Hexaconazole exposure may lead to Parkinson via disrupting glucocerebrosidase and parkin: molecular interaction, dynamics, MMPBSA and DFT based in-silico predictive toxicology.

Hexaconazole is a known fungicide for agricultural purposes. It has bioaccumulation ability which makes it important for its toxicological characterization. There are various neurological impacts of pollutants on human health. Therefore, in this study, we have done predictive analyses of the interaction mechanism of hexaconazole by molecular interaction analysis, molecular dynamics simulation, and Poisson-Boltzmann surface area (MM-PBSA) to assess hexaconazole's potency to disrupt the homeostasis of glucocerebrosidase (-7.9 kcal/mol) and parkin (-5.67 kcal/mol) proteins which have significant roles in the manifestation of Parkinson disease. The findings reveal that hexaconazole has the potency to form stable interactions with glucocerebrosidase and parkin. This research provides a molecular and atomic-level understanding of how hexaconazole exposure may disrupt the homeostasis of glucocerebrosidase and parkin. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration, and hydrogen bonding exhibited the potent molecular interactions of hexaconazole, which may lead to neurological manifestations such as Parkinson disease.

Zerumbone reduces TLR2 stimulation-induced M1 macrophage polarization pattern via upregulation of Nrf-2 expression in murine macrophages.

Hyperuricemia contributes significantly to gout arthritis pathogenesis, which promotes urate crystal deposition in the joints and activates joint-resident macrophages and circulating monocytes to initiate a state of inflammatory arthritis. In the joint, macrophages have an immune defense role where the presence of urate crystals results in the inflammatory mediators secretion, inflammatory cells recruitment to the joint, and shift macrophage population toward M1 pro-inflammatory phenotypes. Current treatment modalities of gout arthritis have side effects that limit their use in the elderly. A novel treatment that targets macrophage polarization to re-establish homeostasis may initiate a drug discovery program of novel disease-modifying agents for gout. Zerumbone (Zer) is a sesquiterpenoid bioactive compound found in the rhizome of Zingiberaceae family and possesses anti-inflammatory, antioxidant, and anti-proliferative activity. Our study hypothesized that soluble uric acid (sUA) and Pam3CSK4 (TLR2 agonist) reduce the anti-inflammatory function of murine M2 bone marrow-derived macrophages and change the expression of M2 genetic markers toward M1 phenotypes. We observed that priming of M2 macrophages with sUA and Pam3CSK4 significantly decreased M2 specific markers expression, e.g., Arg-1, Ym-1, and Fizz-1, enhanced mRNA expression of IL-1ß, TNF-α, CXCL2, and iNOS and increased oxidative stress in M2 macrophages, as exhibited by a reduction in Nrf2 expression. We also aimed to study the impact of Zer on reducing the pro-inflammatory effect of sUA in TLR2-stimulated M2 macrophages. We noticed that Zer treatment significantly reduced L-1ß and TNF-α production following Pam3CSK4 + sUA treatment on M2 macrophages. Furthermore, Zer reduced the caspase-1 activity without altering cytosolic NLRP3 content in challenged M2 BMDMs. We also observed that Zer significantly enhanced M2-associated marker's expression, e.g., Arg-1, Ym-1, and Fizz-1, and augmented Nrf-2 and other antioxidant proteins, including HMOX1 and srxn1expression following Pam3CSK4 + sUA treatment. We draw the conclusion that Zer is a potentially effective anti-inflammatory treatment for gout arthritis linked to hyperuricemia.

Assessing medication adherence and their associated factors amongst type-2 diabetes mellitus patients of Jazan Province, Saudi Arabia: A single-center, cross-sectional study.

Background: The prevalence of type 2 diabetes mellitus (T2DM) globally is reaching epidemic proportions. By 2035, it is projected to increase to 417 million, which is of significant concern as T2DM represents the most oversized budget item in many healthcare systems, primarily due to the high rates of morbidity and mortality associated with the disease. The worldwide cost burden of T2DM has been inexorably growing. A key contributor to the remarkably high morbidity and mortality rates is poor glycemic control potentially associated with medication non-adherence. Aim: The present research's main objective included assessing medication adherence among patients with T2DM in a single center in Jazan Province. Methods: Three hundred nine patients with T2DM participated in a cross-sectional survey over three months (September to November 2022). The study participants comprised 50.8 % (females) and 49.2 % (males), with a mean age of 44.12 years (SD ± 12.70). A 31-item self-report questionnaire was used for data collection. Results: Sixty-six percent of the sample were found to be adherent to their T2DM therapy. A positive association was noticed between the GMAS score and the participant's age (r = 0.24; p < 0.01). The participants' medication adherence was significantly associated with having age above 50 years (χ2 = 13.62; p = 0.001), residing in urban localities (χ2 = 21.37; p < 0.001), being married (χ2 = 12.80; p = 0.002), having glycated hemoglobin level more than 8 % (χ2 = 6.99; p = 0.03) and taking between one to three medications per day (χ2 = 17.63; p < 0.001). Conclusion: The majority of T2DM patients in the present study were found adherent to their anti-diabetic medications, particularly older patients. Future studies should focus on exploring the reasons for the reported high adherence among older patients and non-adherence among younger patients, as this could facilitate the development of a strategy to enhance adherence.

Hepatoprotective and Antioxidant Effects of Nanopiperine against Cypermethrin via Mitigation of Oxidative Stress, Inflammations and Gene Expression Using qRT-PCR.

Cypermethrin (Cyp) is a pyrethroid that has been associated with the toxicity of various organs. The aim of our study was to evaluate the hepatoprotective and antioxidant activities of nano-piperine (NP) against Cyp toxicity. Cyp (50 mg/kg) was administered orally in all animals of groups III-VI for 15 days. Groups IV-VI each received three doses of NP (125, 250, and 500 µg/kg/day) for 10 days after receiving the Cyp dosage, which was given after 1 h. A rise in serum biomarkers (ALT, AST, ALP, total protein, and albumin), which are indicators of toxicity alongside anomalous oxidative stress indices (lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD) and catalase), was detected. After Cyp treatment, we observed upregulated cytokines, caspase expression, and histological analysis that the showed distortion of cell shape. However, the administration of NP dramatically reversed all of the Cyp-induced alterations, inducing reductions in serum marker levels, stress level, the production of cytokines, and caspase expression. Additionally, all of the histopathological alterations were minimized to values that were comparable to normal levels. The present findings suggested that NP exhibits potent antioxidant and anti-inflammatory activities that can protect rats' livers against Cyp-induced liver damage through hepatoprotective activities.

Targeting CD44 Receptor Pathways in Degenerative Joint Diseases: Involvement of Proteoglycan-4 (PRG4).

Rheumatoid arthritis (RA), osteoarthritis (OA), and gout are the most prevalent degenerative joint diseases (DJDs). The pathogenesis underlying joint disease in DJDs remains unclear. Considering the severe toxicities reported with anti-inflammatory and disease-modifying agents, there is a clear need to develop new treatments that are specific in their effect while not being associated with significant toxicities. A key feature in the development of joint disease is the overexpression of adhesion molecules, e.g., CD44. Expression of CD44 and its variants in the synovial tissues of patients with DJDs is strongly associated with cartilage damage and appears to be a predicting factor of synovial inflammation in DJDs. Targeting CD44 and its downstream signaling proteins has emerged as a promising therapeutic strategy. PRG4 is a mucinous glycoprotein that binds to the CD44 receptor and is physiologically involved in joint lubrication. PRG4-CD44 is a pivotal regulator of synovial lining cell hemostasis in the joint, where lack of PRG4 expression triggers chronic inflammation and fibrosis, driven by persistent activation of synovial cells. In view of the significance of CD44 in DJD pathogenesis and the potential biological role for PRG4, this review aims to summarize the involvement of PRG4-CD44 signaling in controlling synovitis, synovial hypertrophy, and tissue fibrosis in DJDs.

Stroke-Induced Central Pain: Overview of the Mechanisms, Management, and Emerging Targets of Central Post-Stroke Pain.

The incidence of stroke plays the foremost role in the genesis of central neuropathic pain. Central post-stroke pain (CPSP) is a central pain arising from a vascular lesion in the central nervous system that elicits somatosensory deficits, often contralateral to stroke lesions. It is expressed as continuous or intermittent pain accompanied by sensory abnormalities like dysesthesia and allodynia. CPSP remains de-emphasized due to the variation in onset and diversity in symptoms, besides the difficulty of distinguishing it from other post-stroke pains, often referred to as a diagnosis of exclusion. Spinothalamic dysfunction, disinhibition of the medial thalamus, and neuronal hyperexcitability combined with deafferentation in thalamocortical regions are the mechanisms underlying central pain, which play a significant role in the pathogenesis of CPSP. The treatment regimen for CPSP seems to be perplexed in nature; however, based on available studies, amitriptyline and lamotrigine are denoted as first-line medications and non-pharmacological choices may be accounted for cases intractable to pharmacotherapy. This review attempts to provide an overview of the mechanisms, existing management approaches, and emerging targets of CPSP. A profound understanding of CPSP aids in optimizing the quality of life among stroke sufferers and facilitates further research to develop newer therapeutic agents for managing CPSP.

Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats.

Chemotherapy-induced kidney damage is an emerging problem that restricts cancer treatment effectiveness. The proteasome inhibitor carfilzomib (CFZ) is primarily used to treat multiple myeloma and has been associated with severe renal injury in humans. CFZ-induced nephrotoxicity remains an unmet medical need, and there is an urgent need to find and develop a nephroprotective and antioxidant therapy for this condition. Thymoquinone (TQ) is a bioactive compound that has been isolated from Nigella sativa seeds. It has a wide range of pharmacological properties. Therefore, this experimental design aimed to study the effectiveness of TQ against CFZ-induced renal toxicity in rats. The first group of rats was a normal control (CNT); the second group received CFZ (4 mg/kg b.w.); the third and fourth groups received TQ (10 and 20 mg/kg b.w.) 2 h before receiving CFZ; the fifth group received only TQ (20 mg/kg b.w.). This experiment was conducted for 16 days, and at the end of the experiment, blood samples and kidney tissue were collected for biochemical assays. The results indicated that administration of CFZ significantly enhanced serum marker levels such as BUN, creatinine, and uric acid in the CFZ group. Similarly, it was also noticed that CFZ administration induced oxidative stress by reducing antioxidants (GSH) and antioxidant enzymes (CAT and SOD) and increasing lipid peroxidation. CFZ treatment also enhanced the expression of IL-1ß, IL-6, and TNF-α production. Moreover, CFZ increased caspase-3 concentrations and reduced Nrf2 expression in the CFZ-administered group. However, treatment with 10 and 20 mg/kg TQ significantly decreased serum markers and increased antioxidant enzymes. TQ treatment considerably reduced IL-1ß, IL-6, TNF-α, and caspase-3 concentrations. Overall, this biochemical estimation was also supported by histopathological outcomes. This study revealed that TQ administration significantly mitigated the negative effects of CFZ treatment on Nrf2 expression. Thus, it indicates that TQ may have utility as a potential drug to prevent CFZ-induced nephrotoxicity in the future.

Cinnamon Oil Alleviates Acetaminophen-Induced Uterine Toxicity in Rats by Abrogation of Oxidative Stress, Apoptosis, and Inflammation.

Paracetamol, or acetaminophen (APAP), is one of the first-line medications that is used for fever and pain. However, APAP can induce uterine toxicity when overused. The mode of action of APAP toxicity is due to the production of free radicals. The main goal of our study is to determine uterine toxicity from APAP overdose and the antioxidative activity of cinnamon oil (CO) in female rats. The effect of different doses of CO (50-200 mg/kg b.w.) was assessed in the uterus toxicity induced by APAP. Additionally, the imbalance in oxidative parameters, interleukins, and caspases was evaluated for the protective effects of CO. A single dose of APAP (2 g/kg b.w.) resulted in uterus toxicity, indicated by a significant increase in the level of lipid peroxidation (LPO), inflammatory interleukins cytokines (IL-1 and 6), expression of caspases 3 and 9, and a marked change in uterus tissue architecture evaluated by histopathology. Co-treatment of CO resulted in a significant amelioration of all the parameters such as LPO, interleukins IL-1ß, IL-6, caspases 3 and 9 expression, and distortion of tissue architecture in a dose-dependent manner. Therefore, we can conclude that APAP-induced uterine injury due to oxidative stress can be restored by co-treatment with cinnamon oil (CO).

Mitochondrial oxidative damage by co-exposure to bisphenol A and acetaminophen in rat testes and its amelioration by melatonin.

OBJECTIVE: Human exposure to multiple xenobiotics, over various developmental windows, results in adverse health effects arising from these concomitant exposures. Humans are widely exposed to bisphenol A, and acetaminophen is the most commonly used over-the-counter drug worldwide. Bisphenol A is a well-recognized male reproductive toxicant, and increasing evidence suggests that acetaminophen is also detrimental to the male reproductive system. The recent recognition of male reproductive system dysfunction in conditions of suboptimal reproductive outcomes makes it crucial to investigate the contributions of toxicant exposures to infertility and sub-fertility. We aimed to identify toxicity in the male reproductive system at the mitochondrial level in response to co-exposure to bisphenol A and acetaminophen, and we investigated whether melatonin ameliorated this toxicity. METHODS: Male Wistar rats were divided into six groups (n=10 each): a control group and groups that received melatonin, bisphenol A, acetaminophen, bisphenol A and acetaminophen, and bisphenol A and acetaminophen with melatonin treatment. RESULTS: Significantly higher lipid peroxidation was observed in the testicular mitochondria and sperm in the treatment groups than in the control group. Levels of glutathione and the activities of catalase, glutathione peroxidase, glutathione reductase, and manganese superoxide dismutase decreased significantly in response to the toxicant treatments. Likewise, the toxicant treatments significantly decreased the sperm count and motility, while significantly increasing sperm mortality. Melatonin mitigated the adverse effects of bisphenol A and acetaminophen. CONCLUSION: Co-exposure to bisphenol A and acetaminophen elevated oxidative stress in the testicular mitochondria, and this effect was alleviated by melatonin.

Structural Complementarity of Bruton's Tyrosine Kinase and Its Inhibitors for Implication in B-Cell Malignancies and Autoimmune Diseases.

Bruton's tyrosine kinase (BTK) is a critical component in B-cell receptor (BCR) signaling and is also expressed in haematogenic and innate immune cells. Inhibition of BTK hyperactivity is implicated in B-cell malignancies and autoimmune diseases. This review derives the structural complementarity of the BTK-kinase domain and its inhibitors from recent three-dimensional structures of inhibitor-bound BTK in the protein data bank (PDB). Additionally, this review analyzes BTK-mediated effector responses of B-cell development and antibody production. Covalent inhibitors contain an α, ß-unsaturated carbonyl moiety that forms a covalent bond with Cys481, stabilizing αC-helix in inactive-out conformation which inhibits Tyr551 autophosphorylation. Asn484, located two carbons far from Cys481, influences the stability of the BTK-transition complex. Non-covalent inhibitors engage the BTK-kinase domain through an induced-fit mechanism independent of Cys481 interaction and bind to Tyr551 in the activation kink resulting in H3 cleft, determining BTK selectivity. Covalent and non-covalent binding to the kinase domain of BTK shall induce conformational changes in other domains; therefore, investigating the whole-length BTK conformation is necessary to comprehend BTK's autophosphorylation inhibition. Knowledge about the structural complementarity of BTK and its inhibitors supports the optimization of existing drugs and the discovery of drugs for implication in B-cell malignancies and autoimmune diseases.

Therapeutic Potential of Capsaicin against Cyclophosphamide-Induced Liver Damage.

Cyclophosphamide (CPM) is a classical alkylating agent used in different cancer chemotherapy regimens and is restricted due to severe adverse effects, including hepatotoxicity. Natural or plant-derived antioxidants such as capsaicin were utilized in this study to examine the hepatoprotective benefits against cyclophosphamide-induced hepatotoxicity. The rats were divided into five groups: a normal control group, a toxic group (CPM), an intraperitoneal injection of a single dose of 200 mg/kg b.w. on the fourth day, a pretreated group with two doses of CPS (10 mg and 20 mg/kg b.w.) orally for six consecutive days, and an intraperitoneal administration of 200 mg/kg b.w. on the fourth day of treatment. The fifth group was administered with the highest dose of CPS (20 mg/kg b.w.) orally for six consecutive days. After 24 h of administration of CPS, the rats were anesthetized, blood was collected, and the serum enzyme toxicity was evaluated. After the blood sampling and euthanasia of all the animals, the liver was isolated for further toxicity and histopathological examination. The results revealed that serum liver markers (AST, ALT, ALP, BLI) significantly increased after CPM administration, but were subsequently restored after CPS treatment with both doses. In addition, lipid peroxidation (MDA), inflammatory cytokines (IL-1ß, TNF-α), and apoptotic markers (Caspase-3) increased, and antioxidant enzymes (GSH, CAT, SOD) were significantly decreased after CPM administration, and it was re-established by CPS treatment. However, CPS effectively protected against the CPM-induced histopathological architects of liver tissues. In conclusion, CPS attenuates CPM-induced hepatotoxicity via modulating oxidative stress, apoptotic signals, and cytokine pathway. Therefore, CPS could play a significant role as a supplement during the chemotherapy of patients.

Hepatoprotective Effect of Curcumin Nano-Lipid Carrier against Cypermethrin Toxicity by Countering the Oxidative, Inflammatory, and Apoptotic Changes in Wistar Rats.

This study investigated the potential hepatoprotective activity of curcumin-incorporated nano-lipid carrier (Cur-NLC) against cypermethrin (Cyp) toxicity in adult Wistar male rats. All animals in groups III, IV, V, and VI were subjected to Cyp (50 mg/kg) toxicity for 15 days. Three different doses of Cur-NLC (1, 2.5, and 5 mg/kg/day) were administered orally for 10 days. The toxic effects were evaluated considering the increases in serum hepatic biomarkers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein and albumin, and lipid peroxidation (LPO), as well as a decrease in antioxidative activity (reduced glutathione (GSH), superoxide dismutase (SOD), and catalase) and the upregulation of inflammatory cytokines (IL-1ß, IL-6, and TNF-α). Immunohistochemistry studies of proteins (NF-κB, Apaf-1, 4-HNE, and Bax) showed enhanced expression, and histopathological examination revealed architectural changes in liver cells, indicating liver toxicity in animals. Toxicity was determined by quantitative and qualitative determinations of DNA fragmentation, which show massive apoptosis with Cyp treatment. The administration of Cur-NLC significantly ameliorates all changes caused by Cyp, such as a decrease in the levels of serum liver markers, an increase in antioxidative parameters, a decrease in expression of inflammatory cytokines (IL-1ß, IL-6, TNF-α, and NF-κB), and apoptosis (caspases-3, 9, Apaf-1, 4-HNE, and Bax), according to calorimetric and immunohistochemistry studies. The smear-like pattern of DNA is ameliorated similarly to the control at a high dose of Cur-NLC. Furthermore, all histopathological changes were reduced to a level close to the control. In conclusion, Cur-NLC could be a potent nutraceutical that exhibits a hepatoprotective effect against Cyp-induced hepatotoxicity in rats.

Amplification of Inflammation by Lubricin Deficiency Implicated in Incident, Erosive Gout Independent of Hyperuricemia.

OBJECTIVE: In gout, hyperuricemia promotes urate crystal deposition, which stimulates the NLRP3 inflammasome and interleukin-1ß (IL-1ß)-mediated arthritis. Incident gout without background hyperuricemia is rarely reported. To identify hyperuricemia-independent mechanisms driving gout incidence and progression, we characterized erosive urate crystalline inflammatory arthritis in a young female patient with normouricemia diagnosed as having sufficient and weighted classification criteria for gout according to the American College of Rheumatology (ACR)/EULAR gout classification criteria (the proband). METHODS: We conducted whole-genome sequencing, quantitative proteomics, whole-blood RNA-sequencing analysis using serum samples from the proband. We used a mouse model of IL-1ß-induced knee synovitis to characterize proband candidate genes, biomarkers, and pathogenic mechanisms of gout. RESULTS: Lubricin level was attenuated in human proband serum and associated with elevated acute-phase reactants and inflammatory whole-blood transcripts and transcriptional pathways. The proband had predicted damaging gene variants of NLRP3 and of inter-α trypsin inhibitor heavy chain 3, an inhibitor of lubricin-degrading cathepsin G. Changes in the proband's serum protein interactome network supported enhanced lubricin degradation, with cathepsin G activity increased relative to its inhibitors, SERPINB6 and thrombospondin 1. Activation of Toll-like receptor 2 (TLR-2) suppressed levels of lubricin mRNA and lubricin release in cultured human synovial fibroblasts (P < 0.01). Lubricin blunted urate crystal precipitation and IL-1ß induction of xanthine oxidase and urate in cultured macrophages (P < 0.001). In lubricin-deficient mice, injection of IL-1ß in knees increased xanthine oxidase-positive synovial resident M1 macrophages (P < 0.05). CONCLUSION: Our findings linked normouricemic erosive gout to attenuated lubricin, with impaired control of cathepsin G activity, compounded by deleterious NLRP3 variants. Lubricin suppressed monosodium urate crystallization and blunted IL-1ß-induced increases in xanthine oxidase and urate in macrophages. The collective activities of articular lubricin that could limit incident and erosive gouty arthritis independently of hyperuricemia are subject to disruption by inflammation, activated cathepsin G, and synovial fibroblast TLR-2 signaling.

Hematotoxicity of Co-Administration of Bisphenol A and Acetaminophen in Rats and its Amelioration by Melatonin.

BACKGROUND: Hematotoxicity is an underexplored endpoint of toxicity in most of the chemical exposures. An adverse effect on the hematological system arising out of xenobiotic exposure causes impaired hemostasis and coagulation leading to disease. BPA and acetaminophen are widely used synthetic chemicals worldwide and both are known and have numerous toxic effects. Since both can be simultaneously exposed to humans over a period of time, we hypothesized that their exposure can cause hematotoxicity, which may be ameliorated by melatonin. OBJECTIVE: In the current study, we aimed to find the effect of single and co-treatment of bisphenol A and acetaminophen on the RBC and coagulation factors in rats, and amelioration of impairment by melatonin. METHODS: Oxidative stress in red blood cells, bleeding time, blood clotting time, prothrombin time, partial thromboplastin time, and fibrinogen levels were assessed as indicators of hematotoxicity with single and co-exposure to bisphenol A and acetaminophen in rats. The effect of melatonin as a hemato-protective agent was assessed in the co-exposure. RESULTS: An increase in RBC oxidative stress and decrease in bleeding time, blood clotting time, prothrombin time, and partial thromboplastin time along with an increase in fibrinogen levels were observed with bisphenol A and acetaminophen treatment, which were further aggravated with cotreatment of the two. Melatonin treatment, however, was seen to decrease the increase in oxidative stress and ameliorate the impairment in coagulation factors. CONCLUSION: Bisphenol A and acetaminophen cause an increase in the oxidative stress in the red blood cells, and cause a shift toward pro-coagulation, which is alleviated by treatment with melatonin.

Global Prevalence and Associated Clinical Markers of Thrombocytopenia in People Living with HIV: Evidence from Meta-Analysis.

Thrombocytopenia is one of the complications in human immunodeficiency virus (HIV) patients. To improve the health outcomes of patients living with HIV, it is important to understand the prevalence and pattern of associated key clinical markers globally. This meta-analysis, therefore, aimed to estimate the pooled prevalence of and associated clinical marker of thrombocytopenia globally. Methodology: The meta-analysis was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All statistical analyses were conducted using Stata. Twelve full-text papers out of 454 were eligible for meta-analysis. Results: Among 6686 participants, overall pooled prevalence of thrombocytopenia was 10.90% (95% CI: 7.91, 13.88) I2 = 93.62%. In addition, thrombocytopenia was more prevalent by 25.11% (95% CI: 13.33, 36.88) in patients with CD + T < 200 cells/µL, and less prevalent in patients with CD + T < 200 cells/µL 10.10% (95% CI: 7.37, 12.83), respectively. Conclusions and recommendations: This meta-analysis established the prevalence of thrombocytopenia among patients living with HIV, and that it may be more prevalent in patients with CD + T < 200 cells/µL indicating the necessity of routine screening for various haematological markers and a careful treatment plan for HIV patients.

The Protective Effects of Sesamin against Cyclophosphamide-Induced Nephrotoxicity through Modulation of Oxidative Stress, Inflammatory-Cytokines and Apoptosis in Rats.

Cyclophosphamide is an anticancer drug with a wide spectrum of clinical uses, but its typical side effects are multiple complications, including nephron toxicity. The possible molecular mechanism of the nephroprotective action of sesamin (SM) against cyclophosphamide (CP) induced renal toxicity was investigated in rats by understanding oxidative stress and inflammatory cytokines. In this study, rats were arbitrarily grouped into the following four groups: a normal control group (CNT); a CP-induced toxicity group; a treatment group with two doses of sesamin SM10 and SM20; a group with sesamin (SM20) alone. A single dose of CP (150 mg/kg body, i.p.) was administered on day 4 of the experiments, while treatment with SM was given orally for seven days from day 1. The group treated with SM showed a significant protective effect against CP-induced renal damage in rats. Treatment with SM significantly increased the antioxidant enzymes (GSH, CAT, and SOD) and reduced malondialdehyde (MDA) levels. Thus, SM significantly overcame the elevated kidney function markers (creatinine, blood urea nitrogen, and uric acid) by attenuating oxidative stress. The SM also significantly reduced the elevated cytokines (IL-1ß and TNFα) and caspase-3 in the treated group. Histopathological studies confirmed the protective effect of sesamin (SM) on CP-induced nephrotoxicity. In conclusion, the current findings support the nephroprotective effect of sesamin against CP-induced renal injury.

Knowledge, Attitudes and Perception toward COVID-19 Vaccines among Adults in Jazan Province, Saudi Arabia.

BACKGROUND: Saudi Arabia is one of the countries that initiated early vaccination programs despite the global challenges concerning the availability of COVID-19 vaccines. Massive vaccination campaigns have been undertaken in the country; however, negative perception and hesitancy toward vaccines may exist which could reduce public response to vaccination. Further, studies evaluating the current perception and attitude toward COVID-19 vaccines are scarce. Thus, this study aims to assess the community attitudes and perceptions toward COVID-19 vaccines in Jazan Province, Saudi Arabia. METHODS: A cross-sectional, retrospective study using an online questionnaire was conducted among the public in Jazan, the southern region of Saudi Arabia. General and demographic data were collected, and perception and attitude toward COVID-19 vaccines were evaluated. RESULTS: Most participants in this study were female (67%) with a median age of 23 years. The majority held a bachelor's degree, and they trusted the Saudi healthcare system. Our survey showed that 67% of the study participants had positive perceptions toward COVID-19 vaccines, a finding that is significantly associated with receiving the influenza vaccine in the past, the existence of trust on the current healthcare system and holding positive beliefs toward the effectiveness of the current COVID-19 vaccines in reducing the risk of infection, complication, and mortality. CONCLUSIONS: The proportion of the public in Jazan who believed in the COVID-19 vaccine effectiveness is not inferior from similar international reports. Thus, national awareness programs toward the effectiveness of the vaccine could be enhanced to accelerate vaccination coverage. Further, nationwide surveys are warranted to include larger populations from different communities to assess the overall perception toward COVID-19 vaccines in the whole country.

Side Effects of COVID-19 Pfizer-BioNTech mRNA Vaccine in Children Aged 12-18 Years in Saudi Arabia.

Background: Massive vaccination campaigns have been undertaken globally to combat the spread of the Coronavirus Disease 2019 (COVID-19). While most COVID-19 vaccines have shown excellent efficacy and safety profiles in clinical studies, real-world monitoring of vaccine safety is still important. In this study, we aimed to investigate the early side effects of Pfizer-BioNTech (BNT162b2) mRNA vaccine in children between 12-18 years old in Saudi Arabia. Method: To investigate the side effects in children in this age range following the administration of either one or two doses of Pfizer-BioNTech (BNT162b2) mRNA vaccine, we conducted a retrospective, cross-sectional study using a self-administered online survey. General and demographic data were collected, and vaccine-associated side effects following vaccination were evaluated. Results: The study recruited a total of 965 eligible participants. Overall, 571 (60%) of the study participants reported at least one side effect following Pfizer-BioNTech (BNT162b2) mRNA vaccination. The most frequently reported side effects were pain or redness at the site of injection (90%), fatigue (67%), fever (59%), headache (55%), nausea or vomiting (21%), and chest pain and shortness of breath (20%). Joint or bone pain were reported less frequently among our participants (2%). Our data showed that more female participants reported side effects compared to male participants, with 52% and 48%, respectively. Side effects were more common after the second dose compared to the first dose in our study cohort. Conclusions: While 60% of the children (12-18 years old) who received Pfizer-BioNTech (BNT162b2) mRNA vaccine reported side effects, our data showed that these side effects were not different from those that were reported in the clinical trials which lasted only for a few days. Side effects were more common after the second dose. Larger epidemiological and molecular studies are needed to evaluate the safety and the effectiveness of COVID-19 vaccine in protection of children against SARS-CoV-2 reinfections.

Proteoglycan-4 is an essential regulator of synovial macrophage polarization and inflammatory macrophage joint infiltration.

BACKGROUND: Synovial macrophages perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. The functional diversity of macrophages is enabled by distinct subpopulations that express unique surface markers. Proteoglycan-4 (PRG4) is an important regulator of synovial hyperplasia and fibrotic remodeling, and the involvement of macrophages in PRG4's synovial role is yet to be defined. Our objectives were to study the PRG4's importance to macrophage homeostatic regulation in the synovium and infiltration of pro-inflammatory macrophages in acute synovitis and investigate whether macrophages mediated synovial fibrosis in Prg4 gene-trap (Prg4GT/GT) murine knee joints. METHODS: Macrophage phenotyping in Prg4GT/GT and Prg4+/+ joints was performed by flow cytometry using pan-macrophage markers, e.g., CD11b, F4/80, and surface markers of M1 macrophages (CD86) and M2 macrophages (CD206). Characterizations of the various macrophage subpopulations were performed in 2- and 6-month-old animals. The expression of inflammatory markers, IL-6, and iNOS in macrophages that are CD86+ and/or CD206+ was studied. The impact of Prg4 recombination on synovial macrophage populations of 2- and 6-month-old animals and infiltration of pro-inflammatory macrophages in response to a TLR2 agonist challenge was determined. Macrophages were depleted using liposomal clodronate and synovial membrane thickness, and the expression of fibrotic markers α-SMA, PLOD2, and collagen type I (COL-I) was assessed using immunohistochemistry. RESULTS: Total macrophages in Prg4GT/GT joints were higher than Prg4+/+ joints (p<0.0001) at 2 and 6 months, and the percentages of CD86+/CD206- and CD86+/CD206+ macrophages increased in Prg4GT/GT joints at 6 months (p<0.0001), whereas the percentage of CD86-/CD206+ macrophages decreased (p<0.001). CD86+/CD206- and CD86+/CD206+ macrophages expressed iNOS and IL-6 compared to CD86-/CD206+ macrophages (p<0.0001). Prg4 re-expression limited the accumulation of CD86+ macrophages (p<0.05) and increased CD86-/CD206+ macrophages (p<0.001) at 6 months. Prg4 recombination attenuated synovial recruitment of pro-inflammatory macrophages in 2-month-old animals (p<0.001). Clodronate-mediated macrophage depletion reduced synovial hyperplasia, α-SMA, PLOD2, and COL-I expressions in the synovium (p<0.0001). CONCLUSIONS: PRG4 regulates the accumulation and homeostatic balance of macrophages in the synovium. In its absence, the synovium becomes populated with M1 macrophages. Furthermore, macrophages exert an effector role in synovial fibrosis in Prg4GT/GT animals.