Association of Polymorphisms in PD-1 and LAG-3 Genes with Acute Myeloid Leukemia.

Background and objectives: Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation of immature myeloid cells. Immune checkpoint molecules such as programmed cell death protein 1 (PD-1) and lymphocyte activation gene-3 (LAG-3) are essential for controlling anti-tumor immune responses. This study aims to explore the correlation between specific genetic variations (SNPs) in the PDCD1 (rs2227981) and LAG3 (rs12313899) genes and the likelihood of developing AML in the Saudi population. Material and methods: total of 98 Saudi AML patients and 131 healthy controls were genotyped for the PDCD1 rs2227981 and LAG3 rs12313899 polymorphisms using TaqMan genotyping assays. A logistic regression analysis was conducted to evaluate the relationship between the SNPs and AML risk using several genetic models. Results: The results revealed a significant association between the PDCD1 rs2227981 polymorphism and increased AML risk. In AML patients, the frequency of the G allele was considerably greater than in healthy controls (OR = 1.93, 95% CI: 1.31-2.81, p = 0.00080). The GG and AG genotypes were associated with a very high risk of developing AML (p < 0.0001). In contrast, no significant association was observed between the LAG3 rs12313899 polymorphism and AML risk in the studied population. In silico analysis of gene expression profiles from public databases suggested the potential impact of PDCD1 expression levels on the overall survival of AML patients. Conclusions: This study provides evidence for the association of the PDCD1 rs2227981 polymorphism with an increased risk for AML in the Saudi population.

Comprehensive analysis of prohibited substances and methods in sports: Unveiling trends, pharmacokinetics, and WADA evolution.

This review systematically compiles sports-related drugs, substances, and methodologies based on the most frequently detected findings from prohibited lists published annually by the World Anti-Doping Agency (WADA) between 2003 and 2021. Aligned with structure of the 2023 prohibited list, it covers all proscribed items and details the pharmacokinetics and pharmacodynamics of five representatives from each section. Notably, it explores significant metabolites and metabolic pathways associated with these substances. Adverse analytical findings are summarized in tables for clarity, and the prevalence is visually represented through charts. The review includes a concise historical overview of doping and WADA's role, examining modifications in the prohibited list for an understanding of evolving anti-doping measures.

Fentanyl and its derivatives: Pain-killers or man-killers?

Fentanyl is a synthetic µ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed.

Several lines of antioxidant defense against oxidative stress: antioxidant enzymes, nanomaterials with multiple enzyme-mimicking activities, and low-molecular-weight antioxidants.

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are well recognized for playing a dual role, since they can be either deleterious or beneficial to biological systems. An imbalance between ROS production and elimination is termed oxidative stress, a critical factor and common denominator of many chronic diseases such as cancer, cardiovascular diseases, metabolic diseases, neurological disorders (Alzheimer's and Parkinson's diseases), and other disorders. To counteract the harmful effects of ROS, organisms have evolved a complex, three-line antioxidant defense system. The first-line defense mechanism is the most efficient and involves antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). This line of defense plays an irreplaceable role in the dismutation of superoxide radicals (O2•-) and hydrogen peroxide (H2O2). The removal of superoxide radicals by SOD prevents the formation of the much more damaging peroxynitrite ONOO- (O2•- + NO• → ONOO-) and maintains the physiologically relevant level of nitric oxide (NO•), an important molecule in neurotransmission, inflammation, and vasodilation. The second-line antioxidant defense pathway involves exogenous diet-derived small-molecule antioxidants. The third-line antioxidant defense is ensured by the repair or removal of oxidized proteins and other biomolecules by a variety of enzyme systems. This review briefly discusses the endogenous (mitochondria, NADPH, xanthine oxidase (XO), Fenton reaction) and exogenous (e.g., smoking, radiation, drugs, pollution) sources of ROS (superoxide radical, hydrogen peroxide, hydroxyl radical, peroxyl radical, hypochlorous acid, peroxynitrite). Attention has been given to the first-line antioxidant defense system provided by SOD, CAT, and GPx. The chemical and molecular mechanisms of antioxidant enzymes, enzyme-related diseases (cancer, cardiovascular, lung, metabolic, and neurological diseases), and the role of enzymes (e.g., GPx4) in cellular processes such as ferroptosis are discussed. Potential therapeutic applications of enzyme mimics and recent progress in metal-based (copper, iron, cobalt, molybdenum, cerium) and nonmetal (carbon)-based nanomaterials with enzyme-like activities (nanozymes) are also discussed. Moreover, attention has been given to the mechanisms of action of low-molecular-weight antioxidants (vitamin C (ascorbate), vitamin E (alpha-tocopherol), carotenoids (e.g., ß-carotene, lycopene, lutein), flavonoids (e.g., quercetin, anthocyanins, epicatechin), and glutathione (GSH)), the activation of transcription factors such as Nrf2, and the protection against chronic diseases. Given that there is a discrepancy between preclinical and clinical studies, approaches that may result in greater pharmacological and clinical success of low-molecular-weight antioxidant therapies are also subject to discussion.

TIM3 and CTLA4 immune checkpoint polymorphisms are associated with acute myeloid leukemia in Saudi Arabia.

BACKGROUND: Immune checkpoints are receptors on the surface of T cells that function crucially in suppressing the immune response, and they are implicated in autoimmunity and cancer diseases. AIM: The present study aimed to investigate the relationship between functional single nucleotide polymorphisms (SNPs) of two immune checkpoint molecules, CTLA-4 and TIM-3, and acute myeloid leukemia (AML) in a Saudi population. METHODS: Two SNPs in CTLA-4 (rs231775, A > G) and TIM-3 (rs10515746, A > C) were genotyped in 229 subjects, including 98 patients and 131 healthy controls, from the Saudi population using TaqMan assay methods. Differential expression of these two genes was performed using in silico analysis. RESULTS: An association was found between polymorphisms in TIM-3 (OR: 6.01; 95% CI: 3.99-9.05, P < 0.0001) and the risk of AML. Inversely, the rs231775 SNP in the CTLA-4 gene was found to protect against AML in allelic, dominant, and additive models (P < 0.05). A significantly higher expression of TIM-3 in the blood of individuals with AML was observed. CONCLUSION: This is the first study focusing on single nucleotide polymorphisms (SNPs) for CTLA-4 and TIM-3 in acute myeloid leukemia patients in a Saudi community and could be a potential new prognostic factor for this disease.

Niosomal Bupropion: Exploring Therapeutic Frontiers through Behavioral Profiling.

Bupropion (Bup) belongs to the norepinephrine-dopamine reuptake inhibitor (NDRI) class and it is the only FDA-approved drug of its class for the treatment of major depressive disorder (MDD), sold under the name of Wellbutrin. Although bupropion is effective in suppressing the symptoms, its regular use and overdose might lead to seizures and liver failure. Thus, we aimed to nanoformulate bupropion onto a niosomal vesicle to improve its efficacy and achieve the same therapeutic effect at lower scheduled doses. A thin film hydration method was adopted to synthesize and optimize Bup entrapped niosomes using three different surfactants of the sorbitan ester series (Span 20, 40, and 60) in combination with cholesterol. The optimization data determined that the niosome formulated with a cholesterol-to-surfactant ratio of 1:1.5 is the most stable system, with the Bup entrapped niosomes containing Span 20 (Bup@N20C) exhibiting minimal in vitro and in vivo toxicity, and demonstrating the sustained release of Bup in artificial cerebrospinal fluid (ACSF). The Bup@N20C formulation showed increased exploration activity and reduced irregular movements in reserpine-induced depression in the adult zebrafish model, suggesting the potential for mood improvement through the suppression of depression-like behavior which was established by statistical analysis and trajectory data. The Bup@N20C-treated group even surpasses the treatment effect of the positive control group and is comparable to the control group. Hence, it can be inferred that niosomal formulations of Bup represent a promising delivery system capable of achieving the brain delivery of the cargo by bypassing the blood-brain barrier facilitated by their small architectural structure.

Predicting immunogenicity of COVID-19 vaccines in hemodialysis patients with renal disease.

Individuals who are diagnosed with chronic kidney disease, particularly those receiving maintenance hemodialysis treatment, face a greater likelihood of suffering from severe symptoms and fatality due to COVID-19. This study aimed to explore the optimal vaccination approach for these individuals. The study used data analysis tasks such as data preprocessing, cleaning, and exploration, and machine learning models including linear regression, random forest, XGBoost, gradient boosting, AdaBoost, decision trees, Lasso, and ridge regression were used to construct the predictive model. The study found that the Lasso model performed the best overall in predicting anti-S IgG antibodies levels in response to COVID-19 vaccines for people with kidney failure with MAE of 8.81, RMSE of 19.59, and R2 value of 0.93. The adjusted R2 value for the Lasso model was also 0.93, indicating that the model's ability to explain the variance in the data was not affected by the number of predictors in the model. The Random Forest model best predicted the duration of immunogenicity, with R2 and adjusted R2 values of 0.71 and 0.69, respectively. The ensemble model that includes all eight models, i.e., Ridge, Lasso, Linear Regression, Random Forest, AdaBoost, Gradient Boosting, XGBoost, and Decision Tree, has the best performance with the lowest MAE, the lowest RMSE, the highest R2, and the highest adjusted R2 values of 3.91, 5.00, 0.73, and 0.72, respectively. However, further research is required to validate these models and extend their application to different populations and vaccine types, as well as considering other factors that may affect immune response to COVID-19 vaccines. These findings can be helpful in improving vaccination strategies and promoting public health.

Isolation and in vitro assessment of chicken gut microbes for probiotic potential.

Poultry production occupies an important place in the economy of any country. High broiler production in recent years has badly affected its profitability due to bad feed quality, excessive use of chemotherapeutic agents, emergence of diverse pathogens, and the deficiencies in management practices during rearing cycle. Microbiological improvement of the meat quality using potential probiotics can be beneficial for broiler farming. Present study was initiated to isolate chicken gastrointestinal tract (GIT) bacteria with probiotic potential. To isolate probiotics from chicken gut, alimentary canal of chickens of known sizes and ages was suspended in ringers soln. Under shaking conditions for overnight followed by serial dilutions of ringers soln. Bacterial isolates were analyzed via growth curve analysis, biochemical testing using RapID™ NF Plus Panel kit, molecular characterization, antimicrobial activity assay, antibiotic sensitivity assay, GIT adherence assay, bile salt and gastric acid resistant assay, and cholesterol assimilation assay. Four bacteria isolated in present study were identified as Limosilactobacillus antri strain PUPro1, Lactobacillus delbrueckii strain PUPro2, Lacticaseibacillus casei strain PUPro3, and Ligilactobacillus salivarius strain PUPro4. L. delbrueckii strain PUPro2 grew extremely fast. All isolates exhibited exceptional resistance to increasing concentrations of NaCl and bile salts with value of p >0.5. L. delbrueckii strain PUPro2 adhered to chicken ileum epithelial cells and demonstrated the highest viable counts of 320 colony forming units (CFUs). Antagonistic action was found in all isolates against P. aeruginosa, B. subtilis, B. proteus, and S. aureus, with value of p >0.5. Antibiotic susceptibility testing showed sensitivity to all the antibiotics used. Cholesterol assimilation was detected in all bacteria, with values ranging from 216.12 to 192.2 mg/dL. All isolates exhibited γ-hemolysis. In future, these bacteria might be tested for their impact on broilers meat quality and growth and can be recommended for their use as supplements for broilers diet with positive impact on poultry production.

Valorization of non-edible fruit seeds into valuable products: A sustainable approach towards circular bioeconomy.

Global imperatives have recently shown a paradigm shift in the prevailing resource utilization model from a linear approach to a circular bioeconomy. The primary goal of the circular bioeconomy model is to minimize waste by effective re-usage of organic waste and efficient nutrient recycling. In essence, circular bioeconomy integrates the fundamental concept of circular economy, which strives to offer sustainable goods and services by leveraging biological resources and processes. Notably, the circular bioeconomy differs from conventional waste recycling by prioritizing the safeguarding and restoration of production ecosystems, focusing on harnessing renewable biological resources and their associated waste streams to produce value-added products like food, animal feed, and bioenergy. Amidst these sustainability efforts, fruit seeds are getting considerable attention, which were previously overlooked and commonly discarded but were known to comprise diverse chemicals with significant industrial applications, not limited to cosmetics and pharmaceutical industries. While, polyphenols in these seeds offer extensive health benefits, the inadequate conversion of fruit waste into valuable products poses substantial environmental challenges and resource wastage. This review aims to comprehend the known information about the application of non-edible fruit seeds for synthesising metallic nanoparticles, carbon dots, biochar, biosorbent, and biodiesel. Further, this review sheds light on the potential use of these seeds as functional foods and feed ingredients; it also comprehends the safety aspects associated with their utilization. Overall, this review aims to provide a roadmap for harnessing the potential of non-edible fruit seeds by adhering to the principles of a sustainable circular bioeconomy.

Targeted Inhibition of the PI3K/Akt/mTOR Signaling Axis: Potential for Sarcoma Therapy.

Sarcoma is a heterogeneous group of malignancies often resistant to conventional chemotherapy and radiation therapy. The phosphatidylinositol-3-kinase/ protein kinase B /mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway has emerged as a critical cancer target due to its central role in regulating key cellular processes such as cell growth, proliferation, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of bone sarcomas (BS) and soft tissue sarcomas (STS). PI3K/Akt/mTOR inhibitors have shown promising preclinical and clinical activity in various cancers. These agents can inhibit the activation of PI3K, Akt, and mTOR, thereby reducing the downstream signaling events that promote tumor growth and survival. In addition, PI3K/Akt/mTOR inhibitors have been shown to enhance the efficacy of other anticancer therapies, such as chemotherapy and radiation therapy. The different types of PI3K/Akt/mTOR inhibitors vary in their specificity, potency, and side effect profiles and may be effective depending on the specific sarcoma type and stage. The molecular targeting of PI3K/Akt/mToR pathway using drugs, phytochemicals, nanomaterials (NMs), and microbe-derived molecules as Pan-PI3K inhibitors, selective PI3K inhibitors, and dual PI3K/mTOR inhibitors have been delineated. While there are still challenges to be addressed, the preclinical and clinical evidence suggests that these inhibitors may significantly improve patient outcomes. Further research is needed to understand the potential of these inhibitors as sarcoma therapeutics and to continue developing more selective and effective agents to meet the clinical needs of sarcoma patients.

The correlation between soluble human leukocyte antigen (sHLA-G) levels and +3010 polymorphism.

Human leukocyte antigen-G (HLA-G) is classified as non-classical HLA, located in the short arm of chromosome 6 and composed of seven introns and eight exons. The HLA-G gene has a lower frequency polymorphism in the coding area and higher variability at the regulatory 5'- and 3'-untranslated regions linked to HLA-G microRNA regulation. HLA-G molecule is known to have an immunomodulatory and tolerogenic features role. In 199 Saudi individuals, we examined the association between plasma soluble HLA-G (sHLA-G) levels and eight polymorphic different sites, including 14 bp ins/del/+3003T-C/+3010C-G/+3027C-A/+3035C-T/+3142C-G/+3187A-G/+3196C-G single nucleotide polymorphisms (SNPs) in exon 8 in the HLA-G gene. Our results revealed higher frequency for rs17179101C (97%), rs1707T (92%) and rs9380142A (73%) alleles. Greater frequencies for the tested genotypes were observed in 3027C/C (rs17179101) (93%), 14 bp (rs1704) ins/del (92%), +3003T/T (rs1707) (85%) and +3035C/T (rs17179108) (79%) SNP genotypes. Moreover, we observed a significant association of sHLA-G with +3010G/C (rs1710) SNP. In conclusion, we showed a significant association between 3010G/C (rs1710) SNP and the sHLA-G level among our sample for Saudi populations. Our findings demonstrated that specific SNP within the HLA-G gene is linked to sHLA-G molecule secretion, suggesting sHLA-G levels may be regulated genetically.

Fabrication and Characterization of PVA-WPI Based Nanofiber Mats for Improved Viability of Lactobacillus rhamnosus GG.

In the current study, whey protein-based nanofibers were fabricated to encapsulate Lactobacillus rhamnosus. Purposely, different ratios of PVA (polyvinyl alcohol) and WPI (whey protein isolate) were blended to fabricate nanofibers. Nanofiber mats were characterized in terms of particle size, diameter, tensile strength, elongation at break, and loading efficiency. Morphological and molecular characterizations were carried out using scanning electron microscopy (SEM) and Fourier transform infrared (FTIR). Moreover, in vitro viability under simulated gastrointestinal (GI) conditions and thermal stability were also assessed. The results reveal that by increasing the PVA concentration, the conductivity increased while the viscosity decreased. SEM micrographs showed that probiotics were successfully loaded within the nanofiber. The FTIR spectra show strong bonding between the encapsulating materials with the addition of probiotics. In vitro and thermal analyses revealed that the survival of encapsulated probiotics significantly (p < 0.05) improved. In a nutshell, PVA-WPI composite nanofibers have promising potential when used to enhance the viability and stability of probiotics under adverse conditions.

Frentizole derivatives with mTOR inhibiting and senomorphic properties.

Frentizole is immunosuppressive drug with low acute toxicity and lifespan-prolonging effect. Recently, frentizole´s potential to disrupt toxic amyloid ß (Aß) - Aß-binding alcohol dehydrogenase (ABAD) interaction in mitochondria in Alzheimer´s brains has been revealed. Another broadly studied drug with anti-aging and immunosuppressive properties is an mTOR inhibitor - rapamycin. Since we do not yet precisely know what is behind the lifespan-prolonging effect of rapamycin and frentizole, whether it is the ability to inhibit the mTOR signaling pathway, reduction in mitochondrial toxicity, immunosuppressive effect, or a combination of all of them, we have decided within our previous work to dock the entire in-house library of almost 240 Aß-ABAD modulators into the FKBP-rapamycin-binding (FRB) domain of mTOR in order to interlink mTOR-centric and mitochondrial free radical-centric theories of aging and thus to increase the chances of success. Based on the results of the docking study, molecular dynamic simulation and MM-PBSA calculations, we have selected nine frentizole-like compounds (1 - 9). Subsequently, we have determined their real physical-chemical properties (logP, logD, pKa and solubility in water and buffer), cytotoxic/cytostatic, mTOR inhibitory, and in vitro anti-senescence (senolytic and senomorphic) effects. Finally, the three best candidates (4, 8, and 9) have been forwarded for in vivo safety studies to assess their acute toxicity and pharmacokinetic properties. Based on obtained results, only compound 4 demonstrated the best results within in vitro testing, the ability to cross the blood-brain barrier and the lowest acute toxicity (LD50 in male mice 559 mg/kg; LD50 in female mice 575 mg/kg).

Association of Inflammatory Cytokine Levels with Extra Glandular Manifestations, Fatigue, and Disease Activity in Primary Sjögren's Syndrome in Saudi Patients: A Cross-Sectional Study.

BACKGROUND: Primary Sjögren's syndrome (pSS) is an autoimmune disease that can cause fatigue and extraglandular manifestations (EGMs). pSS is associated with cytokine network dysregulation, which may be related to the immune-mediated destruction of exocrine glands. OBJECTIVE: We determined cytokine levels and their relationship to EGMs, the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI), and fatigue in Saudi patients with pSS. METHODS: This study was a cross-sectional, single-center study. We included forty-one patients and 71 controls. Serum samples were collected from random healthy people and pSS patients who were followed in the rheumatology and pulmonary clinics of King Saud University Medical City in Riyadh, Saudi Arabia. Levels of the frequently studied cytokines were measured using Luminex xMAP technology. Each ESSDAI score and EGM were recorded, and the Arabic version of the fatigue severity scale (FSS) was applied to assess fatigue. The main outcome measures were cytokine levels in pSS Saudi patients using/not using immune-suppressive medications (ISMs). RESULTS: Thirty-six (87.8%) patients had one or more EGMs, and the mean ESSDAI score was 9.95 ± 7.73. There was a significant decrease in TNFα and IL-21 levels in the pSS group compared to those in the control group (p = 0.034 and p < 0.001, respectively), whereas IL-12 levels were significantly elevated in the pSS group (p = 0.002). Cytokine levels in patients who used ISMs were the same as those in patients who did not use medications. Decreased IL-1ß (p = 0.014), IL-2 (p = 0.035), IL-6 (p = 0.014), and IL-35 (p = 0.010) levels were observed in patients who had EGMs. Patients who had low disease activity exhibited low IL-10 (p = 0.018) and high IFN-α (p = 0.049), IFN-ß (p = 0.049), IL-1ß (p = 0.006), and IL-35 (p = 0.032) levels compared to patients with high disease activity. A negative association between a positive fatigue score and IL-1ß (p = 0.010), IL-2 (p = 0.037), IFN-α (p = 0.025), TNFα (p = 0.030), IL-17 (p = 0.029), IL-12 (p = 0.046), and IL-21 (p = 0.005) levels was found. CONCLUSIONS: Cytokine profiles correlate with EGMs, ESSDAI, and fatigue. Patients with controlled disease activity have a normal cytokine profile that is similar to that of controls.

Role of Citrullus colocynthis and Psidium guajava Mediated Green Synthesized Silver Nanoparticles in Disease Resistance against Aeromonas hydrophila Challenge in Labeo rohita.

Green synthesis of metallic nanoparticles is an auspicious method of preparing nanoparticles using plant extracts that have lesser toxicity to animal cells and the host. In the present work, we analyzed the antibacterial activity of Citrullus colocynthis and Psidium guajava-mediated silver nanoparticles (Cc-AgNPs and Pg-AgNPs, respectively) against Aeromonas hydrophila (A. hydrophila) in an in vivo assay employing Labeo rohita (L. rohita). L. rohita were divided into six groups for both Cc-AgNPs and Pg-AgNPs treatments separately: Control, A. hydrophila infected, A. hydrophila + Ampicillin, A. hydrophila + Cc/Pg-AgNPs (25 µg/L), A. hydrophila + Cc/Pg-AgNPs (50 µg/L), and A. hydrophila + Cc/Pg-AgNPs (75 µg/L). Changes in different bio-indicators such as hematological, histological, oxidative stress, and cytokine analysis were observed. Interestingly, the infected fish treated with both types of AgNPs (Cc-AgNPs and Pg-AgNPs) exhibited a higher survival rate than the untreated infected fish and demonstrated signs of recovery from the infection, providing a compelling indication of the positive impact of phytosynthesized AgNPs. Disruptions in hematological and histological parameters were found in the infected fish. Both Cc-AgNPs and Pg-AgNPs showed recovery on the hematological and histological parameters. Analysis of oxidative stress and cytokine markers also revealed provoking evidence of the positive impact of Cc-AgNPs and Pg-AgNPs treatment against disease progression in the infected fish. The major finding of the study was that the higher concentrations of the nanoparticles (50 µg/L in the case of Cc-AgNPs and 75 µg/L in the case of Pg-AgNPs) were more effective in fighting against disease. In conclusion, our work presents novel insights for the use of green-synthesized AgNPs as economic and innocuous antibacterial candidates in aquaculture.

Increased expression of HPV-E7 oncoprotein correlates with a reduced level of pRb proteins via high viral load in cervical cancer.

Human Papillomavirus (HPV) is the most common cause of sexually transmitted diseases and causes a wide range of pathologies including cervical carcinoma. Integration of the HR-HPV DNA into the host genome plays a crucial role in cervical carcinoma. An alteration of the pRb pathways by the E7 proteins is one of the mechanisms that's account for the transforming capacity of high-risk papillomavirus. For the proper understanding of the underline mechanism of the progression of the disease, the present study investigate the correlation of concentration of host pRb protein, viral E7 oncoprotein and viral load in early and advanced stages of cervical carcinoma. It was found that the viral load in early stages (stage I and II) was less (log10 transformed mean value 2.6 and 3.0) compared to advanced stages (stage III and IV) (Log10 transformed value 5.0 and 5.8) having high expression of HPV E7 onco-protein and reduced level of pRb protein, signifying the role of viral load and expression level of E7 oncoprotein in the progression of cervical cancer.

Assesment of polyphenolic compounds against biofilms produced by clinical Acinetobacter baumannii strains using in silico and in vitro models.

Several types of microbial infections are caused by Acinetobacter baumanii that has developed resistance to antimicrobial agents. We therefore investigated the role of plant polyphenols against A. baumannii using in silico and in vitro models. The clinical strains of A. baumannii were investigated for determination of resistance pattern and resistance mechanisms including efflux pump, extended spectrum beta lactamase, phenotype detection of AmpC production, and Metallo-ß-lactamase. The polyphenolic compounds were docked against transcription regulator BfmR (PDB ID 6BR7) and antimicrobial, antibiofilm, and anti-quorum sensing activities were performed. The antibiogram studies showed that all isolated strains were resistant. Strain A77 was positive in Metallo-ß-lactamase production. Similarly, none of strains were producers of AmpC, however, A77, A76, A75 had active efflux pumps. Molecular docking studies confirmed a strong binding affinity of Rutin and Catechin towards transcription regulator 6BR7. A significant antimicrobial activity was recorded in case of quercetin and syringic acid (MIC 3.1 µg/mL) followed by vanillic acid and caffeic acid (MIC 12.5 µg/mL). All tested compounds presented a strong antibiofilm activity against A. baumanii strain A77 (65 to 90%). It was concluded that all tested polyphenols samples posess antimicrobial and antibiofilm activities, and hence they may be utilized to treat multidrug resistance A. baumannii infections.

In-Vivo Bactericidal Potential of Mangifera indica Mediated Silver Nanoparticles against Aeromonas hydrophila in Cirrhinus mrigala.

The present study reports the green synthesis of silver nanoparticles from leaves' extract of Mangifera indica (M. indica) and their antibacterial efficacy against Aeromonas hydrophila (A. hydrophila) in Cirrhinus mrigala (C. mrigala). The prepared M. indica mediated silver nanoparticles (Mi-AgNPs) were found to be polycrystalline in nature, spherical in shapes with average size of 62 ± 13 nm. C. mrigala (n = ±15/group) were divided into six groups i.e., G1: control, G2: A. hydrophila challenged, G3: A. hydrophila challenged + Mi-AgNPs (0.01 mg/L), G4: A. hydrophila challenged + Mi-AgNPs (0.05 mg/L), G5: A. hydrophila challenged + Mi-AgNPs (0.1 mg/L) and G6: A. hydrophila challenged + M. indica extract (0.1 mg/L). Serum biochemical, hematological, histological and oxidative biomarkers were evaluated after 15 days of treatment. The liver enzyme activities, serum proteins, hematological parameters and oxidative stress markers were found to be altered in the challenged fish but showed retrieval effects with Mi-AgNPs treatment. The histological analysis of liver, gills and kidney of the challenged fish also showed regaining effects following Mi-AgNPs treatment. A CFU assay from muscle tissue provided quantitative data that Mi-AgNPs can hinder the bacterial proliferation in challenged fish. The findings of this work suggest that M. indica based silver nanoparticles can be promising candidates for the control and treatment of microbial infections in aquaculture.

Reactive oxygen species, toxicity, oxidative stress, and antioxidants: chronic diseases and aging.

A physiological level of oxygen/nitrogen free radicals and non-radical reactive species (collectively known as ROS/RNS) is termed oxidative eustress or "good stress" and is characterized by low to mild levels of oxidants involved in the regulation of various biochemical transformations such as carboxylation, hydroxylation, peroxidation, or modulation of signal transduction pathways such as Nuclear factor-κB (NF-κB), Mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase, nuclear factor erythroid 2-related factor 2 (Nrf2) and other processes. Increased levels of ROS/RNS, generated from both endogenous (mitochondria, NADPH oxidases) and/or exogenous sources (radiation, certain drugs, foods, cigarette smoking, pollution) result in a harmful condition termed oxidative stress ("bad stress"). Although it is widely accepted, that many chronic diseases are multifactorial in origin, they share oxidative stress as a common denominator. Here we review the importance of oxidative stress and the mechanisms through which oxidative stress contributes to the pathological states of an organism. Attention is focused on the chemistry of ROS and RNS (e.g. superoxide radical, hydrogen peroxide, hydroxyl radicals, peroxyl radicals, nitric oxide, peroxynitrite), and their role in oxidative damage of DNA, proteins, and membrane lipids. Quantitative and qualitative assessment of oxidative stress biomarkers is also discussed. Oxidative stress contributes to the pathology of cancer, cardiovascular diseases, diabetes, neurological disorders (Alzheimer's and Parkinson's diseases, Down syndrome), psychiatric diseases (depression, schizophrenia, bipolar disorder), renal disease, lung disease (chronic pulmonary obstruction, lung cancer), and aging. The concerted action of antioxidants to ameliorate the harmful effect of oxidative stress is achieved by antioxidant enzymes (Superoxide dismutases-SODs, catalase, glutathione peroxidase-GPx), and small molecular weight antioxidants (vitamins C and E, flavonoids, carotenoids, melatonin, ergothioneine, and others). Perhaps one of the most effective low molecular weight antioxidants is vitamin E, the first line of defense against the peroxidation of lipids. A promising approach appears to be the use of certain antioxidants (e.g. flavonoids), showing weak prooxidant properties that may boost cellular antioxidant systems and thus act as preventive anticancer agents. Redox metal-based enzyme mimetic compounds as potential pharmaceutical interventions and sirtuins as promising therapeutic targets for age-related diseases and anti-aging strategies are discussed.

A Comparative Analysis on the Innate Immune Responses of Cirrhinus mrigala Challenged with Pseudomonas aeruginosa and Fusarium oxysporum.

Microbes are the most significant ubiquitous pathogens that cause serious infections in freshwater fish, leading to tremendous economic losses. The present study was designed to investigate the extent of changes in cytokine expression, hemato-biochemical parameters, and tissue histology of Cirrhinus mrigala (C. mrigala) challenged with Pseudomonas aeruginosa (P. aeruginosa) and Fusarium oxysporum (F. oxysporum). Fish were divided into three major groups: control, P. aeruginosa-challenged, and F. oxysporum-challenged. The infection in both challenge assays was allowed to progress until 7 days post infection. Upregulated expression of TNF-α and IL-1ß was found in blood, gills, livers, and kidneys of the challenged fish. Significant differences were noted in hematological parameters of challenged fish. Alanine aminotransferase, aspartate aminotransferase, and alkaline aminotransferase levels also showed significant differences in infected and control groups. An increase in serum albumin and globulin and a decrease in total protein were noted in infected groups as compared to the control group. Severe histological alterations were noted in gill, liver, and kidney tissues of the infected groups as compared to control. The order of histological alteration index for P. aeruginosa challenge was liver > kidney > gills, and for F. oxysporum challenge it was kidney > liver > gills. These changes in fish infected by P. aeruginosa and F. oxysporum can be used as an effective and subtle index to monitor the physiological and pathological conditions of fish.