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Nagla A El-Shitany,1,2 Steve Harakeh,3 Shaimaa M Badr-Eldin,4,5 Amina M Bagher,1 Basma Eid,1 Haifa Almukadi,1 Badrah S Alghamdi,6 Ahlam A Alahmadi,7 Nibal A Hassan,8 Nariman Sindi,9 Samar A Alghamdi,10 Hailah M Almohaimeed,11 Zuhair M Mohammedsaleh,12 Turki M Al-Shaikh,13 Mohammed S Almuhayawi,14 Soad S Ali,15 Manal El-Hamamsy16,17 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta, Egypt; 3Special Infectious Agents Unit, King Fahd Medical Research Center, Yousef Abdullatif Jameel Chair of Prophetic Medicine Application, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 4Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 5Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt; 6Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 7Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia; 8Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia; 9Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia; 10Department of Oral Biology, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia; 11Department of Basic Science, Faculty of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; 12Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, Saudi Arabia; 13Department of Biology, College of Science and Arts at Khulis, University of Jeddah, Jeddah, Saudi Arabia; 14Department of Microbiology and Medical Parasitology, Faculty of Medicine, King Abdulaziz University, Jeddah, 21589, Saudi Arabia; 15Department of Histology, Faculty of Medicine, Assiut University, Assiut, Egypt; 16Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 17Department of Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, EgyptCorrespondence: Nagla A El-ShitanyDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Al-Sheekh Kamal Street, Alsulimaniah, Jeddah, Saudi ArabiaTel +966 545923440Email nagla_fouad@yahoo.comBackground: The Pfizer-BioNTech COVID-19 vaccine has recently received emergency approval from the US FDA. The mRNA technology was used to manufacture the Pfizer vaccine; however, as a pioneering technology that has never been used in the manufacture of vaccines, many people have concerns about the vaccine’s side effects. Thus, the current study aimed to track the short-term side effects of the vaccine.Methods: The information in this study was gathered by a Google Form-questionnaire (online survey). The results included the responses of 455 individuals, all of whom are Saudi Arabia inhabitants. Adverse effects of the vaccine were reported after the first and the second doses.Results: The most common symptoms were injection site pain, headaches, flu-like symptoms, fever, and tiredness. Less common side effects were a fast heartbeat, whole body aches, difficulty breathing, joint pain, chills, and drowsiness. Rare side effects include Bell’s palsy and lymph nodes swelling and tenderness. Flu-like symptoms were more common among those under 60 years of age, while injection site pain was more frequent among recipients who were 60 years and older. The study revealed a significant increase in the number of females who suffered from the vaccine side effects compared to males. Difficulty of breathing was more reported among recipients who had been previously infected with the coronavirus compared to those who had not been previously infected.Conclusion: Most of the side effects reported in this study were consistent with Pfizer’s fact sheet for recipients and caregivers. Further studies are required to determine the long-term side effects.Keywords: Pfizer-BioNTech COVID-19 vaccine, side effects, injection site pain, hypersensitivity, flu-like symptoms, online survey

Producing recombinant proteins in plants has become a valuable alternative to traditional microbial or mammalian systems due to its cost-effectiveness, scalability, and ability to perform post-translational modifications. This study investigates the use of the Tobacco Mosaic Virus (TMV)-based vector system for producing the Dengue virus serotype 3 (DENV-3) envelope domain III (EDIII) protein in plants.. A fragment of the gene that encodes domain III of the dengue 3 envelope protein (D3EIII, comprising 300-420 amino acids), was effectively expressed within Nicotiana tabacum plants utilizing a transient expression system based on tobacco mosaic virus (TMV). The N-terminal 5' UTR region upstream of D3EIII notably enhanced protein yield in infected tissues. The produced recombinant protein exhibited reactivity with both (anti) D3EIII polyclonal antibodies and antibodies of anti-His tag. Upon injection of EDIII in mice, it stimulated the generation of antibodies against the dengue-specific virus. The induced antibodies demonstrated neutralizing activity against dengue virus type 3. These findings indicate that the TMV expression system is effective for producing dengue virus antigens in plants, resulting in antigens with appropriate properties and strong immunogenic potential.

Background: The growth arrest and DNA damage-inducible 45 (Gadd45) gene has been implicated in various central nervous system (CNS) functions, both normal and pathological, including aging, memory, and neurodegenerative diseases. In this study, we examined whether Gadd45A deletion triggers pathways associated with neurodegenerative diseases including Alzheimer's disease (AD)., Methods: Utilizing transcriptome data from AD-associated hippocampus samples, we identified Gadd45A as a pivotal regulator of autophagy. Comprehensive analyses, including Gene Ontology enrichment and protein-protein interaction network assessments, highlighted Cdkn1A as a significant downstream target of Gadd45A. Experimental validation confirmed Gadd45A's role in modulating Cdkn1A expression and autophagy levels in hippocampal cells. We also examined the effects of autophagy on hippocampal functions and proinflammatory cytokine secretion. Additionally, a murine model was employed to validate the importance of Gadd45A in neuroinflammation and AD pathology., Results: Our study identified 20 autophagy regulatory factors associated with AD, with Gadd45A emerging as a critical regulator. Experimental findings demonstrated that Gadd45A influences hippocampal cell fate by reducing Cdkn1A expression and suppressing autophagic activity. Comparisons between wild-type (WT) and Gadd45A knockout (Gadd45A -/- ) mice revealed that Gadd45A -/- mice exhibited significant cognitive impairments, including deficits in working and spatial memory, increased Tau hyperphosphorylation, and elevated levels of kinases involved in Tau phosphorylation in the hippocampus. Additionally, Gadd45A -/- mice showed significant increases in pro-inflammatory cytokines and decreases autophagy markers in the brain. Neurotrophin levels and dendritic spine length were also reduced in Gadd45A -/- mice, likely contributing to the observed cognitive deficits., Conclusions: These findings support the direct involvement of the Gadd45A gene in AD pathogenesis, and enhancing the expression of Gadd45A may represent a promising therapeutic strategy for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cardiovascular complications are prevalent manifestations of type 2 diabetes mellitus (T2DM) and are usually the main cause of death. This study aims to show the underlying mechanisms of the potential therapeutic effect of mesenchymal stem cells (MSCs) on diabetic cardiac dysfunction. Twenty-four male Wistar rats were randomly assigned to one of three groups The control group received standard laboratory chow, and the groups with T2DM received a single dose of 45 mg/kg body weight of streptozotocin (STZ) after 3 weeks of pretreatment with a high-fat diet (HFD). Eight weeks after the diagnosis of T2DM, rats were divided into two groups: the T2DM model group and the T2DM + MSCs group. BM-MSCs were administered systemically at 2 × 10 6  cells/rat doses. A Significant amelioration in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and dyslipidemia was noted 2 weeks post-administration of MSCs. Administration of MSCs improved dyslipidemia, the altered cardiac injury biomarkers (p ≤ 0.0001), downregulated Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3)/inducible Nitric oxide synthase (iNOS) and iNOS/Apoptosis signaling pathways. This was associated with improved cardiac dysfunction (impaired left ventricular performance and decreased contractility index). Our results show that MSCs ameliorate cardiac dysfunction associated with diabetic cardiomyopathy by lowering dyslipidemia and insulin resistance, inhibiting oxidative stress, and inflammation, downregulating JAK2/STAT3/iNOS and iNOS/Apoptosis signaling pathways., Competing Interests: Declaration of competing interest I declare that I have no conflicts of interest relevant to this work." The authors declare that they have no financial or non-financial conflicts of interest related to this research." The authors report no conflicts of interest in this work. The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rotavirus, a dsRNA virus in the Reoviridae family, shows a segmented genome. The VP1 gene encodes the RNA-dependent RNA polymerase (RdRp). This study aims to develop a multiepitope-based vaccine targeting RdRp using immunoinformatic approaches. In this study, 100 available nucleotide sequences of VP1-Rotavirus belonging to different strains across the world were retrieved from NCBI database. The selected sequences were aligned, and a global consensus sequence was developed by using CLC work bench. The study involved immunoinformatic approaches and molecular docking studies to reveal the promiscuous epitopes that can be eventually used as active vaccine candidates for Rotavirus. In total, 27 highly immunogenic, antigenic, and non-allergenic T-cell and B-cell epitopes were predicted for the Multiepitope vaccine (MEV) against rotavirus. It was also observed that MEV can prove to be effective worldwide due to its high population coverage, demonstrating the consistency of this vaccine. Moreover, there is a high docking interaction and immunological response with a binding score of -50.2 kcal/mol, suggesting the vaccine's efficacy. Toll-like receptors (TLRs) also suggest that the vaccine is physiologically and immunologically effective. Collectively, our data point to an effective MEV against rotavirus that can effectively reduce viral infections and improve the health status worldwide.

Purpose: Co-administration of microRNAs and chemotherapy drugs effectively treats several cancers. The current study sought to investigate the function of matrix metalloproteinase 16 (MMP16) and miR-193a-5p in the pathogenesis of gastric cancer (GC)., Materials/methods: Sixty-five surgical patients, 15 receiving 5-fluorouracil (5-FU), provided GC and adjacent non-cancerous tissue. Following that, qPCR was used to assess the expression levels of MMP16 and miR-193a-5p in GC cells. The impact of miR-193a-5p and 5-FU administration on MMP16 mRNA expression was evaluated using qRT-PCR and Western blotting. MTT and Scratch tests were also conducted to assess their effects on cell viability and migration. Moreover, a rescue experiment using an MTT assay was performed. Using flow cytometry, the apoptotic rate was calculated. Finally, it was evaluated how MMP16 and miR-193a-5p related to the clinicopathological characteristics of the patients., Results: The current study found that while MMP16 expression increased in GC patients (P ​< ​0.0001), miR-193a-5p expression significantly decreased (P ​< ​0.001). MMP16 down-regulation was another effect of miR-193a-5p replacement, particularly when 5-FU was added (P ​< ​0.01). In addition, this study found that miR-193a-5p, by concentrating on MMP16, decreased the migration of GC cells brought on by MMP16. In GC cell lines, miR-193 and 5-FU induce apoptosis, with the 5-FU being more pronounced when combined with mir-193, according to flow cytometry results. A strong correlation was also found between clinicopathological traits associated with MMP16 and miR-193a-5p., Conclusions: These findings suggest that miR-193a-5p, in conjunction with 5-FU, down-regulates MMP16 in GC, where it suppresses tumor growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Diabetic wounds require a multifactorial approach because several factors are involved in its occurrence. Herein we investigated whether transplantation of hyaluronic acid (HA) in combination with menstrual blood derived stem cells (MenSCs) could promote healing in diabetic rats. Thirty days after induction of diabetes, sixty animals were randomly planned into four equal groups: the untreated group, HA group, MenSC group, and HA+MenSC group. Sampling was done for histological, molecular, and tensiometrical assessments. Our results indicated that the wound contraction rate, volumes of new epidermis and dermis, collagen density, as well as tensiometrical parameter were considerably increased in the treatment groups compared to the untreated group and these changes were more obvious in the HA+MenSC ones. In addition, the expression levels of TGF-β and VEGF genes were significantly upregulated in treatment groups in comparison with the untreated group and were greater in the HA+MenSC group. This is while expression levels of TNF-α and IL-1β genes were more considerably downregulated in the HA+MenSC group than the other groups. We concluded that the combined use of HA and MenSCs has more effects on diabetic wound healing., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest associated with this study., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Diabetic retinopathy (DR) stands as a prevalent secondary complication of diabetes, notably Type 1 Diabetes Mellitus (T1D), characterized by immune system involvement potentially impacting the retinal immune response mediated by microglia. Early stages of DR witness blood-retinal barrier permeabilization, facilitating peripheral immune cell interaction with the retinal immune system. Kaempferol (Kae), known for its potent anti-inflammatory activity, presents a promising avenue in DR treatment by targeting the immune mechanisms underlying its onset and progression. Our investigation delves into the molecular intricacies of innate immune cell interaction during DR progression and the attenuation of inflammatory processes pivotal to its pathology., Methods: Employing in vitro studies, we exposed HAPI microglial and J774.A1 macrophage cells to pro-inflammatory stimuli in the presence or absence of Kae. Ex vivo and in vivo experiments utilized BB rats, a T1D animal model. Retinal explants from BB rats were cultured with Kae, while intraperitoneal Kae injections were administered to BB rats for 15 days. Quantitative PCR, Western blotting, immunofluorescence, and Spectral Domain - Optical Coherence Tomography (SD-OCT) facilitated survival assessment, cellular signaling analysis, and inflammatory marker determination., Results: Results demonstrate Kae significantly mitigates inflammatory processes across in vitro, ex vivo, and in vivo DR models, primarily targeting immune cell responses. Kae administration notably inhibits proinflammatory responses during DR progression while promoting an anti-inflammatory milieu, chiefly through microglia-mediated synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). In vivo, Kae administration effectively preserves retinal integrity amid DR progression., Conclusions: Our findings elucidate the interplay between retinal and systemic immune cells in DR progression, underscoring a differential treatment response predominantly orchestrated by microglia's anti-inflammatory action. Kae treatment induces a phenotypic and functional shift in immune cells, delaying DR progression, thereby spotlighting microglial cells as a promising therapeutic target in DR management., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181., Methods: The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis., Results: The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group ( p  < 0.01). The expression levels of IL-1β and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL ( p  < 0.001)., Conclusion: Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Almohaimeed, Almars, Alsulaimani, Basri, Althobaiti, Albalaw, Alsharif, Al Abdulmonem, Hershan and Soliman.)

Background: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied., Methods: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg., Results: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and β-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO 2 and neuronal cytokines TNF-α and IL-1β and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels., Conclusion: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2 years. The B.1.1.529 strain, later called "Omicron," was named a Variant of Concern on November 24, 2021. The SARS-CoV-2 virus has gone through a never-ending chain of changes that have never happened before. As a result, it has many different traits. Most of these changes have occurred in the spike protein, where antibodies bind. Because of these changes, the Omicron type is very contagious and easy to pass on. There have been a lot of studies done to try to figure out this new challenge in the COVID-19 strains race, but there is still a lot that needs to be explained. This study focuses on virtual screening, docking, and molecular dynamic analysis; we aimed to identify therapeutic candidates for the SARS-CoV-2 variant Omicron based on their ability to inhibit non-structural proteins. We investigate the prediction of the properties of a substantial database of drug molecules obtained from the OliveNet™ database. Compounds that did not exhibit adequate gastrointestinal absorption and failed the Lipinski test are not considered for further research. The filtered compounds were coupled with our primary target, SARS-CoV-2 Omicron spike protein. We focused on SARS-CoV-2 Omicron spike protein and filtering potent olive compounds. Pinoresinol, the most likely candidate, is bound best (- 8.5 kcal/mol). Pinoresinol's strong interaction with the active site made the complex's dynamic structure more resilient. MD simulations explain the protein-ligand complex's stability and function. Pinoresinol may be a promising SARS-CoV-2 Omicron spike protein receptor lead drug, and additional research may assist the scientific community., (© 2023. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)

A serine protease called prolyl endopeptidase (PEP) hydrolyses the peptide bonds on the carboxy side of the proline ring. The excessive PEP expression in brain results in neurodegenerative illnesses like dementia, Alzheimer's disease, and Parkinson's disease. Results of the prior studies on antioxidant activity, and the non-cytotoxic effect of bi-carbazole-linked triazoles, encouraged us to extend our studies towards its anti-diabetic potential. Hence, for this purpose all compounds 1-9 were evaluated to reveal their anti-prolyl endo peptidase activity. Fortunately, seven compounds resulted into significant inhibitory capability ranging from 26 to 63 µM. Among them six compounds 4-9 exhibited more potent inhibitory activity with IC 50 values 46.10 ± 1.16, 42.30 ± 1.18, 37.14 ± 1.21, 26.29 ± 0.76, 28.31 ± 0.64 and 31.11 ± 0.84 µM respectively, while compound 3 was the least active compound in the series with IC 50 value 63.10 ± 1.58 µM comparing with standard PEP inhibitor bacitracin (IC 50  = 125 ± 1.50 µM). Moreover, mechanistic study was performed for the most active compounds 7 and 8 with K i values 24.10 ± 0.0076 and 23.67 ± 0.0084 µM respectively. Further, the in silico studies suggested that the compounds exhibited potential interactions and significant molecular conformations, thereby elucidating the structural basis for their inhibitory effects., (© 2024. The Author(s).)

The objective of this study was to evaluate various wheat supplementation levels on rumen microbiota and fermentation parameter in Tibetan sheep. A total of ninety ram with an average 12.37 ± 0.92 kg at the age of 2 months were randomly allocated to three treatments: 0% wheat diet (CW, N = 30), 10% wheat diet (LW, N = 30), and 15% wheat diet (HW, N = 30) on a dry matter basis. The experiment was conducted over a period of 127 days, including 7 days of adaption to the diets. Our results showed that sheep fed 10% wheat exhibited optimal average daily gain and feed gain ratio compared with HW group (p < 0.05). The serum alkaline phosphatase concentration was the lowest when fed the 10% wheat diet (p < 0.05), whereas serum aspartate aminotransferase concentration was the highest (p < 0.05). Both acetate and propionate increased with increase in dietary wheat ratio (p < 0.05), while a greater decrease in concentrations of NH 3 -N was observed (p < 0.05). In rumen fluid, 3413 OTUs were obtained with 97% consistency. Phylum Firmicutes was the predominant bacteria and accounted for 49.04%. The CW groups supported significantly increased the abundance of Bacteroidetes (p < 0.05), as compared with the HW group. The abundance of Bacteroidales&#95;UCG-001, Ruminococcus, and Mitsuokella possessed a higher relative abundance in HW group (p < 0.05). No differences in the bacterial community and fermentation parameters were observed between the sheep fed 0% and 10% wheat (p > 0.05). Ruminal bacterial community structure was significantly correlated with isobutyrite (r 2  = 0.4878, p = 0.035) and valerate (r 2  = 0.4878, p = 0.013). In conclusion, supplementation of 10% wheat in diet promoted the average daily gain and never altered microbial community structure and fermentation pattern, which can be effectively replace partial corn in Chinese Tibetan Sheep., (© 2023 Wiley-VCH GmbH. Published by John Wiley & Sons Ltd.)

Melanoma, a highly invasive type of skin cancer that penetrates the entire dermis layer, is associated with increased mortality rates. Excessive exposure of the skin to sunlight, specifically ultraviolet radiation, is the underlying cause of this malignant condition. The appearance of unique skin moles represents a visible clue, referred to as the "ugly duckling" sign, indicating the presence of melanoma and its association with cellular DNA damage. This research aims to explore potential biomarkers derived from microarray data, employing bioinformatics techniques and methodologies, for a thorough investigation of melanoma skin cancer. The microarray dataset for melanoma skin cancer was obtained from the GEO database, and thorough data analysis and quality control measures were performed to identify differentially expressed genes (DEGs). The top 14 highly expressed DEGs were identified, and their gene information and protein sequences were retrieved from the NCBI gene and protein database. These proteins were further analyzed for domain identification and network analysis. Gene expression analysis was conducted to visualize the upregulated and downregulated genes. Additionally, gene metabolite network analysis was carried out to understand the interactions between highly interconnected genes and regulatory transcripts. Molecular docking was employed to investigate the ligand-binding sites and visualize the three-dimensional structure of proteins. Our research unveiled a collection of genes with varying expression levels, some elevated and others reduced, which could function as promising biomarkers closely linked to the development and advancement of melanoma skin cancer. Through molecular docking analysis of the GINS2 protein, we identified two natural compounds (PubChem-156021169 and PubChem-60700) with potential as inhibitors against melanoma. This research has implications for early detection, treatment, and understanding the molecular basis of melanoma., (© 2023. The Author(s), under exclusive licence to Institute of Plant Genetics Polish Academy of Sciences.)

Uranyl acetate (UA) is used in civilian and military applications, predisposing it to wide dispersion in ecosystems. Using high-performance liquid chromatography, gas chromatography-mass spectrometry, and 2,2-Diphenyl-1-picrylhydrazyl scavenging radical analysis, we confirmed that Moringa oleifera leaf ethanolic extract (MLEE) is rich in biologically active phytochemicals. Thus, this study aims to investigate the possible defensive effect of MLEE against UA-induced testicular dysfunction. To achieve this, rats were divided randomly and evenly into three groups for 14 days. The control group received no treatment, while the UA group received a single intraperitoneal injection of UA at a dose of 5 mg/kg BW dissolved in saline on the 12th day of the experiment, followed by no treatment the following day. The MLEE + UA group received daily oral administration of MLEE (300 mg/kg BW) dissolved in distilled water before exposure to UA intoxication. The disruption observed in the pituitary-gonadal axis of UA-intoxicated rats was characterized by a significant decrease in luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol 17beta levels. Additionally, there was a notable increase in malondialdehyde and a decrease in catalase, superoxide dismutase, reduced glutathione, and nitric oxide, accompanied by an up-regulation in the immuno-expression of nuclear factor-kappa B, indicating a disturbance in the redox balance. The TUNEL assay confirmed a substantial rise in apoptotic cell numbers in the UA group. Testicular histopathological changes, excessive collagen deposition, and reduced glycogen content were evident following UA exposure. However, supplementation with MLEE effectively countered these mentioned abnormalities. MLEE is proposed to combat the toxicological molecular targets in the UA-affected testis by restoring the balance between oxidants and antioxidants while obstructing the apoptotic cascade. MLEE contains an abundance of redox-stabilizing and cytoprotective phytochemicals that have the potential to counteract the mechanistic pathways associated with UA exposure. These findings encourage further research into other plausible protective aspects of Moringa oleifera against the UA challenge., (© 2024. The Author(s).)

Neuro-oncological and neurodegenerative disorders, represented paradigmatically by glioblastoma and Alzheimer's disease, respectively, persist as formidable challenges in the biomedical realm. The interconnected molecular underpinnings of these conditions necessitate rigorous and novel therapeutic examinations. This comprehensive research was anchored on the premise of unveiling the therapeutic potential and specificity of Lupenone, a potent phytoconstituent, in targeting the molecular pathways underpinning both glioblastoma and Alzheimer's amyloid beta pathology. This was gauged through its interactions with key protein structures, 5H08 and 2ZHV. An integrative approach was adopted, marrying advanced proteomics and modern computer-aided drug design techniques. Molecular docking of Lupenone with 5H08 and 2ZHV was meticulously executed, with subsequent molecular dynamics simulations providing insights into the stability, viability, and intricacies of these interactions. Lupenone demonstrated profound binding affinities, evidenced by robust docking scores of -9.54 kcal/mol for 5H08 and -10.59 kcal/mol for 2ZHV. These interactions underscored Lupenone's eminent therapeutic potential in mitigating glioblastoma and modulating the amyloid beta pathology inherent to Alzheimer's. The introduction of Proteolysis Targeting Chimeras (PROTACs) further magnified the therapeutic prospects, accentuating Lupenone's efficacy. The findings of this study not only underscore the therapeutic acumen of Lupenone in addressing the challenges posed by glioblastoma and Alzheimer's but also lay a strong foundation for its consideration as a leading candidate in future neuro-oncological and neurodegenerative research endeavors. Given the compelling in-silico data, a clarion call is made for its empirical validation in holistic in-vivo settings, potentially pioneering a new therapeutic epoch in both glioblastoma and Alzheimer's interventions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ebola virus (EBOV) poses a severe threat as a highly infectious pathogen, causing devastating hemorrhagic fever in both humans and animals. The EBOV virus VP35 protein plays a crucial role in viral replication and exhibits the ability to suppress the host interferon cascade, leading to immune system depletion. As a potential drug target, VP35 protein inhibition holds promise for combating EBOV. To discover new drug candidates, we employed a computer-aided drug design approach, focusing on compounds capable of inhibiting VP35 protein replication. In this connection, a pharmacophore model was generated using molecular interactions between the VP35 protein and its inhibitor. ZINC and Cambridge database were screened using validated pharmacophore model. Further the compounds were filtered based on Lipinski's rule of five and subjected to MD simulation and relative binding free energy calculation. Six compounds manifest a significant docking score and strong binding interaction towards VP35 protein. MD simulations further confirmed the remarkable stability of these six complexes. Relative binding free energy calculations also showed significant Δ G value in the range of -132.3 and -49.3 kcal/mol. This study paves the way for further optimization of these compounds as potential inhibitors of VP35, facilitating subsequent experimental in vitro studies.Communicated by Ramaswamy H. Sarma.

This study aimed to understand the influence of the non-genetic factors that include breeding year, season, and sex of growth and development traits of Qinchuan cattle and to estimate the heritability of body weight at different growth stages. The Qinchuan cattle measurement records were by the Experiment farm of the National Beef Cattle Improvement Center (Yangling, China) from 2000 to 2017. SPSS and R software were used to analyze the influence of non-genetic factors on body size traits that include body weight (BW), withers height (WH), hip height (HH), body length (BL), chest circumference (CC), abdominal girth (AG), and calf girth (CG), at birth, 6, 12, 18, and 24 months of age. Meanwhile, the single-trait animal model of DMU software was used to estimate the variance component and the heritability of body weight. The results of GLM analysis showed as follows: sex, birth year, and birth season had effects on the body size traits of Qinchuan cattle at different growth stages. Respectively, the heritability of body weight at birth, 6, 12, 18, and 24 months of age were 0.43, 0.32, 0.37, 0.32, and 0.38.

Methotrexate (MTX) is a chemotherapeutic agent widely used to treat a variety of tumors. Nonetheless, MTX-induced hippocampal neurotoxicity is a well-defined dose-limiting adverse effect that limits clinical utility. Proinflammatory cytokine production and oxidative stress are possible mechanisms for MTX-induced neurotoxicity. Buspirone (BSP), a partial agonist of the 5-HT1a receptor (5-HT1aR), has emerged as an anxiolytic drug. BSP has been shown to possess antioxidant and anti-inflammatory effects. The current study investigated BSP's potential anti-inflammatory and antioxidant effects in attenuating MTX-induced hippocampal toxicity. Rats received either BSP (1.5 mg/kg) orally for 10 days and MTX (20 mg/kg) i.p. on Day 5. BSP administration markedly protected hippocampal neurons from drastic degenerated neuronal changes induced by MTX. BSP significantly attenuated oxidative injury by downregulating Kelch-like ECH-associated protein 1 expression while potently elevating hippocampal Nrf2, heme oxygenase-1, and peroxisome proliferator-activated receptor expression. BSP dampened inflammation by reducing NO 2 - , tumor necrosis factor-alpha, IL-6, and interleukin 1 beta levels mediated by downregulating NF-κB and neuronal nitric oxides synthase expression. Moreover, BSP potently counteracted hippocampal pyroptosis by downregulating NLRP3, ASC, and cleaved-caspase-1 proteins. Therefore, BSP may represent a promising approach to attenuate neurotoxicity in patients receiving MTX., (© 2023 Wiley Periodicals LLC.)

Monoamine oxidase (MAO, EC 1.4.3.4) is responsible for the oxidative breakdown of both endogenous and exogenous amines and exists in MAO-A and MAO-B isomers. Eighteen indole-based phenylallylidene derivatives were synthesized via nucleophilic addition reactions comprising three sub-series, IHC , IHMC , and IHNC , and were developed and examined for their ability to inhibit MAO. Among them, compound IHC3 showed a strong MAO-B inhibitory effect with an IC 50 ( half-maximal inhibitory concentration ) value of 1.672 μM, followed by IHC2 (IC 50 = 16.934 μM). Additionally, IHC3 showed the highest selectivity index (SI) value of >23.92. The effectiveness of IHC3 was lower than the reference pargyline (0.14 μM); however, the SI value was higher than pargyline (17.16). Structurally, the IHC (-H in the B-ring) sub-series exhibited relatively stronger MAO-B inhibition than the others. In the IHC series, IHC3 (-F in the A-ring) exhibited stronger MAO-B suppression than the other substituted derivatives in the order -F > -Br > -Cl > -OCH 3 , -CH 3 , and -H at the 2-position in the A-ring. In the reversibility and enzyme kinetics experiments, IHC3 was a reversible inhibitor with a K i value of 0.51 ± 0.15 μM for MAO-B. Further, it was observed that IHC3 greatly decreased the cell death caused by rotenone in SH-SY5Y neuroblastoma cells. A molecular docking study of the lead molecule was also performed to determine hypothetical interactions in the enzyme-binding cavity. These findings suggest that IHC3 is a strong, specific, and reversible MAO-B inhibitor that can be used to treat neurological diseases.

A growing amount of evidence in the last few years has begun to unravel that non-coding RNAs have a myriad of functions in gene regulation. Intensive investigation on non-coding RNAs (ncRNAs) has led to exploring their broad role in neurodegenerative diseases (NDs) owing to their regulatory role in gene expression. RNA sequencing technologies and transcriptome analysis has unveiled significant dysregulation of ncRNAs attributed to their biogenesis, upregulation, downregulation, aberrant epigenetic regulation, and abnormal transcription. Despite these advances, the understanding of their potential as therapeutic targets and biomarkers underpinning detailed mechanisms is still unknown. Advancements in bioinformatics and molecular technologies have improved our knowledge of the dark matter of the genome in terms of recognition and functional validation. This review aims to shed light on ncRNAs biogenesis, function, and potential role in NDs. Further deepening of their role is provided through a focus on the most recent platforms, experimental approaches, and computational analysis to investigate ncRNAs. Furthermore, this review summarizes and evaluates well-studied miRNAs, lncRNAs and circRNAs concerning their potential role in pathogenesis and use as biomarkers in NDs. Finally, a perspective on the main challenges and novel methods for the future and broad therapeutic use of ncRNAs is offered., Competing Interests: Competing Interests The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The objective of this study was to evaluate the effect of the level of wheat substitution for corn on the fat metabolism of Tibetan lamb. A total of 90 Tibetan lambs [body weight (BW) of 19.78 ± 2.45 kg] were arranged with three substitution levels of wheat: WC (100 % corn), WL (10 % wheat substitution for corn), and WH (15 % wheat substitution for corn) on a dry matter basis. After the experiment, cry section technology was used to scrutinize the subcutaneous adipose tissue morphology, and genes related to fat metabolism were excavated using high-throughput sequencing technology. According to the study results, fat diameter and fat biovolume of the WL and WH groups were less than the WC group. A total of 506 differentially expressed genes (DEGs) were identified by RNA sequencing (RNA-Seq) technology. Compared with the WC group, 66 DEGs were upregulated and 59 DEGs were downregulated in the WL group, and 179 DEGs were upregulated and 269 DEGs were downregulated in the WH group. The top 20 DEGs were analyzed by Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathway, indicating significant differences in the fat metabolism pathway. Five DEGs were randomly screened for quantitative reverse transcription-polymerase chain reaction (qRT-PCR) verification, and the results were consistent with the RNA-Seq results, which proved the accuracy of sequencing. In summary, with the increase in the proportion of supplemental wheat, the fat cells became smaller, and the genes related to fat decomposition were significantly upregulated., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As an important downstream effector gene in the hippo signaling pathway, large tumor suppressor gene 2 (LATS2) is involved in cell proliferation and differentiation, organ size and tissue regeneration, and plays an important role in regulating the growth and development of animal muscles. The purpose of this study is to explore the temporal expression of bovine LATS2 gene, and determine the key transcription factors for regulating bovine LATS2 gene. The result showed that bovine LATS2 gene was highly expressed in liver and longissimus dorsi, and was up-regulated in infancy muscle. In addition, it was highly expressed on the 2th day during the differentiation stage of myoblast. The upstream 1.7 Kb sequence of the 5 'translation region of bovine LATS2 gene was cloned, and 7 different deletion fragments were amplified by the upstream primers. These fragments were constructed into double luciferase reporter vectors and transfected into myoblasts and myotubes cells, respectively to detect the core promoter regions. In addition, the key transcription factors of the core promoter sequence of the bovine LATS2 gene were analyzed and predicted by online software. Combining with site-directed mutations, siRNA interference and chromatin immunoprecipitation technology, it was identified that MEF2A and MyoG combined in core promoter region (-248/-56) to regulate the transcription activity of bovine LATS2 gene. The results have laid a theoretical foundation for exploring the molecular regulation mechanism of LATS2 gene in the process of muscle growth., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Bromobenzene (BB) is a hazardous environmental contaminant because of its multiple routes of exposure and the toxicity of its bio-derivates. It could elicit neuronal alterations by stimulating redox imbalance and apoptotic pathways. Gum Arabic (GA) protected the hippocampus of a type 2 diabetic rat model from cognitive decline. Whether gum Arabic nanoemulsion (GANE) can increase the neuroprotectant potency of GA in fighting BB-associated neurological lesions is the question to be answered. To accomplish this objective, 25 adult male Wistar rats were randomly and equally assigned into five groups. Control received olive oil (vehicle of BB). BB group received BB at a dose of 460 mg/kg BW. Blank nanoemulsion (BNE) group supplemented with BNE at 2 mL of 10% w/v aqueous suspension/kg BW. GANE group received GANE at a dose of 2 mL of 10% w/v aqueous suspension/kg BW. BB + GANE group exposed to BB in concomitant with GANE at the same previous doses. All interventions were carried out daily by oral gavage for ten consecutive days. BB caused a marked increase in malondialdehyde and succinate dehydrogenase together with a marked decrease in reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase, and lactate dehydrogenase in the brain. BB was accompanied by pathological deteriorations, amyloidosis, and reduced immuno-expression of integrase interactor 1 in the hippocampal region. Administration of GANE was beneficial in reversing the aforementioned abnormalities. These results pave the road for further discovery of nano-formulated natural products to counter the threats of BB., (© 2022. The Author(s).)

Background: Hypothyroidism has been linked to many testicular structural and dysfunctional changes in males. Thymoquinone (TQ) has shown a potent testicular protective effect through its antioxidant, anti-inflammatory, antiapoptotic, fertility-enhancing, and endocrine modulatory activities. Objectives: This study aimed to investigate the efficacy of TQ in preserving the testicular structure of a model of experimentally induced hypothyroidism in rats and identify the mechanism behind this effect. Materials and methods: Propylthiouracil (PTU) was used to induce hypothyroidism in adult male Wistar rats, who were then treated with TQ (50 mg/kg/body weight) for 4 weeks and compared to the untreated rats. Thyroid hormonal profile, oxidants/antioxidants profile, and serum testosterone levels were assessed. Gene expression and immune expression of SIRT1 and pro-inflammatory cytokines TNF-α and NF-κB were also assessed in the testicular tissue. Results: TQ administration successfully improved PTU-induced disturbance in the thyroid hormonal profile (T3, T4, and TSH), serum testosterone level, and pancreatic antioxidants compared to the untreated hypothyroid group. TQ significantly downregulated ( p = 0.001, p ˂ 0.001) TNF-α and NF-κB transcription, while it significantly upregulated ( p = 0.01) SIRT1 transcription in the testes of hypothyroid rats. TQ markedly relieved the histopathological testicular changes induced by PTU and significantly increased ( p = 0.002, p = 0.01) the sectional area of seminiferous tubules and germinal epithelial height, respectively. TUNEL-positive apoptotic germinal cells were significantly decreased ( p ˂ 0.001), while PCNA-positive proliferating germinal cells and androgen receptor expression were significantly increased ( p ˂ 0.001) in the testes of TQ-treated hypothyroid rats. Conclusion: Thymoquinone could limit the hypothyroidism-induced structural changes in the testis, mostly through the upregulation of SIRT1 expression, which seems to mediate its promising antioxidant, anti-inflammatory and antiapoptotic effects that were evident in this study. Therefore, TQ is recommended as an adjuvant safe supplement in managing hypothyroidism, especially in males., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Algaidi, Faddladdeen, Alrefaei, Qahl, Albadawi, ALmohaimeed and Ayuob.)

Due to the demand for high-quality animal protein, there has been consistent interest in how to obtain more high-quality beef. As well-known, the adipose content of beef has a close connection with the taste and quality of beef, and cattle with different energy or protein diet have corresponding effects on the lipid metabolism of beef. Thus, we performed weighted gene co-expression network analysis (WGCNA) with subcutaneous adipose genes from Norwegian red heifers fed different diets to identify hub genes regulating bovine lipid metabolism. For this purpose, the RNA sequencing data of subcutaneous adipose tissue of 12-month-old Norwegian red heifers ( n = 48) with different energy or protein levels were selected from the GEO database, and 7,630 genes with the largest variation were selected for WGCNA analysis. Then, three modules were selected as hub genes candidate modules according to the correlation between modules and phenotypes, including pink, magenta and grey60 modules. GO and KEGG enrichment analysis showed that genes were related to metabolism, and participated in Rap, MAPK, AMPK, VEGF signaling pathways, and so forth. Combined gene interaction network analysis using Cytoscape software, eight hub genes of lipid metabolism were identified, including TIA1, LOC516108, SNAPC4, CPSF2, ZNF574, CLASRP, MED15 and U2AF2 . Further, the expression levels of hub genes in the cattle tissue were also measured to verify the results, and we found hub genes in higher expression in muscle and adipose tissue in adult cattle. In summary, we predicted the key genes of lipid metabolism in the subcutaneous adipose tissue that were affected by the intake of various energy diets to find the hub genes that coordinate lipid metabolism, which provide a theoretical basis for regulating beef quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Raza, Deng, Ma, Qu, Yu, Zhang, Alshammari, Almohaimeed and Zan.)

Noncoding RNAs, such as long noncoding RNAs (lncRNAs), are abundant in livestock. Many lncRNAs that affect the growth rate of livestock have been identified in muscles. However, some of their physiological functions and regulatory mechanisms remain unclear. In this study, we identified a new lncRNA (lncPRRX1) and investigated its effect on the proliferation of bovine myoblasts. LncPRRX1 was highly expressed in muscle tissue, and interference with lncPRRX1 inhibited the proliferation of bovine myoblasts in vitro. The RNA molecules of lncPRRX1 act on miR-137 as competitive endogenous RNAs (ceRNAs). Overexpression of miR-137 suppressed the proliferation of myoblasts, while inhibition of miR-137 had the opposite effect. In addition, the predicted target genes of miR-137 were significantly enriched in the mitogen-activated protein kinase (MAPK) signaling pathway, in which Cell Division Cycle 42 (CDC42) was shown to be the direct target gene of miR-137, and interference with CDC42 inhibited myoblast proliferation. Furthermore, interference with lncPRRX1 repaired the defects in CDC42 protein levels and cell proliferation caused by miR-137 inhibitors. Our results suggested that lncPRRX1 promoted bovine myoblast proliferation by regulating the miRNA-137/CDC42 axis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Manganese neurotoxicity has been reported to cause a neurodegenerative disease known as parkinsonism. Previous reports have shown that the expression of the KH-type splicing regulatory protein (KHSRP), a nucleic acid-binding protein, and NLRP3 is increased upon Mn exposure. However, the relation between these two during Mn toxicity has not been fully deduced. The mouse neuroblastoma (N2a) and SD rats are treated with LPS and MnCl 2 to evaluate the expression of KHSRP and NLRP3. Further, the effect of the NLRP3 inhibitor MCC950 is checked on the expression of NLRP3, KHSRP and pro-inflammatory markers (TNFα, IL-18 and IL-1β) as well as the caspase-1 enzyme. Our results demonstrated an increment in NLRP3 and KHSRP expression post-MnCl 2 exposure in N2a cells and rat brain, while on the other hand with LPS exposure only NLRP3 expression levels were elevated and KHSRP was found to be unaffected. An increased expression of KHSRP, NLRP3, pro-inflammatory markers and the caspase-1 enzyme was observed to be inhibited with MCC950 treatment in MnCl 2 -exposed cells and rats. Manganese exposure induces NLRP3 and KHSRP expression to induce neuroinflammation, suggesting a correlation between both which functions in toxicity-related pathways. Furthermore, MCC950 treatment reversed the role of KHSRP from anti-inflammatory to pro-inflammatory.

Aflatoxins are the secondary metabolites produced by Aspergillus flavus and Aspergillus parasiticus and have severe pathological effects on the health of human and animals. The present study was designed to investigate the toxicopathological changes induced by aflatoxins and mitigative potential of Lactobacillus plantarum in broiler birds. One hundred and eighty broiler chicks at one day of age was procured from the local market, and chicks were equally divided into six groups with thirty birds in each group. These birds were treated with aflatoxins (300 and 600 µg/kg) and Lactobacillus plantarum (1 × 10 8 cfu/kg of feed) in different combinations. The first group was kept as the control, and only a basal diet was provided to birds (BD). In the second group (AF1), the first level of aflatoxins (300 µg/kg) was fed to the birds. In the third group (AF2), the second level of aflatoxins (600 µg/kg) was fed to birds. In the fourth group (AF1LP), Lactobacillus plantarum was given with first level of aflatoxins. In the fifth group (AF2LP), Lactobacillus plantarum was given with the second level of aflatoxins, and in the 6th group (BDLP), Lactobacillus plantarum alone was fed to the chicks. This experimental study was continued for 42 days. Birds were slaughtered after 42 days, and different parameters were assessed. Parameters studied were gain in body weight, organ weight along with some histopathological, hematological, biochemical parameters and residues of aflatoxins in liver and kidney. Lactobacillus plantarum improved the body weight gain and restored the relative organ weight. Hepatic and renal biomarkers returned to normal concentrations, serum proteins were restored in combination group AF1LP, and partial amelioration was observed in the AF2LP group. Red blood cells, white blood cells, hemoglobin centration and packed cell volume became normalized in the AF1LP group, while partial amelioration was observed in the AF2LP group. LP also reduced the concentration of aflatoxin residues in liver kidney and improved the TAC concentrations. The results of this study elucidated the mitigative potential of Lactobacillus plantarum against serum biochemical, histopathological, hematological and toxicopathological changes induced by aflatoxins in the chicks.

Gut microbial dysbiosis during the development of Hepatitis C virus and liver-related diseases is not well studied. Nowadays, HCV and liver cirrhosis are the major concerns that cause gut bacterial alteration, which leads to dysbiosis. For this purpose, the present study was aimed at correlating the gut bacterial community of the control group in comparison to HCV and liver cirrhotic patients. A total of 23 stool samples were collected, including control (9), liver cirrhotic (8), and HCV (6). The collected samples were subjected to 16 S rRNA Illumina gene sequencing. In comparison with control, a significant gut bacterial alteration was observed in the progression of HCV and liver cirrhosis. Overall, Firmicutes were significantly abundant in the whole study. No significant difference was observed in the alpha diversity of the control and patient studies. Additionally, the beta diversity based on non-metric multidimensional scaling (NMDS) has a significant difference (p = 0.005) (ANOSIM R 2  = 0.14) in all groups. The discriminative results based on the LEfSe tool revealed that the HCV-infected patients had higher Enterobacteriaceae and Enterobacterial, as well as Lactobacillus and Bacilli in comparison than the liver-cirrhotic patients. These taxa were significantly different from the control group (p < 0.05). Regarding prospects, a detailed analysis of the function through metagenomics and transcriptomics is needed., Competing Interests: Declaration of competing interest The authors declare no conflict of interes, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Intramuscular fat (IMF) content is a crucial determinant of meat quality traits in livestock. A network of transcription factors act in concert to regulate adipocyte formation and differentiation, which in turn influences intramuscular fat. Several genes and associated transcription factors have been reported to influence lipogenesis and adipogenesis during fetal and subsequent growth stage. Specifically in cattle, Krüppel-like factors (KLFs), which represents a family of transcription factors, have been reported to be involved in adipogenic differentiation and development. KLFs are a relatively large group of zinc-finger transcription factors that have a variety of functions in addition to adipogenesis. In mammals, the participation of KLFs in cell development and differentiation is well known. Specifically in the context of adipogenesis, KLFs function either as positive (KLF4, KLF5, KLF6, KLF8, KLF9, KLF10, KLF11, KLF12, KLF13, KLF14 and KLF15) or negative organizers (KLF2, KLF3 and KLF7), by a variety of different mechanisms such as crosstalk with C/EBP and PPARγ. In this review, we aim to summarize the potential functions of KLFs in regulating adipogenesis and associated pathways in cattle. Furthermore, the function of known bovine adipogenic marker genes, and associated transcription factors that regulate the expression of these marker genes is also summarized. Overall, this review will provide an overview of marker genes known to influence bovine adipogenesis and regulation of expression of these genes, to provide insights into leveraging these genes and transcription factors to enhance breeding programs, especially in the context of IMF deposition and meat quality., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Environmental factors, genetic factors, and epigenetics are involved in animal growth and development. Among them, methylation is one of the abundant modifications of epigenetics. N6-methyladenosine(m 6 A) is extensive in cellular RNA, of which mRNA is the most common internal modification. m 6 A modification regulates life activities dynamically and reversibly, including expressed genes, RNA metabolism, and protein translation. The m 6 A modifications are closely related to human diseases involving heart failure, tumors, and cancer. It is relatively in-depth in the medical field. However, there are few studies on its biochemical function in animals. We summarized the latest paper related to the chemical structure and role of the writers, the erasers, and the readers to study exerting dynamic regulation of m 6 A modification of animal growth and development. Furthermore, the key roles of m 6 A modification were reported in the process of RNA metabolism. Finally, the dynamic regulation of m 6 A modification in animal growth and development was reviewed, including brain development, fertility, fat deposition, and muscle production. It reveals the key roles of m 6 A modification and the regulation of gene expression, aiming to provide new ideas for m 6 A methylation in animal growth and development., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Type 2 diabetes mellitus (T2DM) is one of the most common forms of diabetes. We are living in the middle of a global diabetes epidemic. Emerging pieces of evidence are suggesting the increased expression of protein tyrosine phosphatase 1B (PTP1B) in the pancreas and adipose tissues during T2DM. The negative regulation of the insulin signaling pathway by PTP1B helps the researchers to consider it as a potential therapeutic target for the treatment of insulin resistance and its associated complications. From the literature, we found that compound 5,7-dihydroxy-3,6-dimethoxy-2-(4-methoxy-3-(3-methyl-2-enyl)phenyl)-4H-chromen-4-one (Viscosol) extracted from Dodonaea viscosa can inhibit PTP1B in vitro. Therefore, in this study, we aimed to evaluate the antidiabetic effect of this compound in a high-fat diet (HFD) and low-dose streptozotocin- (STZ-) induced T2DM mouse model. For this purpose, T2DM was induced in C57BL/6 male mice by using an already established protocol with minor modification. The compound-treated T2DM mice showed improvements in biochemical parameters, i.e., decrease in the fasting blood glucose level, increased body weight, improved liver profile, and reduction in oxidative stress. Furthermore, to elucidate the inhibition of PTP1B, the expression level of PTP1B was also measured at mRNA and protein levels by real-time PCR and western blot, respectively. Additionally, downstream targets (INSR, IRS1, PI3K, and GLUT4) were examined for confirming the inhibitory effect of PTP1B. Our results suggest that the compound can specifically inhibit PTP1B in vivo and might have the ability to improve insulin resistance and insulin secretion. Based on our experiment, we can confidently state that this compound can be a new PTP1B drug candidate for the treatment of T2DM in the coming future., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Aamir Sohail et al.)

Background: Chronic stress can hinder wound healing as it suppresses both the cellular and innate immune responses. Objectives: The study aims to assess the effectiveness of the administration of topical and oral Cucurbita pepo L. (CP) ethanolic extract in prompting excisional wound healing in rats exposed to chronic stress, and to explain how it works. Materials and methods: Fifty albino rats assigned to five groups (n = 10) were utilized in this study. The chronic unpredictable mild stress (CUMS) model was used for 4 weeks to induce depressive-like behavior in rats, and a forced swim test and corticosterone were assessed to confirm its occurrence. During the experiment, an excisional wound was induced in the rats and followed. Oxidant/antioxidants status and pro-inflammatory cytokines levels were measured in the serum and wound area. Gene expression of pro-inflammatory cytokines was also assessed using RT-PCR. Wound closure histopathological changes and immunohistochemical expression of CD68, CD3, and CD4 at the wound area was assessed. Results: The administration of CP, both orally and topically, significantly reduced (p < 0.001) the depressive-like behavior and corticosterone and pro-inflammatory cytokines levels, while it significantly up-regulated the antioxidant activity compared to the untreated and topically CP-treated groups. Both topically CP-treated and combined CP-treated groups showed complete re-epithelialization, reduced inflammatory cells infiltration, collagen fibers deposition, and significantly increased CD3, CD4 positive T cells count, with a superior effect in the combined CP-treated groups. Conclusion: Cucurbita pepo L., administrated both topically and orally, can enhance the wound healing process in rats with depressive-like behavior mostly through the antioxidant, anti-inflammatory, and antidepressant activities observed in this study.

Benign prostatic hyperplasia (BPH) is a widespread androgenic illness influencing elderly men. It is distinguished by prostatic epithelial and stromal muscle cell proliferation. Inflammation, oxidative stress, and apoptosis have all been interrelated to the development of BPH. Marjoram ( Origanum majorana L.) is a herb with reported antiproliferative, proapoptotic, and antioxidative properties, which have not yet been studied in relation to BPH. Consequently, in this work, an ethanolic extract of O. majorana was prepared in two doses (250 and 500 mg/kg/day) to be injected into castrated rats after induction of a testosterone-BPH model. Testosterone propionate (TP) was subcutaneously injected (0.5 mg/kg/day) for one week after castration to induce BPH. Forty adult Wistar male rats were randomly allocated into five groups: control, BPH model, high and low O. majorana doses (250, 500 mg/kg/day), and finasteride (FN) (0.8 mg/kg/day) as a positive control. Treatment was continued with drugs/normal saline for 28 days. Rat's body and prostate were weighed, prostate index (PI) and % of prostate growth inhibition were calculated, serum dihydrotestosterone (DHT), prostatic content of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and malondialdehyde (MDA), DN damage, histopathological changes, immune expression of proliferating cell nuclear antigen (PCNA), caspase-3, α-SMA, and TGF-β1 were assessed. In addition, molecular quantitative PCR and ELISA analyses were performed to identify the expression of mRNAs and related proteins of both caspase-3 and TGF-β1 in prostate tissue from O. majorana -treated and untreated groups. Rats with BPH had significantly higher prostate weights and PI, higher DHT, DNA damage (8-hydroxyguanine, 8-OH-dG), and MDA levels with prominent PCNA, α-SMA, and TGF-β expression, but lower SOD, CAT, and TAC activity and caspase-3 expression. O. majorana (250 and 500 mg/kg/day)-treated groups revealed a decrease in prostate weights and PI, lower levels of DHT, suppressed oxidative stress, reduced tissue proliferation and fibrosis, and restored antioxidant and proapoptotic activity. Additionally, quantitative PCR and ELISA analysis showed that treatment with O. majorana significantly upregulated the expression of caspase-3 and downregulated the expression of TGF-β in prostate tissues of BPH rats. The data were confirmed by the immunohistological reactivity of these targeted markers in the prostate tissues. These effects were more significant with O. majorana 500 mg/mL/rat. In conclusion, the current study indicates the efficient use of O. majorana in the treatment of testosterone-induced BPH through its antiproliferative, proapoptotic, and antioxidative mechanisms.

Background: Pumpkins ( Cucurbita pepo L.) were described to have antioxidant, anti-inflammatory, anti-fatigue, and antidepressant-like effect. The adrenal gland is an important stress-responsive organ that maintains homeostasis during stress. Objectives: This study aimed to assess the efficacy of the administration of Cucurbita pepo L. (CP) extract in relieving behavioral, biochemical, and structural changes in the adrenal gland induced by exposure to chronic unpredictable mild stress (CUMS) and to explore the mechanism behind this impact. Materials and Methods: Forty male albino rats were divided into 4 groups ( n = 10): control, CUMS, fluoxetine-treated, and CP-treated groups. Behavioral changes, corticosterone level, pro-inflammatory cytokines TNF-α and IL-6, and oxidant/antioxidant profile were assessed in the serum at the end of the experiment. Adrenal glands were processed for histopathological and immunohistochemical assessment. Gene expression of caspase-3 and Ki67 and heat shock protein 70 (HSP70) were assessed in adrenal glands using RT-PCR. Results: The CP extract significantly reduced the corticosterone level ( p < 0.001), immobility time ( p < 0.001), and inflammatory and oxidative changes associated with CUMS-induced depression compared to the untreated group. The CP extract alleviated CUMS-induced adrenal histopathological changes and significantly reduced apoptosis ( p < 0.001) and significantly upregulated antioxidant levels in the serum. Conclusion: Cucurbita pepo L. effectively ameliorated the chronic stress-induced behavioral, biochemical, and adrenal structural changes mostly through its antioxidant and anti-inflammatory effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Almohaimeed, Hamed, Seleem, Batawi, Mohammedsaleh, Balgoon, Ali, Al Jaouni and Ayuob.)

Background: Acute and chronic stresses affect the salivary glands, representing the source of plasma BDNF during stressful conditions. Pumpkin is a medicinal plant with an evident antioxidant, anti-inflammatory and potential antidepressant effects., Objective: To assess the structural and biochemical effects induced by exposure to chronic unpredictable mild stress (CUMS) on salivary glands of albino rats, and to evaluate the role of pumpkin extract (Pump) in ameliorating this effect., Methodology: Four groups (n=10 each) of male albino rats were included in this study: the control, CUMS, Fluoxetine-treated and Pump-treated. The corticosterone, the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and the oxidant/antioxidant profile were all assessed in the serum. The level of BDNF mRNA was measured in the salivary glands using qRT-PCR. Histopathological changes of the salivary glands were also assessed., Results: The depressive-like status was confirmed behaviorally and biochemically. Exposure to CUMS significantly up-regulated (p<0.001) the level of serum corticosterone. CUMS induced degenerative changes in the secretory and ductal elements of the salivary glands evident by increased apoptosis. Both Fluoxetine and Pumpkin significantly up-regulated (p<0.001) BDNF expression in the salivary glands and ameliorated the CUMS-induced histopathological and biochemical alterations in the salivary glands. Pumpkin significantly (p<0.001) increased the serum levels of antioxidant enzymes SOD, GPX and CAT, and reduced the serum levels of the pro-inflammatory cytokines TNF-α, IL-6., Conclusion: Pumpkin ameliorates the depressive-like status induced in rats following exposure to chronic stress through exerting a promising anti-inflammatory, antioxidant and anti-depressant-like effects. The pumpkin, subsequently, improved stress-induced structural changes in the salivary glands that might be due to up-regulation of BDNF expression in the glands.

Background: Depression has been reported as a common comorbidity in diabetes mellitus although the underlying mechanism responsible for this is not well known. Although both ginger and cinnamon has anti-diabetic, antioxidant, and neuroprotective properties, their efficacy in inhibiting neuroinflammation, when simultaneously administrated, has not been investigated yet. Objectives: The study was designed to assess the synergistic effect of Cinnamomum cassia and Z ingiber officinale on regulating blood glucose, improve hippocampal structural changes and depressive-like alternations in diabetic rats, and try to identify the mechanism behind this effect. Materials and Methods: Thirty male Sprague-Dawley rats were divided into five equal groups ( n = 6): the normal control, untreated streptozotocin (STZ)-diabetic, cinnamon-treated diabetic [100 mg/kg of body weight (BW)/day for 6 weeks], ginger-treated diabetic (0.5 g/kg BW/day for 6 weeks), and ginger plus cinnamon-treated diabetic groups. Forced swim test and elevated plus maze behavioral tests were performed at the end of the experiment. HOMA-IR, HOMA β-cells, blood glucose, insulin, corticosterone, pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6), and total anti-oxidant capacity (TAC) were assessed in the serum. BDNF mRNA level was assessed in hippocampus using qRT-PCR. Hippocampal histopathological changes were also assessed, and immunoexpression of glial fibrillary acidic protein (GFAP), caspase-3, and Ki-67 was measured. Results: Diabetes-induced depressive-like changes in the STZ group were biochemically confirmed by assessing serum corticosterone level, as well as behaviorally using FST and EPM tests. Diabetes also induced degenerative changes in the hippocampus. Treatment of diabetic rats with ginger, cinnamon, or the combination of these alleviated the degenerative structural changes and significantly up-regulated serum insulin, TAC, hippocampal BDNF mRNA, and hippocampal immunoexpression of ki67, while they significantly reduced serum blood glucose, IL-6, TNF-α, IL1β, as well as hippocampal immunoexpression of GFAP and Caspase-3 compared to the untreated diabetic group. Improvement induced by the combination of ginger and cinnamon was superior to the single administration of either of these. Conclusion: Cinnamomum cassia and Z ingiber officinale have synergistic anti-diabetic, antioxidant, anti-inflammatory, antidepressant-like, and neuroprotective effects. The use of a combination of these plants could be beneficial as alternative or complementary supplements in managing DM and decreasing its neuronal and psychiatric complications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AO declared a shared affiliation, with no collaboration, with one of the authors, NA, to the handling editor at the time of the review., (Copyright © 2021 ALmohaimeed, Mohammedsaleh, Batawi, Balgoon, Ramadan, Baz, Al Jaouni and Ayuob.)

Background: Musk ( Moschus moschiferus ) has been described to have a significant impact on the central nervous system, as well as anticonvulsion and antidepressant effects. This study was designed to evaluate the efficacy of musk in alleviating alterations induced in olfactory bulb of depressed mice exposed to chronic stress and identify the mechanism behind it., Methods: Fifty male albino mice were divided into five groups ( n = 10 each): control, musk, chronic unpredictable mild stress (CUMS), fluoxetine-treated, and musk-treated groups were included in this study. Behavioral changes and serum levels of corticosterone and proinflammatory cytokines included tumor necrosis factor α, interleukin 6, and oxidant/antioxidant profile were assessed at the end of the experiment. Main olfactory bulb (MOB) has been processed for histopathological examination. Gene expression of caspase-3, glial fibrillary acidic protein, and Ki67 were assessed in the MOB using quantitative real-time polymerase chain reaction., Results: The study showed that musk inhalation significantly reduced ( p < 0.001) corticosterone level, immobility time, inflammatory cytokines, and oxidative stress markers in CUMS-exposed mice compared to the untreated CUMS group. Musk lessened CUMS-associated neuronal alterations in the MOB and significantly reduced apoptosis and enhanced neural cell proliferation ( p < 0.001) comparable to fluoxetine. Musk significantly enhanced the level of antioxidants in the serum and significantly reduced inflammatory cytokines. The anti-inflammatory and antioxidant activity of musk and its constituents seemed to be behind its neuroprotective effect observed in this study., Conclusion: Musk effectively ameliorated the chronic stress-induced behavioral, biochemical, and neuronal structural changes in MOB mostly through its antioxidant and anti-inflammatory effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Almohaimeed, Batawi, Mohammedsaleh, Al Jaouni, Mutlq Alsawat, Abd El Wahab, AbdElfattah and Ayuob.)

Background: Ocimum basilicum (O. basilicum ) was described to have antidepressant and anxiolytic activities. Although the relationship between the main olfactory bulb (MOB) and depression was recently reported, the chronic stress-induced dysfunction of the MOB is not clearly described., Objectives: This study aimed to assess the efficacy of inhalation of O. basilicum essential oils in improving chronic unpredictable mild stress (CUMS)-induced changes in MOB of mice and understand the mechanism underlying such effect., Materials and Methods: Adult male mice (n=40) were assigned into four groups included the control, CUMS-exposed, CUMS + fluoxetine (FLU), CUMS + O. basilicum . Behavioral changes, serum corticosterone level, and gene expression of GFAP, Ki 67, and caspase-3 were assessed using real-time PCR (RT-PCR). Histopathological and immunochemical examination of the MOB was performed., Results: FLU and O. basilicum significantly down-regulated (p = 0.002, p<0.001) caspase-3 gene expression indicating reduced apoptosis and up-regulated (p = 0.002, p < 0.001) Ki67 gene expression indicating enhanced neurogenesis in MOB, respectively. FLU and O. basilicum -treated mice markedly improved MOB mitral cell layer distortion and shrinkage induced by CUMS., Conclusion: O. basilicum relieved both biochemically and histopathological chronic stress-induced changes in the main olfactory bulb possibly through up-regulation of gene expression of GFAP and Ki67 and down-regulation of caspase-3 in the MOB., (Copyright © 2020 Ayuob, Balgoon, Ali, Alnoury, ALmohaimeed and AbdElfattah.)