Immunopathogenesis of Salmonellosis

Salmonella is an intracellular pathogenic, gram-negative, facultative anaerobe and non-spore-forming and usually a motile bacillus that leads to salmonellosis in the host. It is a common food-borne disease that ranges from local gastrointestinal inflammation and diarrhoea to life-threatening typhoid fever and presents usually a serious threat to public health due to its socio-economic value. Inadequate sanitation and impure water help in the propagation of this disease. Despite advancement in the sanitation standards, Salmonella enters the food chain and affects communities globally. There is an immediate need to develop improved vaccines to minimise Salmonella-related illnesses. Some Salmonella serovars infect a wide range of hosts, while others are known to be host restricted. Many different factors determine the adaptability and host specificity of Salmonella. The host-pathogen interactions play a unique role in Salmonella invasion and progression which needs to be studied in detail. This chapter shall focus on our current understanding of Salmonella invasion, pathogenesis and interactions with the host, host specificity and adaptability

Synthesis, characterization, x-ray structure and antimicrobial activity of N-(4-chlorophenyl)-2-(pyridin-4- ylcarbonyl) hydrazinecarbothioamide

Purpose: To synthesize thiosemicarbazide and determine its antimicrobial properties.Methods: Pyridine-based thiosemicarbazide was synthesized, characterized and evaluated for antimicrobial activity. The structure of the synthesized compound was established by spectral analysis, namely, Fourier transform infrared spectroscopy (FT-IR), proton nuclear magnetic resonance spectroscopy (1H NMR), carbon 13 magnetic resonance spectroscopy (13C NMR), liquid chromatography-mass spectroscopy (LC-MS), single crystal x-ray analysis as well as by elemental analysis.Results: The title compound crystallized in monoclinic form with space group P21/c of a = 11.6050 (3) Å, b = 13.3130 (4) Å, c = 9.9884 (3) Å, β = 94.911 (2)°, V = 1537.52 (8) Å3, Z = 4 and Rint = 0.033. The pyridine ring formed dihedral angles of 74.1(3) and 88.2(5)° with major and minor components of disordered benzene ring, respectively. In the crystal packing, molecules were linked via intermolecular N—H•••N, N—H•••S and N—H•••O hydrogen bonds into zigzag layers. Compound 2 was most effective against Bacillus subtilis ATCC 10400, MRSA 85N, MRSA 66N and MRSA 15G, compared to the reference drugs, ampicillin and ceftriaxone.Conclusion: The title compound represents a good lead for the development of potent antibacterial agent against Gram positive bacteria and MRSA strains.Keywords: Isoniazid, Thiosemicarbazide, Single crystal x-ray, Antimicrobial activit

Genetics of Disease Resistance in Chicken

Although poultry industry has gained momentum during the last few decades, there are still various impediments like improper infrastructure, unscientific management and above all various deadly infectious diseases which incur huge economic losses on poultry industry. These diseases include viral diseases like Avian Influenza, Marek’s Disease, New Castle disease and bacterial diseases like Colibacillosis, Pasteurellosis and Salmonellosis, etc. Development of disease resistant poultry has been found successful practice over the use of drugs or vaccines for disease control. Studies involving genome wide associations to figure out certain candidate genes that are involved in disease resistance have also been carried out. Single nucleotide polymorphism studies to unveil the mechanisms underlying disease resistance in chicken show that SNPs and other candidate gene approaches play a vital role in providing disease resistance. Also, understanding the genes and biological pathways that confer genetic resistance to various infections will lead towards the development of more resistant commercial poultry flocks or improved vaccines against various diseases. This chapter shall focus on various factors involved in disease resistance in chicken that interact with the pathogen and provide resistance against the pathogen

Identification of Disalicyloyl Curcumin as a Potential DNA Polymerase Inhibitor for Marek’s Disease Herpesvirus: A Computational Study Using Virtual Screening and Molecular Dynamics Simulations

Marek’s disease virus (MDV) is a highly contagious and persistent virus that causes T-lymphoma in chickens, posing a significant threat to the poultry industry despite the availability of vaccines. The emergence of new virulent strains has further intensified the challenge of designing effective antiviral drugs for MDV. In this study, our main objective was to identify novel antiviral phytochemicals through in silico analysis. We employed Alphafold to construct a three-dimensional (3D) structure of the MDV DNA polymerase, a crucial enzyme involved in viral replication. To ensure the accuracy of the structural model, we validated it using tools available at the SAVES server. Subsequently, a diverse dataset containing thousands of compounds, primarily derived from plant sources, was subjected to molecular docking with the MDV DNA polymerase model, utilizing AutoDock software V 4.2. Through comprehensive analysis of the docking results, we identified Disalicyloyl curcumin as a promising drug candidate that exhibited remarkable binding affinity, with a minimum energy of −12.66 Kcal/mol, specifically targeting the DNA polymerase enzyme. To further assess its potential, we performed molecular dynamics simulations, which confirmed the stability of Disalicyloyl curcumin within the MDV system. Experimental validation of its inhibitory activity in vitro can provide substantial support for its effectiveness. The outcomes of our study hold significant implications for the poultry industry, as the discovery of efficient antiviral phytochemicals against MDV could substantially mitigate the economic losses associated with this devastating disease.Funder: King Saud University, Riyadh, Saudi Arabia; Grant(s): RSPD2023R74

QSAR-driven screening uncovers and designs novel pyrimidine-4,6-diamine derivatives as potent JAK3 inhibitors

This study presents a robust and integrated methodology that harnesses a range of computational techniques to facilitate the design and prediction of new inhibitors targeting the JAK3/STAT pathway. This methodology encompasses several strategies, including QSAR analysis, pharmacophore modeling, ADMET prediction, covalent docking, molecular dynamics (MD) simulations, and the calculation of binding free energies (MM/GBSA). An efficacious QSAR model was meticulously crafted through the employment of multiple linear regression (MLR). The initial MLR model underwent further refinement employing an artificial neural network (ANN) methodology aimed at minimizing predictive errors. Notably, both MLR and ANN exhibited commendable performance, showcasing R2 values of 0.89 and 0.95, respectively. The model's precision was assessed via leave-one-out cross-validation (CV) yielding a Q2 value of 0.65, supplemented by rigorous Y-randomization. , The pharmacophore model effectively differentiated between active and inactive drugs, identifying potential JAK3 inhibitors, and demonstrated validity with an ROC value of 0.86. The newly discovered and designed inhibitors exhibited high inhibitory potency, ranging from 6 to 8, as accurately predicted by the QSAR models. Comparative analysis with FDA-approved Tofacitinib revealed that the new compounds exhibited promising ADMET properties and strong covalent docking (CovDock) interactions. The stability of the new discovered and designed inhibitors within the JAK3 binding site was confirmed through 500 ns MD simulations, while MM/GBSA calculations supported their binding affinity. Additionally, a retrosynthetic study was conducted to facilitate the synthesis of these potential JAK3/STAT inhibitors. The overall integrated approach demonstrates the feasibility of designing novel JAK3/STAT inhibitors with robust efficacy and excellent ADMET characteristics that surpass Tofacitinib by a significant margin

Alleviative effects of pinostrobin against cadmium-induced renal toxicity in rats by reducing oxidative stress, apoptosis, inflammation, and mitochondrial dysfunction

IntroductionCadmium (Cd) is a highly toxic heavy metal that can be found everywhere in the environment and can have harmful effects on both human and animal health. Pinostrobin (PSB) is a bioactive natural flavonoid isolated from Boesenbergia rotunda with several pharmacological properties, such as antiinflammatory, anticancer, antioxidant, and antiviral. This investigation was intended to assess the therapeutic potential of PSB against Cd-induced kidney damage in rats.MethodsIn total, 48 Sprague Dawley rats were divided into four groups: a control, a Cd (5 mg/kg), a Cd + PSB group (5 mg/kg Cd and 10 mg/kg PSB), and a PSB group (10 mg/kg) that received supplementation for 30 days.ResultsExposure to Cd led to a decrease in the activities of catalase (CAT), glutathione reductase (GSR), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), whereas levels of reactive oxygen species (ROS) and malondialdehyde (MDA) increased. Cd exposure also caused a substantial increase in urea, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and creatinine levels. Moreover, a noticeable decline was noticed in creatinine clearance. Moreover, Cd exposure considerably increased the levels of inflammatory indices, including interleukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), nuclear factor kappa-B (NF-kB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) activity. Cd treatment decreased the expression of the antiapoptotic markers (Bcl-2) while increasing the expression of apoptotic markers (Bax and Caspase-3). Furthermore, Cd treatment substantially reduced the TCA cycle enzyme activity, such as alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase. Moreover, mitochondrial electron transport chain enzymes, succinatedehydrogenase, NADH dehydrogenase, cytochrome c-oxidase, and coenzyme Q-cytochrome reductase activities were also decreased following Cd exposure. PSB administration substantially reduced the mitochondrial membrane potential while inducing significant histological damage. However, PSB treatment significantly reduced Cd-mediated renal damage in rats.ConclusionThus, the present investigation discovered that PSB has ameliorative potential against Cd-induced renal dysfunction in rats

Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

This research study describes the development of new small molecules based on 2,4-thiazolidinedione (2,4-TZD) and their aldose reductase (AR) inhibitory activities. The synthesis of 17 new derivatives of 2,4-TZDs hybrids was feasible by incorporating two known bioactive scaffolds, benzothiazole heterocycle, and nitro phenacyl moiety. The most active hybrid (8b) was found to inhibit AR in a non-competitive manner (0.16 µM), as confirmed by kinetic studies and molecular docking simulations. Furthermore, the in vivo experiments demonstrated that compound 8b had a significant hypoglycaemic effect in mice with hyperglycaemia induced by streptozotocin. Fifty milligrams per kilogram dose of 8b produced a marked decrease in blood glucose concentration, and a lower dose of 5 mg/kg demonstrated a noticeable antihyperglycaemic effect. These outcomes suggested that compound 8b may be used as a promising therapeutic agent for the treatment of diabetic complications

Targeting Cancer Stem Cells with Novel 4-(4-Substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thiones

Novel 4-(4-substituted phenyl)-5-(3,4,5-trimethoxy/3,4-dimethoxy)-benzoyl-3,4-dihydropyrimidine-2(1H)-one/thione derivatives (DHP 1–9) were designed, synthesized, characterized and evaluated for antitumor activity against cancer stem cells. The compounds were synthesized in one pot. Enaminones E1 and E2 were reacted with substituted benzaldehydes and urea/thiourea in the presence of glacial acetic acid. The synthesized compounds were characterized by spectral analysis. The compounds were screened in vitro against colon cancer cell line (LOVO) colon cancer stem cells. Most of the compounds were found to be active against side population cancer stem cells with an inhibition of >50% at a 10 μM concentration. Compounds DHP-1, DHP-7 and DHP-9 were found to be inactive. Compound DHP-5 exhibited an in vitro anti-proliferative effect and arrested cancer cells at the Gap 2 phase (G2) checkpoint and demonstrated an inhibitory effect on tumor growth for a LOVO xenograft in a nude mouse experiment

Synthesis and in vivo anti-ulcer evaluation of some novel piperidine linked dihydropyrimidinone derivatives

Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1–18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities. All the active compounds inhibited the formation of gastric ulcers and increased the formation of gastric mucin secretion. Compound 15 was found to be the most potent compound of the series as anti-ulcer agent. Additional experimental studies on lead compound 15 will result in a new class of orally active molecule for anti-ulcer activity

Synthesis of New [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazines and Study of Their Anti-Candidal and Cytotoxic Activities

New triazolothiadiazine derivatives 5a–h were synthesized from 4-amino-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole (3) with substituted aryl hydrazonoyl chlorides 4a–h. The compounds were tested in vitro against eleven Candida species and compared with standard drug ketoconazole. Among these compounds, the compounds bearing p-chlorophenyl 5e, p-methoxyphenyl 5c, phenyl 5a, and p-sulphonamidophenyl 5g substituents on triazolothiadiazine system were found to be the most effective derivatives against Candida species. Compound 5e was the most effective compound against C. parapsilosis (ATCC 22019), C. albicans (ATCC 66027), C. specie [blood] 12810, and C. specie [urine] 300 with MIC value of 6.25 μg/mL, whereas ketoconazole exhibits the inhibitory activity with MIC value of 3–30 μg/mL against all tested strains. It was clear that there is a positive correlation between anti-Candidal activity and p-chlorophenyl substitution on triazolothiadiazine ring. All the synthesized compounds were also investigated for their potential cytotoxicity on noncancer cell line (MCF-12) using WST-1 assay. Three compounds 5d, 5a, and 5h were found to have the same IC50 value as that of standard drug ketoconazole against noncancer cell line MCF-12 (IC50 ≥ 1.0 × 105 μg/mL)