascular risk and significantly extend lifespan. Despite the availability of numerous lipid-lowering drugs, achieving satisfactory control of lipid disorders remains very challenging. Therefore, there is a need for novel approaches to improve treatment adherence. RECENT FINDINGS: One promising solution under investigation is the development of an anti-PCSK9 vaccine, which could be administered annually to provide long-term control over LDL-C concentrations. Experimental studies and the sole clinical trial conducted thus far have demonstrated that the anti-PCSK9 vaccine induces a durable immune response associated with lipid-lowering and anti-atherosclerotic effects. Furthermore, it has exhibited good tolerability and a satisfactory safety profile. However, we still need data from phase 2, 3, and cardiovascular outcome trial to confirm its safety and efficacy and add value in the armamentarium of available and perspective lipid-lowering drugs. This article highlights the significance of developing an anti-PCSK9 vaccine and provides an overview of the current knowledge on various anti-PCSK9 vaccines.

Cardiovascular Effects of Stimulators of Soluble Guanylate Cyclase Administration: A Meta-analysis of Randomized Controlled Trials.

PURPOSE OF REVIEW: Heart failure (HF) is one of the main causes of cardiovascular mortality in the western world. Despite great advances in treatment, recurrence and mortality rates remain high. Soluble guanylate cyclase is an enzyme which, by producing cGMP, is responsible for the effects of vasodilation, reduction of cardiac pre- and after-load and, therefore, the improvement of myocardial performance. Thus, a new therapeutic strategy is represented by the stimulators of soluble guanylate cyclase (sGCs). The aim of this meta-analysis was to analyze the effects deriving from the administration of sGCs, in subjects affected by HF. A systematic literature search of Medline, SCOPUS, and Google Scholar was conducted up to December 2022 to identify RCTs assessing the cardiovascular effects, as NT-pro-BNP values and ejection fraction (EF), and all-cause mortality, of the sGCs. Quantitative data synthesis was performed using a random-effects model, with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RECENT FINDINGS: The results obtained documented a statistically significant improvement in NT-proBNP values (SMD: - 0.258; 95% CI: - 0.398, - 0.118; p < 0.001) and EF (WMD: 0.948; 95% CI: 0.485, 1.411; p < 0.001) in subjects treated with sGCs; however, no significant change was found in the all-cause mortality rate (RR 0.96; 95% CI 0.868 to 1.072; I2, p = 0). The sGCs represent a valid therapeutic option in subjects suffering from HF, leading to an improvement in cardiac performance.

Application of CRISPR-Cas9 technology in diabetes research.

Diabetes is a chronic disorder with rapidly increasing prevalence that is a major global issue of our current era. There are two major types of diabetes. Polygenic forms of diabetes include type 1 diabetes (T1D) and type 2 diabetes (T2D) and its monogenic forms are maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM). There are no permanent therapeutic approaches for diabetes and current therapies rely on regular administration of various drugs or insulin injection. Recently, gene editing strategies have offered new promise for treating genetic disorders. Targeted genome editing is a fast-growing technology, recruiting programmable nucleases to specifically modify target genomic sequences. These targeted nucleases generate double-strand breaks at target regions in the genome, which induce cellular repair pathways including non-homologous end joining (NHEJ) and homology-directed repair (HDR). Clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) is a novel gene-editing system, permitting precise genome modification. CRISPR/Cas9 has great potential for various applications in diabetic research such as gene screening, generation of diabetic animal models and treatment. In this article, gene-editing strategies are summarized with a focus on the CRISPR/Cas9 approach in diabetes research.

Non-coding RNAs in leukemia drug resistance: new perspectives on molecular mechanisms and signaling pathways.

Like almost all cancer types, timely diagnosis is needed for leukemias to be effectively cured. Drug efflux, attenuated drug uptake, altered drug metabolism, and epigenetic alterations are just several of the key mechanisms by which drug resistance develops. All of these mechanisms are orchestrated by up- and downregulators, in which non-coding RNAs (ncRNAs) do not encode specific proteins in most cases; albeit, some of them have been found to exhibit the potential for protein-coding. Notwithstanding, ncRNAs are chiefly known for their contribution to the regulation of physiological processes, as well as the pathological ones, such as cell proliferation, apoptosis, and immune responses. Specifically, in the case of leukemia chemo-resistance, ncRNAs have been recognized to be responsible for modulating the initiation and progression of drug resistance. Herein, we comprehensively reviewed the role of ncRNAs, specifically its effect on molecular mechanisms and signaling pathways, in the development of leukemia drug resistance.

Regulatory effects of curcumin on nitric oxide signaling in the cardiovascular system.

The continuously rising prevalence of cardiovascular disease (CVD) globally substantially impacts the economic growth of developing countries. Indeed, one of the leading causes of death worldwide is unfavorable cardiovascular events. Reduced nitric oxide (NO) generation is the pathogenic foundation of endothelial dysfunction, which is regarded as the first stage in the development of a number of CVDs. Nitric oxide exerts an array of biological effects, including vasodilation, the suppression of vascular smooth muscle cell proliferation and the functional control of cardiac cells. Numerous treatment strategies aim to increase NO synthesis or upregulate downstream NO signaling pathways. The major component of Curcuma longa, curcumin, has long been utilized in traditional medicine to treat various illnesses, especially CVDs. Curcumin improves CV function as well as having important pleiotropic effects, such as anti-inflammatory and antioxidant, through its ability to increase the bioavailability of NO and to positively impact NO-related signaling pathways. In this review, we discuss the scientific literature relating to curcumin's positive effects on NO signaling and vascular endothelial function.

The pharmaco-epigenetics of hypertension: a focus on microRNA.

Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted.

Superoxide dismutase: a key target for the neuroprotective effects of curcumin.

Over the past few years, the prevalence of neurodegenerative diseases (NDD) has increased dramatically. The community health system is burdened by the high healthcare costs associated with NDD. Superoxide dismutase (SOD) is a type of metalloenzyme that possesses a distinct characteristic of protecting the body from oxidative stress through antioxidants. In this way, SOD supplementation may activate the endogenous antioxidant mechanism in various pathological conditions and could be used to neutralize free radical excess. Several factors are responsible for damaging DNA and RNA in the body, including the overproduction of reactive species, particularly reactive oxygen species (ROS) and reactive nitrogen species (RNS). Excessive ROS/RNS have deleterious effects on mitochondria and their metabolic processes, mainly through increased mitochondrial proteins, lipids and DNA oxidation. Studies have shown that oxidative stress is implicated in the etiology of many diseases, including NDD. It is thought that anti-inflammatory compounds, particularly phytochemicals, can interfere with these pathways and regulate inflammation. Extensive experimental and clinical research has proven that curcumin (Cur) has anti-inflammatory and anti-neurologic properties. In this review, we have compiled the available data on Cur's anti-inflammatory properties, paying special attention to its therapeutic impact on NDD through SOD.

Advancing gastrointestinal cancer diagnostics: a systematic review and meta-analysis of circulating microRNA-1246 as a non-invasive biomarker.

BACKGROUND: Despite numerous reports on the alterations of microRNA-1246 (miR-1246) expression level in digestive system cancers, its role in gastrointestinal cancers (GICs) remains unclear. This meta-analysis aimed to assess the diagnostic potential of circulating miR-1246 in GICs. METHODS: Meta-disc version 1.4 and Comprehensive Meta-Analysis (CMA) version 3.7 software were used to calculate pooled sensitivity, specificity, likelihood ratios, diagnostic odds ratio (DOR), area under the curve (AUC), Q*index and summary receiver-operating characteristic (SROC). Subgroup analyses were conducted for cancer type, sample type and geographical region. Publication bias was assessed using Begg's and Egger's tests. RESULTS: A total of 14 articles involving 18 studies and 1526 participants (972 cases and 554 controls) were included. The diagnostic accuracy of miRNA-1246 in GICs was as follows: pooled sensitivity: 0.81 (95% CI: 0.79 - 0.83), specificity: 0.74 (95% CI: 0.71 - 0.77), PLR: 3.315 (95% CI: 2.33 - 4.72), NLR: 0.221 (95% CI: 0.153 - 0.319), DOR: 16.87 (95% CI: 9.45 - 30.09), AUC: 0.891, and Q*-index: 0.807. No publication bias was found based on Begg's (p = 0.172) and Egger's (p = 0.113) tests. CONCLUSION: Circulating miR-1246 shows promise as a non-invasive biomarker for early detection of GICs.

The association between oxidized low-density lipoprotein and cancer: An emerging targeted therapeutic approach?

Lipids play an important role in varying vital cellular processes including cell growth and division. Elevated levels of low-density lipoprotein (LDL) and oxidized-LDL (ox-LDL), and overexpression of the corresponding receptors including LDL receptor (LDLR), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), and cluster of differentiation 36 (CD36), have shown strong correlations with different facets of carcinogenesis including proliferation, invasion, and angiogenesis. Furthermore, a high serum level of LOX-1 is considered as a poor prognostic factor in many types of cancer including colorectal cancer. Ox-LDL could contribute to cancer progression and metastasis through endothelial-to-mesenchymal transition (EMT) and autophagy. Thus, many studies have shed light on the significant role of ox-LDL as a potential therapeutic target for cancer therapy. In various repurposing approaches, anti-dyslipidemia agents, phytochemicals, autophagy modulators as well as recently developed ldl-like nanoparticles have been investigated as potential tumor therapeutic agents by targeting oxidized-LDL/LOX-1 pathways. Herein, we reviewed the role of oxidized-LDL and LOX-1 in cancer progression, invasion, metastasis, and also cancer-associated angiogenesis. Moreover, we addressed therapeutic utility of several compounds that proved to be capable of targeting the metabolic moieties in cancer. This review provides insights on the potential impact of targeting LDL and ox-LDL in cancer therapy and their future biomedical implementations.

Clinical performance of rapid antigen tests in comparison to RT-PCR for SARS-COV-2 diagnosis in Omicron variant: A systematic review and meta-analysis.

The Omicron variant of concern has a high level of mutations in different genes that has raised awareness about the performance of immunological products such as vaccines and antigen detection kits. In this systematic review and meta-analysis, we investigated whether Omicron had a significant influence on rapid antigen test (RAT) performance in comparison to PCR. We registered this systematic review and meta-analysis in PROSPERO with the registration number CRD42022355510. We searched PubMed, Scopus, Embase, and Web of Science databases systematically to 1 August 2022. After article screening, we assessed the quality of the included studies based on the JBI checklist. Following data extraction, we performed a meta-analysis using R software. We included 18 qualified articles presenting sufficient data about RATs performance in comparison to RT-PCR in Omicron infections. The pooled specificity and sensitivity of RATs were 1.000 (0.997-1.000) and 0.671 (0.595-0.721), respectively. The FDA-approved kits showed a better performance than WHO-approved ones with a sensitivity of 0.728 (0.620-0.815). The use of RATs with nasal swabs showed a higher sensitivity compared with nasopharyngeal swabs. The sensitivity for samples with a CT-value >25 was 0.108 (0.048-0.227). Rapid antigen tests show impaired performance for COVID-19 diagnosis when the Omicron variant is circulating, particularly in samples with low viral loads.

Prevalence and mechanisms of aminoglycoside resistance among drug-resistant Pseudomonas aeruginosa clinical isolates in Iran.

BACKGROUND: Aminoglycosides have been a cornerstone of the treatment of nosocomial infections caused by Pseudomonas aeruginosa for over 80 years. However, escalating emergence of resistance poses a significant challenge. Therefore, this study aimed to investigate the prevailing patterns of aminoglycoside resistance among clinical isolates of P. aeruginosa in Iran; as well as the underlying resistance mechanisms observed in patients referred to Ardabil hospitals. METHODS: A total of 200 isolates from five hospitals were evaluated. The resistance profiles of P. aeruginosa isolates to tobramycin, amikacin, and netilmicin were determined using the disk diffusion method. The capacity of aminoglycoside-resistant isolates to form biofilms was assessed through a phenotypic assay, and the results were confirmed using the gene amplification technique. The presence of genes associated with aminoglycoside resistance was detected using polymerase chain reaction (PCR). Quantitative reverse transcription PCR (qRT-PCR) was performed to measure the expression levels of genes encoding the MexXY-OprM efflux pump and PhoPQ two-component system (TCS). RESULTS: The prevalence of aminoglycoside-resistant P. aeruginosa isolates was 48%, with 94.7% demonstrating multidrug resistance (MDR). All aminoglycoside-resistant P. aeruginosa strains exhibited biofilm-forming capabilities and harbored all the genes associated with biofilm production. Among the nine genes encoding 16S rRNA methylase and aminoglycoside-modifying enzymes, three genes were detected in these isolates: aac(6')-Ib (85.4%), ant(2'')-Ia (18.7%), and aph(3')-VI (3.1%). Additionally, all aminoglycoside-resistant P. aeruginosa isolates carried mexY and phoP genes, although the expression levels of mexY and phoP were 75% and 87.5%, respectively. CONCLUSION: Given the considerably high prevalence of aminoglycoside-resistant P. aeruginosa strains, urgent measures are warranted to transition towards the use of novel aminoglycosides and to uphold vigilant surveillance of resistance patterns.

Effect of Calebin-A on Critical Genes Related to NAFLD: A Protein-Protein Interaction Network and Molecular Docking Study.

Background: Calebin-A is a minor phytoconstituent of turmeric known for its activity against inflammation, oxidative stress, cancerous, and metabolic disorders like Non-alcoholic fatty liver disease(NAFLD). Based on bioinformatic tools. Subsequently, the details of the interaction of critical proteins with Calebin-A were investigated using the molecular docking technique. Methods: We first probed the intersection of genes/ proteins between NAFLD and Calebin-A through online databases. Besides, we performed an enrichment analysis using the ClueGO plugin to investigate signaling pathways and gene ontology. Next, we evaluate the possible interaction of Calebin-A with significant hub proteins involved in NAFLD through a molecular docking study. Results: We identified 87 intersection genes Calebin-A targets associated with NAFLD. PPI network analysis introduced 10 hub genes (TP53, TNF, STAT3, HSP90AA1, PTGS2, HDAC6, ABCB1, CCT2, NR1I2, and GUSB). In KEGG enrichment, most were associated with Sphingolipid, vascular endothelial growth factor A (VEGFA), C-type lectin receptor, and mitogen-activated protein kinase (MAPK) signaling pathways. The biological processes described in 87 intersection genes are mostly concerned with regulating the apoptotic process, cytokine production, and intracellular signal transduction. Molecular docking results also directed that Calebin-A had a high affinity to bind hub proteins linked to NAFLD. Conclusion: Here, we showed that Calebin-A, through its effect on several critical genes/ proteins and pathways, might repress the progression of NAFLD.

Recent advances in gene delivery nanoplatforms based on spherical nucleic acids.

Gene therapy is a therapeutic option for mitigating diseases that do not respond well to pharmacological therapy. This type of therapy allows for correcting altered and defective genes by transferring nucleic acids to target cells. Notably, achieving a desirable outcome is possible by successfully delivering genetic materials into the cell. In-vivo gene transfer strategies use two major classes of vectors, namely viral and nonviral. Both of these systems have distinct pros and cons, and the choice of a delivery system depends on therapeutic objectives and other considerations. Safe and efficient gene transfer is the main feature of any delivery system. Spherical nucleic acids (SNAs) are nanotechnology-based gene delivery systems (i.e., non-viral vectors). They are three-dimensional structures consisting of a hollow or solid spherical core nanoparticle that is functionalized with a dense and highly organized layer of oligonucleotides. The unique structural features of SNAs confer them a high potency in internalization into various types of tissue and cells, a high stability against nucleases, and efficay in penetrating through various biological barriers (such as the skin, blood-brain barrier, and blood-tumor barrier). SNAs also show negligible toxicity and trigger minimal immune response reactions. During the last two decades, all these favorable physicochemical and biological attributes have made them attractive vehicles for drug and nucleic acid delivery. This article discusses the unique structural properties, types of SNAs, and also optimization mechanisms of SNAs. We also focus on recent advances in the synthesis of gene delivery nanoplatforms based on the SNAs.