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The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

The fabrication, characterization and application of a nanoporous Silicon Rugate Filter (pSiRF) loaded with an enzymatically degradable polymer is reported as a bare eye detection optical sensor for enzymes of pathogenic bacteria, which is devoid of any dyes. The nanopores of pSiRF were filled with poly(lactic acid) (PLA), which, upon enzymatic degradation, resulted in a change in the effective refractive index of the pSiRF film, leading to a readily discernible color change of the sensor. The shifts in the characteristic fringe patterns before and after the enzymatic reaction were analyzed quantitatively by Reflectometric Interference Spectroscopy (RIfS) to estimate the apparent kinetics and its dependence on enzyme concentration. A clear color change from green to blue was observed by the bare eye after PLA degradation by proteinase K. Moreover, the color change was further confirmed in measurements in bacterial suspensions of the pathogen Pseudomonas aeruginosa (PAO1) as well as in situ in the corresponding bacterial supernatants. This study highlights the potential of the approach in point of care bacteria detection.

Lynch syndrome (LS) is the most common cause of inherited endometrial cancer (EC). The prevalence and molecular characteristic of LS in Middle Eastern women with EC have been underexplored. To evaluate the frequency of LS in a cohort of EC patients from Saudi Arabia, a total of 436 EC cases were screened utilizing immunohistochemistry (IHC), MLH1 promoter methylation analysis and next-generation sequencing technology. A total of 53 of 436 (12.2%) ECs were classified as DNA mismatch repair-deficient (dMMR). MLH1 promoter hypermethylation was detected in 30 ECs (6.9%). Three ECs (0.7%) were found to be LS harboring germline pathogenic variants (PVs)/likely pathogenic variants (LPVs): two in the MSH2 gene and one in the MSH6 gene. Three ECs (0.7%) were Lynch-like syndrome (LLS) carrying double somatic MSH2 PVs/LPVs. Seven cases were found to have variants of uncertain significance in cancer-related genes other than MMR genes. Our results indicate that LS prevalence is low among Saudi EC patients and LLS is as common as LS in this ethnicity. Our findings could help in better understanding of the prevalence and mutational spectrum of this syndrome in Saudi Arabia, which may help in defining best strategies for LS identification, prevention and genetic counseling for EC patients.

Background and objective This study was designed to compare the efficacy of curcumin (CRN) with that of nano-curcumin (N-CRN) in the mitigation of various biochemical indices in hypoxic lung induced by sodium nitrite (SN) in rats. Methods Twenty-four adult male albino rats were divided into 4 groups. Group 1: control group received carboxy methyl cellulose; Group 2: hypoxic group injected with single dose of SN (60 mg/kg, s.c.); Group 3: SN-intoxicated rats pre-injected with CRN (100 mg/kg, i.p.); and Group 4: SN-intoxicated rats pre-injected with N-CRN (100 mg/kg, i.p.). Curcumin and N-CRN were administered intraperitoneally 2 hour prior to SN intoxication. Hemoglobin concentration, serum tumor necrosis factor-alpha (TNF-α), and caspase-3 were analyzed. Gene expression of hypoxia inducible factor-1 (HIF-1α), matrix metallo-proteinases (MMP)-2, and tissue inhibitors of metalloproteinases (TIMPs)-2, as well as the protein expression of mitogen-activated protein kinases (MAPKs) and c-Jun NH2-terminal kinase (JNK) were examined in lung tissues. Results Hemoglobin level was markedly reduced, and serum TNF-α and caspase-3 were significantly elevated post SN intoxication. The lung MMP-2 and HIF-1α mRNA were overexpressed in the hypoxic group; while TIMP-2 mRNA was downregulated. Sodium nitrite administration increased proteins’ expressions of MAPK and JNK. Pretreatment with CRN or N-CRN markedly mitigated those alterations. These results were supported by histopathological examinations of lung tissue. Conclusion Interestingly, N-CRN exhibited a pronounced protective effect via suppression of inflammatory and apoptotic biomarkers and modulation of MAPK/JNK signaling pathway.

Today, the world is fighting against a dangerous epidemic caused by the novel coronavirus, also known as COVID-19. All have been impacted and countries are trying to recover from the social, economic, and health devastations of COVID-19. Recent epidemiology research has concentrated on using different prediction models to estimate the numbers of infected, recovered, and deceased cases around the world. This study is primarily focused on evaluating two common prediction models: Susceptible – Infected – Recovered (SIR) and Susceptible – Exposed – Infected – Recovered (SEIR). The SIR and SEIR models were compared in estimating the outbreak and identifying the better fitting model for forecasting future spread in Kuwait. Based on the results of the comparison, the SEIR model was selected for predicting COVID-19 infected, recovered, and cumulative cases. The data needed for estimation was collected from official sites of the Kuwait Government between 24 February and 1 December 2020. This study presents estimated values for peak dates and expected eradication of COVID-19 in Kuwait. The proposed estimation model is simulated using the Python Programming language on the collected data. The simulation was performed with various basic reproduction numbers (between 5.2 and 3), the initial exposed population, and the incubation rate. The results show that the SEIR model was better suited than the SIR model for predicting both infection and recovery cases with R0 values ranging from 3 to 4, E0=80 and α=0.2.

Abstract In late 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) emerged in Wuhan, China. SARS‐CoV‐2 and the disease it causes, coronavirus disease 2019 (COVID‐19), spread rapidly and became a global pandemic in early 2020. SARS‐CoV‐2 spike protein is responsible for viral entry and binds to angiotensin converting enzyme 2 (ACE2) on host cells, making it a major target of the immune system – particularly neutralizing antibodies (nAbs) that are induced by infection or vaccines. Extracellular vesicles (EVs) are small membraned particles constitutively released by cells, including virally‐infected cells. EVs and viruses enclosed within lipid membranes share some characteristics: they are small, sub‐micron particles and they overlap in cellular biogenesis and egress routes. Given their shared characteristics, we hypothesized that EVs released from spike‐expressing cells could carry spike and serve as decoys for anti‐spike nAbs, promoting viral infection. Here, using mass spectrometry and nanoscale flow cytometry (NFC) approaches, we demonstrate that SARS‐CoV‐2 spike protein can be incorporated into EVs. Furthermore, we show that spike‐carrying EVs act as decoy targets for convalescent patient serum‐derived nAbs, reducing their effectiveness in blocking viral entry. These findings have important implications for the pathogenesis of SARS‐CoV‐2 infection in vivo and highlight the complex interplay between viruses, extracellular vesicles, and the immune system that occurs during viral infections.

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

Isoproterenol (ISO), a chemically synthesized catecholamine, belongs to β-adrenoceptor agonist used to treat bradycardia. The β-adrenergic agonist is an essential regulator of myocardial metabolism and contractility; however, excessive exposure to ISO can initiate oxidative stress and inflammation. This study aims to investigate the molecular mechanisms underlying ISO-induced cardiac remodeling, the protective efficacy of resveratrol (RSVR), and its liposomal formulation (L-RSVR) against such cardiac change. Wistar albino rats were evenly divided into 4 groups. Control group, ISO group received ISO (50 mg/kg, s.c.) twice a week for 2 weeks, and RSVR- and L-RSVR-treated groups in which rats received either RSVR or L-RSVR (20 mg/kg/day, p.o.) along with ISO for 2 weeks. ISO caused a significant elevation of the expression levels of BAX and MEF2 mRNA, S100A1 and cytochrome C proteins, as well as DNA fragmentation in cardiac tissue compared to the control group. Treatment with either RSVR or L-RSVR for 14 days significantly ameliorated the damage induced by ISO, as evidenced by the improvement of all measured parameters. The present study shows that L-RSVR provides better cardio-protection against ISO-induced cardiac injury in rats, most likely through modulation of cardiac S100A1 protein expression and inhibition of inflammation and apoptosis. [ABSTRACT FROM AUTHOR]

The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% of patients with hereditary ataxia remain genetically undiagnosed. One current shortcoming is the fragmentation of patients and NGS datasets on different analysis platforms and databases around the world. The AGI NGS working group in collaboration with the AGI associated research platforms—CAGC, GENESIS, and RD-Connect GPAP—provides clinicians and scientists access to user-friendly and adaptable interfaces to analyze genome-scale patient data. These platforms also foster collaboration within the ataxia community. These efforts and tools have led to the diagnosis of > 500 ataxia patients and the discovery of > 30 novel ataxia genes. Here, the AGI NGS working group presents their consensus recommendations for NGS data sharing initiatives in the ataxia field, focusing on harmonized NGS variant analysis and standardized clinical and metadata collection, combined with collaborative data and analysis tool sharing across platforms. [ABSTRACT FROM AUTHOR]

Copper is essential for several cellular processes and is an important catalytic factor for many proteins. However, excess copper can provoke oxidative stress and reproductive toxicity. This study evaluated the effect of liposomal nano-curcumin (N-CUR) and CUR on testicular oxidative injury, inflammation, and apoptosis, and altered steroidogenesis and Nrf2/HO-1 signaling induced by copper sulfate (CuSO4). Rats received CuSO4 and N-CUR or CUR via oral gavage for 7 days. CuSO4 induced histopathological changes and altered pituitary-gonadal axis manifested by decreased serum gonadotropins and testosterone. Testicular steroidogenesis genes (StAR, 3β-HSD, CYP17A1, and 17β-HSD) and androgen receptor (AR) were downregulated in rats that received CuSO4. N-CUR and CUR prevented testicular tissue injury, increased circulating FSH, LH, and testosterone, and upregulated testicular steroidogenesis genes and AR. Additionally, N-CUR and CUR decreased testicular MDA, NO, NF-κB, iNOS, TNF-α, Bax, and caspase-3 while enhanced Bcl-2, Nrf2, and the antioxidants GSH, HO-1, SOD, and catalase. In conclusion, N-CUR and CUR prevented CuSO4-induced reproductive toxicity in male rats by suppressing oxidative injury and inflammatory response and boosting steroidogenesis, sex hormones, and Nrf2/HO-1 signaling. N-CUR was more effective in ameliorating tissue injury, oxidative stress, inflammation, and apoptosis and enhancing steroidogenesis and Nrf2/HO-1 than the native form.

Background and Objective: Mercury is one of the most harmful heavy metals and its toxicity causes severe multi-organ dysfunction. This study was designed to explore novel molecular pathways involved in the hepatoprotective effect of vitamin E (Vit-E) and Lactobacillius plantarum (Lac-B) against mercury toxicity. Method: Acute hepatotoxicity was induced by administration of high dose of mercuric chloride (HgCl 2 ) in male rats, Vit-E or/and Lac-B were given along with HgCl 2 for 2 weeks. The effects of those antioxidants were studied focusing on their anti-apoptotic, anti-oxidative stress and anti-inflammatory eficacies. Histopathological examinations were also conducted. Results: The administration of HgCl 2 induced liver injury which manifested by elevation in serum ALT and AST. Liver MDA, caspase-3 and TNF-α levels were markedly increased; whereas, GSH level and SOD activity were declined. HgCl 2 significantly elevated the expressions of hepatic CHOP, GPR87, NF-κB and mTOR. Histopathological examination revealed massive hepatocyte degeneration following HgCl 2 administration. Treatment with Vit-E or/and Lac-B restored the normal levels of the previously mentioned parameters, as well as improved hepatic architecture. Conclusion: Vit-E and Lac-B provided protective effect against HgCl 2 -induced hepatotoxicity via reduction of oxidative stress and inflammation, and downregulation of CHOP, GPR87, NF-κB and mTOR proteins’ expressions.

Objective: Little information is available about the etiology, pathophysiology, risk factors, and epidemiologic features of Bone Tuberculosis (Bone-TB). In this work, we present the epidemiological data about the Bone-TB in the Sultanate of Oman. Methods: Retrospectively, we identified and assessed those patients who were diagnosed with Bone-TB between January 2002 and December 2019 at Khoula Hospital. The following data were collected: demographics, clinical presentation, anatomical location, diagnosis, and treatment of the Bone-TB. Results: During the study period, 115 cases of Bone-TB were diagnosed. Males were affected more than females (57.4% and 42.6%, respectively). About 30% of Bone-TB cases were primary diagnosed in other organs particularly the lungs and then after disseminated to the bone. However, the Bone-TB was detected in hip, leg, hand, shoulder, and skull bones, the most detected Bone-TB was in spine (66% of cases). After vaccination the Bacillus Calmette–Guérin (BCG) strains were identified in the bones of eight babies. Tubercle bacilli were detected by Acid-Fast Stain (AFS) in 59% of cases, and the rest of cases were confirmed using polymerase chain reaction (PCR) tests. There are two used treatment regimens, with 12.4% relapse. The gastrointestinal tract (GIT) disturbances were the most related side effects. The resistance has been detected to pyrazinamide in six cases, rifampicin in three cases, and isoniazid, streptomycin and kanamycin were detected in one case. Conclusion: The most predominant Bone-TB cases were spine-TB that were mainly disseminated from the lungs. AFS failed to detect tubercle bacilli in 40% of cases. There is no statistical significance in relapse between the used two regimens. The death was predominant among skull-TB cases.

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with (“lesional”) and without (“non-lesional”) radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68–75%) compared to models to lateralize the side of TLE (56–73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67–75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68–76%) than models that stratified non-lesional patients (53–62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.

The current study aimed to develop and evaluate a sustained-release transdermal Glipizide (GLP) film to overcome its oral administration problems. Chitosan (CS)-coated deformable liposomes (DLs) were utilized to enhance the drug transdermal delivery. The formulations were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), vesicle deformability, morphology, stability, and in vitro release. Transdermal films of chosen formulations were prepared by the solvent casting technique, and an ex vivo study throughout rat skin was also performed. Moreover, a pharmacokinetics (PK) study was carried out and blood glucose levels were estimated. All the liposomes were in the nanometer range and a high EE% was obtained from DLs compared to conventional liposomes (CL). The prepared formulations showed a high stability and the DLs exhibited a high deformability compared to CL. The in vitro release study confirmed the sustained release of GLP from both CL and DL and a more pronounced sustained release of GLP was detected after coating with CS. Moreover, GLP was shown to efficiently permeate through the rat skin from transdermal films by an ex vivo permeation test. The transdermal films showed a promising PK profile in the rat as compared with oral GLP. Most importantly, GLP-CS-DL1 demonstrated a higher hypoglycemic effect, confirming the possibility of systemic action by the local topical delivery of GLP.

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

Background. Early mobilisation of patients in the intensive care unit (ICU) is associated with positive health benefits. Research literature lacks insight into the current status of ICU physical therapy (PT) practice in the Kingdom of Saudi Arabia. Aim. To determine the current standard of ICU PT practice, attitude, and barriers. Methods. A questionnaire was e-mailed to physiotherapists (PTs) working in the hospital. The questions pertained to experience, qualification, barriers, and most frequently encountered case scenarios in the ICU. Results. The response rate was 28.1% (124/442). Frequent cases referred to the PTs were traumatic paraplegia (n = 111, 89%) and stroke (n = 102, 82.3%) as compared to congestive heart failure (n = 20, 16.1%) and pulmonary infections (n = 7, 5.6%). The preferred treatment of choice among PTs was chest physiotherapy (n = 102, 82.2%) and positioning (n = 73, 58.8%), whereas functional electrical stimulation (n = 12, 9.6%) was least preferred irrespective of the condition. Perceived barriers in the ICU PT management were of low confidence in managing cases (n = 89, 71.7%) followed by inadequate training (n = 53, 42.7%), and the least quoted barrier was a communication gap between the critical care team members (n = 8, 6.4%). Conclusion. PTs reported significant variation in the choice of treatment for different clinical cases inside ICU. The main barriers in the ICU setting were low confidence and inadequate training.

Drug shortages are a multifaceted problem that has been recurring in Saudi Arabia over the past decade with its significant negative impact on patient care. However, there is a dearth of evidence about possible domestic reasons, if any, behind this recurring problem. Recently, the Pharmacy Education Unit at King Saud University College of Pharmacy has called for a meeting with multiple stakeholders from academia, pharmaceutical care, pharmaceutical industry, purchasing and planning, and regulatory bodies to unveil the root domestic causes of the drug shortages in the Kingdom. Four major topics were used to guide the discussion in this meeting, including: current situation of drug shortages in Saudi Arabia, major factors contributing to drug shortages, challenges and obstacles to improve drug supply, and stakeholders’ recommendations to manage drug shortages. The meeting was audio-recorded and transcribed into verbatim by five authors. The text was then reviewed and analyzed to identify different themes by the first and third authors. Multiple causes were identified and several recommendations were proposed. The main domestic causes of drug shortages that were explored in this study included poor medication supply chain management, lack of government regulation that mandates early notification of drug shortages, a government procurement policy that does not keep pace with the changes in the pharmaceutical market, low profit margins of some essential drugs, weak and ineffective law-violation penalties against pharmaceutical companies and licensed drug importers and distributors, and overdependence on drug imports. The participants have also proposed multiple recommendations to address drug shortages. Policy makers should consider these factors that contribute to drug shortages in Saudi Arabia as well as the recommendations when designing future initiatives and interventions to prevent drug shortages. Keywords: Shortage, Drugs, Patient safety

Summary: Tissue-specific mRNA stability is important for cell fate and physiology, but the mechanisms involved are not fully understood. We found that zygotic mRNA stability in Drosophila correlates with codon content: optimal codons are enriched in stable transcripts associated with metabolic functions like translation, while non-optimal codons are enriched in unstable transcripts, including those associated with neural development. Bioinformatic analyses and reporter assays revealed that similar codons stabilize or destabilize mRNAs in the nervous system and other tissues, but the link between codon content and stability is attenuated in the nervous system. We confirmed that optimal codons are decoded by abundant tRNAs while non-optimal codons are decoded by less abundant tRNAs in embryos and in the nervous system. We conclude that codon optimality is a general determinant of zygotic mRNA stability, and attenuation of codon optimality allows trans-acting factors to exert greater influence over mRNA decay in the nervous system. : Burow et al. report that codon optimality is a general determinant of zygotic mRNA stability in Drosophila embryos, but the link between codons and stability is weak in the nervous system. Bioinformatics, reporter transcript assays, and tRNA quantitation show that the attenuation of codon optimality establishes neural-specific mRNA decay. Keywords: codon optimality, mRNA stability, development, nervous system, tRNA, Drosophila

Background: Down syndrome is a genetic disorder that causes physical and cognitive challenges. Identifying the impact of sedentary behavior and physical activity on people with Down syndrome is crucial for early intervention. The purpose of this study is to compare physical activity and sedentary behavior among children with Down syndrome and typically developing children, as well as assess their relationship with quality of life. Methods: In the cross-sectional study, 67 children between the ages of 6 and 12 were enrolled: 29 in the Down syndrome group and 38 in the typically developing group. Each child wore an ActiGraph wGT3X-BT for seven days. Accelerometer data and quality of life data were analysed. Results: Physical activity and sedentary behavior were not significantly different between the Down syndrome and typically developing groups (p ˃.05). With large effect sizes (partial eta squares ranging from 0.21 to 0.59), typically developing children had a significantly better quality of life than children with Down syndrome. There was a weak positive correlation between moderate physical activity and school performance in children with Down syndrome. For typically developing children, there is a weak negative correlation between light physical activity and physical function, school function, and total paediatric quality of life scale scores. Conclusions: This study indicates that children with Down syndrome have participated in more physical activities, resulting in a reduction in differences between them and typically developing children. Additionally, typically developing had higher quality of life than children with Down syndrome. For healthcare professionals and educators, these findings provide valuable insights into developing strategies to enhance physical activity for children with developmental disabilities. [ABSTRACT FROM AUTHOR]

Copper (Cu) is essential for a plethora of biological processes; however, its high redox reactivity renders it potentially toxic. This study investigated the protective effect of curcumin (CUR) and nano-CUR (N-CUR) against Cu cardiotoxicity, emphasizing the role of oxidative stress, TLR4/NF-κB and mitogen-activated protein kinase (MAPK) signaling and cell death in rats. Rats received 100 mg/kg copper sulfate (CuSO4), a pesticide used for repelling pests, and were concurrently treated with CUR or N-CUR for 7 days. Cu caused cardiac injury manifested by elevated serum cardiac troponin I (cTnI), creatine kinase (CK)-MB, and lactate dehydrogenase (LDH), as well as histopathological alterations. Cardiac malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 were increased, and reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were decreased in Cu-treated rats. CUR and N-CUR prevented cardiac tissue injury, decreased serum cTnI, CK-MB, and LDH, and cardiac MDA, NF-κB p65, TNF-α, and IL-6, and enhanced cellular antioxidants. CUR and N-CUR downregulated TLR4 and AP-1, and decreased the phosphorylation levels of p38 MAPK, JNK, and ERK1/2. In addition, CUR and N-CUR increased cardiac Bcl-2 and BAG-1, decreased Bax and caspase-3, and prevented DNA fragmentation. In conclusion, N-CUR prevents Cu cardiotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis, and modulating TLR4/NF-κB and MAPK signaling. The cardioprotective effect of N-CUR was more potent than the native form.

Copper (Cu) is essential for multiple biochemical processes, and copper sulphate (CuSO4) is a pesticide used for repelling pests. Accidental or intentional intoxication can induce multiorgan toxicity and could be fatal. Curcumin (CUR) is a potent antioxidant, but its poor systemic bioavailability is the main drawback in its therapeutic uses. This study investigated the protective effect of CUR and N-CUR on CuSO4-induced cerebral oxidative stress, inflammation, and apoptosis in rats, pointing to the possible involvement of Akt/GSK-3β. Rats received 100 mg/kg CuSO4 and were concurrently treated with CUR or N-CUR for 7 days. Cu-administered rats exhibited a remarkable increase in cerebral malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 associated with decreased GSH, SOD, and catalase. Cu provoked DNA fragmentation, upregulated BAX, caspase-3, and p53, and decreased BCL-2 in the brain of rats. N-CUR and CUR ameliorated MDA, NF-κB p65, and pro-inflammatory cytokines, downregulated pro-apoptotic genes, upregulated BCL-2, and enhanced antioxidants and DNA integrity. In addition, both N-CUR and CUR increased AKT Ser473 and GSK-3β Ser9 phosphorylation in the brain of Cu-administered rats. In conclusion, N-CUR and CUR prevent Cu neurotoxicity by attenuating oxidative injury, inflammatory response, and apoptosis and upregulating AKT/GSK-3β signaling. The neuroprotective effect of N-CUR was more potent than CUR.

Diabetes is a ubiquitous disease that causes several complications. It is associated with insulin resistance, which affects the metabolism of proteins, carbohydrates, and fats and triggers liver diseases such as fatty liver disease, steatohepatitis, fibrosis, and cirrhosis. Despite the effectiveness of Sitagliptin (ST) as an antidiabetic drug, its role in diabetes-induced liver injury is yet to be fully investigated. Therefore, this study aims to investigate the effect of ST on hepatic oxidative injury, inflammation, apoptosis, and the mTOR/NF-κB/NLRP3 signaling pathway in streptozotocin (STZ)-induced liver injury. Rats were allocated into four groups: two nondiabetic groups, control rats and ST rats (100 mg/kg), and two diabetic groups induced by STZ, and they received either normal saline or ST for 90 days. Diabetic rats showed significant hyperglycemia, hyperlipidemia, and elevation in liver enzymes. After STZ induction, the results revealed remarkable increases in hepatic oxidative stress, inflammation, and hepatocyte degeneration. In addition, STZ upregulated the immunoreactivity of NF-κB/p65, NLRP3, and mTOR but downregulated IKB-α in liver tissue. The use of ST mitigated metabolic and hepatic changes induced by STZ; it also reduced oxidative stress, inflammation, and hepatocyte degeneration. The normal expression of NF-κB/p65, NLRP3, mTOR, and IKB-α were restored with ST treatment. Based on that, our study revealed for the first time the hepatoprotective effect of ST that is mediated by controlling inflammation, oxidative stress, and mTOR/NF-κB/NLRP3 signaling. [ABSTRACT FROM AUTHOR]