Lycopene attenuates chlorpyrifos-induced hepatotoxicity in rats via activation of Nrf2/HO-1 axis.

Chlorpyrifos (CPF), is an organophosphate pesticide that is widely used for agricultural purposes. However, it has well-documented hepatotoxicity. Lycopene (LCP) is a plant-derived carotenoid with antioxidant and anti-inflammatory activities. The present work was designed to evaluate the potential hepatoprotective actions of LCP against CPF-induced hepatotoxicity in rats. Animals were assigned into five groups namely: Group I (Control), Group II (LCP), Group III (CPF), Group IV (CPF + LCP 5 mg/kg), and Group V (CPF + LCP 10 mg/kg). LCP offered protection as evidenced by inhibiting the rise in serum activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) induced by CPF. This was confirmed histologically as LCP-treated animals showed liver tissues with less proliferation of bile ducts and periductal fibrosis. LCP significantly prevented the rise in hepatic content of malondialdehyde (MDA), depletion of reduced glutathione (GSH), and exhaustion of glutathione-s-transferase (GST) and superoxide dismutase (SOD). Further, LCP significantly prevented hepatocyte death as it ameliorated the increase in Bax and the decrease in Bcl-2 expression induced by CPF in liver tissues as determined immunohistochemically. The observed protective effects of LCP were further confirmed by a significant enhancement in heme oxygenase-1 (HO-1) and NF-E2-related factor 2 (Nrf2) expression. In conclusion, LCP possesses protective effects against CPF-induced hepatotoxicity. These include antioxidation and activation of the Nrf2/HO-1 axis.

Parthenolide Phytosomes Attenuated Gentamicin-Induced Nephrotoxicity in Rats via Activation of Sirt-1, Nrf2, OH-1, and NQO1 Axis.

Nephrotoxicity is a serious complication that limits the clinical use of gentamicin (GEN). Parthenolide (PTL) is a sesquiterpene lactone derived from feverfew with various therapeutic benefits. However, PTL possesses low oral bioavailability. This study aimed to evaluate the therapeutic protective effects of PTL-phytosomes against GEN-induced nephrotoxicity in rats. The PTL was prepared as phytosomes to improve the pharmacological properties with a particle size of 407.4 nm, and surface morphology showed oval particles with multiple edges. Rats were divided into six groups: control, nano-formulation plain vehicle, PTL-phytosomes (10 mg/kg), GEN (100 mg/kg), GEN + PTL-phytosomes (5 mg/kg), and GEN + PTL-phytosomes (10 mg/kg). The administration of PTL-phytosomes alleviated GEN-induced impairment in kidney functions and histopathological damage, and decreased kidney injury molecule-1 (KIM-1). The anti-oxidative effect of PTL-phytosomes was demonstrated by the reduced malondialdehyde (MDA) concentration and increased superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, PTL-phytosomes treatment significantly enhanced sirtuin 1 (Sirt-1), nuclear factor erythroid-2-related factor-2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1). Additionally, PTL-phytosomes treatment exhibited anti-inflammatory and anti-apoptotic properties in the kidney tissue. These findings suggest that PTL-phytosomes attenuate renal dysfunction and structural damage by reducing oxidative stress, inflammation, and apoptosis in the kidney.

Allele frequency and genotype distribution of the opioid receptor µ-1 (OPRM1) A118G polymorphism in the Western Saudi population.

The single nucleotide polymorphism (SNP) A118G (rs1799971) in the Mu Opioid Receptor 1 (OPRM1) gene is associated with significant variations in analgesic doses and adverse effects of opioids. The A118G OPRM1 allele distributions vary significantly between different populations worldwide. The study aimed to assess the allele frequency and genotype distribution of OPRM1 A118G SNP in Saudis. This cross-sectional study included 124 healthy Saudis (62 males and 62 females) visiting the King Abdulaziz University Hospital in Jeddah, Saudi Arabia. The Oragene®-DISCOVER (OGR-600) kits were used to collect saliva samples from the participants. Polymerase chain reaction-restriction fragment length polymorphism was utilized to assess the SNP. Among the tested population, 79.03% (95% C.I. 70.81-85.82) were homozygous wild-type A118A, 16.13% (95% C.I. 10.14-23.80) were heterozygous A118G, and 4.84% (95% C.I. 1.80-10.23) were homozygous mutant G118G. OPRM1 A118G polymorphism allele frequencies were 87% (95% C.I. 79.89-92.44) and 13% (95% C.I. 7.56-20.11) for the 118A and 118G alleles, respectively. A higher frequency of the OPRM1 118G allele was present in females, 21% (95% C.I. 11.66-33.17) compared to males, 5% (95% C.I. 1.01-13.50). Relative to other Asian countries, the Saudi population showed a low prevalence of the OPRM1 A118G polymorphism, with a higher frequency of the 118G allele in females. Our research will contribute to the existing knowledge on the prevalence of OPRM1 A118G polymorphism, which could be considered for the personalized prescribing of opioid analgesics.

Cannabinoid receptor 1 positive allosteric modulator (GAT229) attenuates cisplatin-induced neuropathic pain in mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of chemotherapies' most often documented side effects. Patients with CIPN experience spontaneous burning, numbness, tingling, and neuropathic pain in their feet and hands. Currently, there is no effective pharmacological treatment to prevent or treat CIPN. Activating the cannabinoid receptor type 1 (CB1) by orthosteric agonists has shown promising results in alleviating the pain and neuroinflammation associated with CIPN. However, the use of CB1 orthosteric agonists is linked to undesirable side effects. Unlike the CB1 orthosteric agonists, CB1 positive allosteric modulators (PAMs) don't produce any psychoactive effects, tolerance, or dependence. Previous studies have shown that CB1 PAMs exhibit antinociceptive effects in inflammatory and neuropathic rodent models. This study aimed to investigate the potential benefits of the newly synthesized GAT229, a pure CB1 PAM, in alleviating neuropathic pain and slowing the progression of CIPN. GAT229 was evaluated in a cisplatin-induced (CIS) mouse model of peripheral neuropathic pain (3 mg/kg/d, 28 d, i.p.). GAT229 attenuated and slowed the progression of thermal hyperalgesia and mechanical allodynia induced by CIS, as evaluated by the hotplate test and von Frey filament test. GAT229 reduced the expression of proinflammatory cytokines in the dorsal root ganglia (DRG) neurons. Furthermore, GAT229 attenuated nerve injuries by normalizing the brain-derived neurotrophic factor and the nerve growth factor mRNA expression levels in the DRG neurons. The CB1 receptor antagonist/inverse agonist AM251 blocked GAT229-mediated beneficial effects. According to our data, we suggest that CB1 PAMs might be beneficial in alleviating neuropathic pain and slowing the progression of CIPN.

Protective Effects of 2-Methoxyestradiol on Acute Isoproterenol-Induced Cardiac Injury in Rats.

Myocardial injury (MI) is an important pathological driver of mortality worldwide., and arises as a result of imbalances between myocardial oxygen demand and supply. In MI, oxidative stress often leads to inflammatory changes and apoptosis. Current therapies for MI are known to cause various adverse effects. Consequently, the development of new therapeutic agents with a reduced adverse event profile is necessary. In this regard, 2-methoxyestradiol (2ME), the metabolic end-product of oestradiol, possesses anti-inflammatory and antioxidant properties. The aim of this research is to assess the impact of 2ME on cardiac injury caused by isoproterenol (ISO) in rats. Animals were separated into six groups; controls, and those receiving 2ME (1 mg/kg), ISO (85 mg/kg), ISO + 2ME (0.25 mg/kg), ISO + 2ME (0.5 mg/kg), and ISO + 2ME (1 mg/kg). 2ME significantly attenuated ISO-induced changes in electrocardiographic changes and the cardiac histological pattern. This compound also decreased lactate dehydrogenase activity, creatine kinase myocardial band and troponin levels. The ability of 2ME to act as an antioxidant was shown by a decrease in malondialdehyde concentration, and the restoration of glutathione levels and superoxide dismutase activity. Additionally, 2ME antagonized inflammation and cardiac cell apoptosis, a process determined to be mediated, at least partially, by suppression of Gal-3/TLR4/MyD88/NF-κB signaling pathway. 2ME offers protection against acute ISO-induced MI in rats and offers a novel therapeutic management option.

The effect of virtual reality distraction on anxiety level during dental treatment among anxious pediatric patients: a randomized clinical trial.

This study evaluated the effect of Virtual Reality Distraction (VRD) on dental anxiety among anxious children undergoing prophylactic dental treatment by utilizing both subjective (Venham Anxiety and Behavioral Rating Scale (VABRS)) and objective (heart rate (HR) and salivary cortisol level (SCL)) measures. This randomized controlled study included 36 (6- to 14-year-old) healthy and anxious children who needed prophylactic dental treatment and had a history of previous dental treatment. The eligible children's anxiety level was evaluated using a modified version of the Abeer Dental Anxiety Scale-Arabic version (M-ACDAS) and those who scored at least 14 or more out of 21 were included. Participants were randomly distributed to either the VRD or control group. In the VRD group, participants wore the VRD eyeglasses during prophylactic dental treatment. In the control group, subjects received their treatment while watching a video cartoon on a regular screen. The participants were videotaped during the treatment, and their HR was recorded at four time points. Also, a sample from each participant's saliva was collected twice, at the baseline and after the procedure. The mean M-ACDAS score at baseline in the VRD and the control groups was not statistically significant (p = 0.424). At the end of the treatment, the SCL was significantly lower in the VRD group (p < 0.001). Neither the VABRS (p = 0.171) nor the HR significantly differed between the VRD and control groups. Virtual reality distraction is a non-invasive method that has the potential to significantly reduce anxiety during prophylactic dental treatment among anxious children.

Genetic polymorphism of the drug-metabolizing enzyme Cytochrome P4502E1 (CYP2E1) in a healthy Saudi population.

OBJECTIVES: Cytochrome P450 2E1 (CYP2E1) is one of the major enzymes involved in the metabolism and detoxification of various drugs and xenobiotics. Polymorphisms in the CYP2E1 gene exhibit high inter-individual variations associated with alterations in CYP2E1 gene expression and enzyme function. This study aimed to determine the genotype distributions and allele frequencies of CYP2E1*1B, *5B, and *6 polymorphisms among Saudis in western Saudi Arabia. METHODS: In total, 140 healthy Saudis attending King Abdulaziz University Hospital between February and April 2021 were included in the study. CYP2E1 gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The genotype frequencies of CYP2E1*1B A2A2, A2A1, and A1A1 were 54.29%, 40%, and 8%, respectively. The frequencies of CYP2E1*5B c1c1 and c1c2 genotypes were approximately 99.93% and 0.07%, respectively. The frequencies of the CYP2E1*6 DD, DC, and CC genotypes were 91.43%, 7.85%, and 0.72%, respectively. The genotype distributions for these polymorphisms were consistent with the expected distribution based on Hardy-Weinberg equilibrium. The allele frequencies were 74.29% A2 and 25.71% A1 for CYP2E1*1B, 99.64% c1 and 0.36% c2 for CYP2E1*5B, and 95.36% D and 4.65% C for CYP2E1*6. CONCLUSION: The genotype distribution of CYP2E1*1B polymorphism was higher in the western Saudi population, whereas the CYP2E1*5B and *6 polymorphisms were lower than the global average. Knowledge of the prevalence of CYP2E1 polymorphisms among our population will provide a better understanding of whether individual patients might benefit from their medication or whether they might develop adverse effects.

Knowledge, perception, and confidence of hospital pharmacists toward pharmacogenetics in Jeddah, Kingdom of Saudi Arabia.

BACKGROUND: Integrating pharmacogenetics (PGx) testing into clinical practice leads to personalized medicine, which improves treatments' efficacy and safety. Successful implementation of such a service requires sufficient knowledge, perception, and self-confidence among healthcare providers, especially pharmacists. OBJECTIVES: To evaluate governmental hospital pharmacists' knowledge, perception, and self-confidence toward PGx testing in Jeddah, Kingdom of Saudi Arabia. METHOD: This cross-sectional study was conducted using previously validated questionnaire. Pharmacists working in five randomly selected general governmental hospitals in Jeddah between August and October 2019 were interviewed. Comparative and descriptive analyses were used to analyze the data, and the significance level was at P-value < 0.05. RESULTS: A total of 119 pharmacists with a mean (±SD) age of 31.2 (±5.05) years were included with a response rate of 79.3%. The average total mean (±SD) score for PGx knowledge-based questions was low (2.4 ± 1.09 out of 5). Most of the participants, with a total mean score of (10.1 ± 1.6 out of 12), revealed a positive perception toward PGx testing and its implications. A moderate self-confidence score for utilizing PGx testing (4.3 ± 2.3 out of 8) was observed among the participants. Pharmacists who had completed postgraduate studies had a statistically higher mean knowledge score (P = 0.006) compared with pharmacists with undergraduate degrees. CONCLUSION: Governmental hospital pharmacists have limited knowledge and understanding about PGx testing; however, the majority expressed a high level of awareness and agreed that PGx testing is a valuable tool for enhancing drug efficacy and safety. The study also highlighted the importance of improving pharmacists' knowledge about PGx testing, which will help them in implementing such a valuable service into their clinical practice in Saudi hospitals.

Heteromer formation between cannabinoid type 1 and dopamine type 2 receptors is altered by combination cannabinoid and antipsychotic treatments.

The cannabinoid type 1 (CB1 ) receptor and the dopamine type 2 (D2 ) receptor are co-localized on medium spiny neuron terminals in the globus pallidus where they modulate neural circuits involved in voluntary movement. Physical interactions between the two receptors have been shown to alter receptor signaling in cell culture. The objectives of the current study were to identify the presence of CB1 /D2 heteromers in the globus pallidus of C57BL/6J male mice, define how CB1 /D2 heteromer levels are altered following treatment with cannabinoids and/or antipsychotics, and determine if fluctuating levels of CB1 /D2 heteromers have functional consequences. Using in situ proximity ligation assays, we observed CB1 /D2 heteromers in the globus pallidus of C57BL/6J mice. The abundance of the heteromers increased following treatment with the nonselective cannabinoid receptor agonist, CP55,940. In contrast, treatment with the typical antipsychotic haloperidol reduced the number of CB1 /D2 heteromers, whereas the atypical antipsychotic olanzapine treatment had no effect. Co-treatment with CP55,940 and haloperidol had similar effects to haloperidol alone, whereas co-treatment with CP55,940 and olanzapine had similar effects to CP55,940. The observed changes were found to have functional consequences as the differential effects of haloperidol and olanzapine also applied to γ-aminobutyric acid release in STHdhQ7/Q7 cells and motor function in C57BL/6J male mice. This work highlights the clinical relevance of co-exposure to cannabinoids and different antipsychotics over acute and prolonged time periods.

Neurodevelopmental and genetic determinants of exposure to adversity among youth at risk for mental illness.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and lower cognitive ability have been linked with increased likelihood of exposure to adversity. We hypothesized that these associations may be partly due to genetic factors. METHODS: We calculated polygenic scores for ADHD and intelligence and assessed psychopathology and general cognitive ability in a sample of 297 youth aged 5-27 years enriched for offspring of parents with mood and psychotic disorders. We calculated an adversity score as a mean of 10 indicators, including socio-economic disadvantage, childhood maltreatment and bullying. We tested the effects of polygenic scores, externalizing symptoms and IQ on adversity scores using mixed-effects linear regression. RESULTS: Externalizing symptoms and general cognitive ability showed expected positive and negative relationships with adversity, respectively. Polygenic scores for intelligence were unrelated to adversity, but polygenic scores for ADHD were associated with adversity (ß = 0.23, 95% CI 0.13 to 0.34, p < .0001). ADHD polygenic scores uniquely explained 4.0% of variance in adversity score. The relationship between polygenic scores for ADHD and adversity was independently significant among individuals with (ß = 0.49, 95% CI 0.25 to 0.75, p < .0001) and without (ß = 0.14, 95% CI 0.02 to 0.26, p = .022) ADHD. CONCLUSIONS: A genetic score indexing liability to ADHD was associated with exposure to adversity in early life. Previously observed associations between externalizing symptoms, lower cognitive ability and adversity may be partially attributed to genetic liability to ADHD.

Endothelin receptor heteromerization inhibits ß-arrestin function in HEK293 cells.

The endothelin receptor A (ETA) and endothelin receptor B (ETB) are G protein-coupled receptors that are co-expressed in vascular smooth muscle cells. Endothelin-1 (ET-1) activates endothelin receptors to cause microvascular vasoconstriction. Previous studies have shown that heteromerization between ETA and ETB prolongs Ca2+ transients, leading to prolongation of Gαq-dependent signaling and sustained vasoconstriction. We hypothesized that these effects are in part mediated by the resistance of ETA/ETB heteromers to ß-arrestin recruitment and subsequent desensitization. Using bioluminescence resonance energy transfer 2 (BRET2), we found that ETB has a relatively equal affinity to form either homomers or heteromers with ETA when co-expressed in the human embryonic kidney 293 (HEK293) cells. When co-expressed, activation of ETA and ETB by ET-1 caused a heteromer-specific reduction and delay in ß-arrestin-2 recruitment with a corresponding reduction and delay in ET-1-induced ETA/ETB co-internalization. Furthermore, the co-expression of ETA and ETB inhibited ET-1-induced ß-arrestin-1-dependent extracellular signal-regulated kinase (ERK) phosphorylation while prolonging ET-1-induced Gαq-dependent ERK phosphorylation. ETA/ETB heteromerization mediates the long-lasting vasoconstrictor response to ET-1 by the prolongation of Gαq-dependent signaling and inhibition of ß-arrestin function.

Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease.

Huntington disease (HD) is an inherited, autosomal dominant, neurodegenerative disorder with limited treatment options. Prior to motor symptom onset or neuronal cell loss in HD, levels of the type 1 cannabinoid receptor (CB1) decrease in the basal ganglia. Decreasing CB1 levels are strongly correlated with chorea and cognitive deficit. CB1 agonists are functionally selective (biased) for divergent signaling pathways. In this study, six cannabinoids were tested for signaling bias in in vitro models of medium spiny projection neurons expressing wild-type (STHdh(Q7/Q7)) or mutant huntingtin protein (STHdh(Q111/Q111)). Signaling bias was assessed using the Black and Leff operational model. Relative activity [ΔlogR (τ/KA)] and system bias (ΔΔlogR) were calculated relative to the reference compound WIN55,212-2 for Gαi/o, Gαs, Gαq, Gßγ, and ß-arrestin1 signaling following treatment with 2-arachidonoylglycerol (2-AG), anandamide (AEA), CP55,940, Δ(9)-tetrahydrocannabinol (THC), cannabidiol (CBD), and THC+CBD (1:1), and compared between wild-type and HD cells. The Emax of Gαi/o-dependent extracellular signal-regulated kinase (ERK) signaling was 50% lower in HD cells compared with wild-type cells. 2-AG and AEA displayed Gαi/o/Gßγ bias and normalized CB1 protein levels and improved cell viability, whereas CP55,940 and THC displayed ß-arrestin1 bias and reduced CB1 protein levels and cell viability in HD cells. CBD was not a CB1 agonist but inhibited THC-dependent signaling (THC+CBD). Therefore, enhancing Gαi/o-biased endocannabinoid signaling may be therapeutically beneficial in HD. In contrast, cannabinoids that are ß-arrestin-biased--such as THC found at high levels in modern varieties of marijuana--may be detrimental to CB1 signaling, particularly in HD where CB1 levels are already reduced.

Antagonism of Dopamine Receptor 2 Long Affects Cannabinoid Receptor 1 Signaling in a Cell Culture Model of Striatal Medium Spiny Projection Neurons.

Activation of dopamine receptor 2 long (D2L) switches the signaling of type 1 cannabinoid receptor (CB1) from Gαi to Gαs, a process thought to be mediated through CB1-D2L heteromerization. Given the clinical importance of D2 antagonists, the goal of this study was to determine if D2 antagonists could modulate CB1 signaling. Interactions between CB1 and D2L, Gαi, Gαs, and ß-arrestin1 were studied using bioluminescence resonance energy transfer 2 (BRET(2)) in STHdh(Q7/Q7) cells. CB1-dependent extracellular regulated kinase (ERK)1/2, CREB phosphorylation, and CB1 internalization following cotreatment of CB1 agonist and D2 antagonist were quantified. Preassembled CB1-Gαi complexes were detected by BRET(2) Arachidonyl-2'-chloroethylamide (ACEA), a selective CB1 agonist, caused a rapid and transient increase in BRET efficiency (BRETEff) between Gαi-Rluc and CB1-green fluorescent protein 2 (GFP(2)), and a Gαi-dependent increase in ERK phosphorylation. Physical interactions between CB1 and D2L were observed using BRET(2) Cotreatment of STHdh(Q7/Q7) cells with ACEA and haloperidol, a D2 antagonist, inhibited BRETEff signals between Gαi-Rluc and CB1-GFP(2) and reduced the EMax and pEC50 of ACEA-mediated Gαi-dependent ERK phosphorylation. ACEA and haloperidol cotreatments produced a delayed and sustained increase in BRETEff between Gαs-Rluc and CB1-GFP(2) and increased the EMax and pEC50 of ACEA-induced Gαs-dependent cAMP response element-binding protein phosphorylation. In cells expressing CB1 and D2L treated with ACEA, binding of haloperidol to D2 receptors switched CB1 coupling from Gαi to Gαs In addition, haloperidol treatment reduced ACEA-induced ß-arrestin1 recruitment to CB1 and CB1 internalization. D2 antagonists allosterically modulate cannabinoid-induced CB1 coupling, signaling, and ß-arrestin1 recruitment through binding to CB1-D2L heteromers. These findings indicate that D2 antagonism, like D2 agonists, change agonist-mediated CB1 coupling and signaling.

Type 1 cannabinoid receptor ligands display functional selectivity in a cell culture model of striatal medium spiny projection neurons.

Modulation of type 1 cannabinoid receptor (CB1) activity has been touted as a potential means of treating addiction, anxiety, depression, and neurodegeneration. Different agonists of CB1 are known to evoke varied responses in vivo. Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor that can signal through multiple pathways. To understand cannabinoid-specific functional selectivity, different groups have examined the effect of individual cannabinoids on various signaling pathways in heterologous expression systems. In the current study, we compared the functional selectivity of six cannabinoids, including two endocannabinoids (2-arachidonyl glycerol (2-AG) and anandamide (AEA)), two synthetic cannabinoids (WIN55,212-2 and CP55,940), and two phytocannabinoids (cannabidiol (CBD) and Δ(9)-tetrahydrocannabinol (THC)) on arrestin2-, Gα(i/o)-, Gßγ-, Gα(s)-, and Gα(q)-mediated intracellular signaling in the mouse STHdh(Q7/Q7) cell culture model of striatal medium spiny projection neurons that endogenously express CB1. In this system, 2-AG, THC, and CP55,940 were more potent mediators of arrestin2 recruitment than other cannabinoids tested. 2-AG, AEA, and WIN55,212-2, enhanced Gα(i/o) and Gßγ signaling, with 2-AG and AEA treatment leading to increased total CB1 levels. 2-AG, AEA, THC, and WIN55,212-2 also activated Gα(q)-dependent pathways. CP55,940 and CBD both signaled through Gα(s). CP55,940, but not CBD, activated downstream Gα(s) pathways via CB1 targets. THC and CP55,940 promoted CB1 internalization and decreased CB1 protein levels over an 18-h period. These data demonstrate that individual cannabinoids display functional selectivity at CB1 leading to activation of distinct signaling pathways. To effectively match cannabinoids with therapeutic goals, these compounds must be screened for their signaling bias.

Icariin inhibits cisplatin-induced ovarian toxicity via modulating NF-κB and PTEN/AKT/mTOR/AMPK axis.

Cisplatin (CP) is a highly effective broad-spectrum chemotherapeutic agent for several solid tumors. However, its clinical use is associated with ovarian toxicity. Icariin (ICA) is a bioactive flavonoid of Epimedium brevicornum with reported protective activities against inflammation, oxidative stress and ovarian failure. This study aimed to explore the protective effects of ICA against CP-associated ovarian toxicity in rats. Rats were randomized into five groups and treated for 17 days: control, ICA (10 mg/kg/day, for 17 days. p.o.), CP (6 mg/kg, i.p. on days 7 and 14), CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 5 mg/kg p.o. daily), and CP + ICA (CP 6 mg/kg i.p. on days 7 and 14 and ICA 10 mg/kg p.o. daily). Our results indicated that ICA effectively improved ovarian reserve as indicated by attenuating CP-induced histolopathological changes and enhancing serum anti-müllerian hormone (AMH). Furthermore, co-administration of ICA with CP showed restoration of the oxidant-anti-oxidant balance in ovarian tissues, evidenced by decreased malondialdehyde (MDA) concentrations and elevated superoxide dismutase (SOD) and catalase (CAT) activities. Also, ICA suppressed ovarian inflammation as evidenced by down-regulation of the expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB). ICA inhibited ovarian apoptosis in CP-treated rats by down-regulation of CASP3 and Bax and up-regulation of Bcl-2 mRNA expression. Further, ICA enhanced PTEN, p-AKT, p-mTOR, and p-AMPKα expression. In conclusion, ICA possesses a protective activity against CP-induced ovarian toxicity in rats by exhibiting antioxidant, antiinflammatory, anti-apoptotic activities and modulating NF-κB expression and PTEN/AKT/mTOR/AMPK axis in ovarian tissues.

Red Bull Energy Drink Impact on Salivary Glands in Wistar Rats: Can Blueberry Extract Reverse the Damage?

Energy drink (ED) consumption has become increasingly popular. Due to a lack of evidence, it was crucial to assess the effects of Red Bull (RB) consumption on the rat submandibular salivary gland and the potential therapeutic impact of blueberry (BB). Thirty rats were randomly assigned to five groups. Group 1 (Control) received distilled water. Group 2 (RB) received RB (10 mL/100 g/day) for 8 weeks. Group 3 (BB) rats were administered BB (500 mg/day for 8 weeks). Group 4 (RB + BB (L)) received RB for 8 weeks, and from the 5th week, were concurrently given BB (250 mg/day) for 4 weeks. Group 5 (RB + BB (H)) received RB for 8 weeks, and from the 5th week, were concurrently given BB (500 mg/day) for 4 weeks. At the end of the experiment, blood samples were collected, the animals were euthanized, and their submandibular salivary glands were harvested. Oxidative stress markers (MDA, GPx, CAT, and SOD) were assessed in both serum and tissue. Inflammatory markers (TNF-α, IL-6, and IL-10) were quantified in tissue. Submandibular gland specimens were prepared for light microscopy, and immunohistochemical staining was performed using anti-α-SMA. RB consumption resulted in a significant increase in MDA, TNF-α, IL-6, and IL-10, while GPx, CAT, and SOD levels decreased significantly. Degenerative changes in the gland's structure were observed in the RB group. A significant increase in α-SMA immunoreaction was detected in myoepithelial cells. Administration of BB, particularly at a high dose, ameliorated the aforementioned findings. In conclusion, blueberry administration exhibited therapeutic effects due to its antioxidative and anti-inflammatory properties.

Berberine alleviates chlorpyrifos-induced nephrotoxicity in rats via modulation of Nrf2/HO-1 axis.

Chlorpyrifos (CPS), an organophosphorus insecticide, is widely used for agricultural and non-agricultural purposes with hazardous health effects. Berberine (BBR) is a traditional Chinese medicine and a phytochemical with anti-inflammatory and anti-oxidative properties. The present study evaluated the effects of BBR against kidney damage induced by CPS and the underlying mechanisms. An initial study indicated that BBR 50 mg/kg was optimal under our experimental conditions. Then, 24 rats (6/group) were randomized into: control, BBR (50 mg/kg/day), CPS (10 mg/kg/day), and CPS + BBR. BBR was administration 1 h prior to CPS. Each treatment was delivered daily for a period of 28 consecutive days using a gastric gavage tube. Compared to CPS-alone treated rats, BBR effectively improved renal function by preventing the rise in serum urea, creatinine, and uric levels. The reno-protective effects of BBR were confirmed through a histological examination of kidney tissues. BBR restored oxidant-antioxidant balance in renal tissues mediated by Keap1/Nrf2/HO-1 axis modulation. In addition, BBR decreased nitric oxide (NO) and myeloperoxidase (MPO) activity. This was paralleled with the potent down-regulation of NF-κB. Furthermore, BBR exhibited anti-apoptotic activities supported by the upregulation of Bcl-2 and down-regulation of Bax and caspase-3 expression. In conclusion, our data suggest that BBR attenuates CPS-induced nephrotoxicity in rats by restoring oxidant-antioxidant balance and inhibiting inflammatory response and apoptosis in renal tissue. This is mediated, at least partly, by modulation of the Nrf2/HO-1 axis.

Association of CYP2C9∗3 and CYP2C8∗3 Non-Functional Alleles with Ibuprofen-Induced Upper Gastrointestinal Toxicity in a Saudi Patient.

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) widely used to alleviate pain and inflammation. Although it is generally considered safe, common adverse drug reactions of ibuprofen include stomach pain, nausea, and heartburn. It can also cause gastrointestinal (GI) bleeding, especially in individuals with a history of GI ulcers or bleeding disorders. Ibuprofen is predominantly metabolized by the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C8. Individuals carrying the CYP2C9∗3 or CYP2C8∗3 non-functional alleles have reduced enzyme activities resulting in elevated ibuprofen plasma concentrations and half-life. We presented a case of a 31-year-old Saudi female patient with a history of rheumatoid arthritis (RA) who had taken ibuprofen at 600 mg twice daily for eight weeks. The patient presented to the emergency department with symptoms including nausea, vomiting, severe abdominal pain, and black tarry stools. An emergency esophagogastroduodenoscopy was performed on the patient, which revealed a deep bleeding ulcer measuring 1 × 1 cm in the antrum of the stomach. Laboratory investigations indicated anemia (hemoglobin: 7.21 g/dL and hematocrit: 22.40 g/dl). The patient received intravenous proton pump inhibitors and a packed red blood cell transfusion. Genetic analysis revealed that the patient was a carrier of CYP2C9∗3 and CYP2C8∗3 variant alleles, indicating that the patient is a poor metabolizer for both enzymes. The patient's symptoms improved over the subsequent days, and she was discharged with instructions to avoid NSAIDs. This is the first reported Saudi patient homozygous for CYP2C9∗3 and CYP2C8∗3 variant alleles, which led to ibuprofen-induced upper GI toxicity. This case demonstrates the importance of contemplating CYP2C9 and CYP2C8 genetic variations when administrating NSAIDs like ibuprofen. Careful assessment of the risks and benefits of NSAID therapy in each patient and consideration of alternative pain management strategies must be conducted when appropriate.

Effects of the CB1 receptor antagonists AM6545 and AM4113 on metabolic syndrome-induced prostatic hyperplasia in rats.

Metabolic syndrome (MetS) is a combination of metabolic disorders that can predispose individuals to benign prostatic hyperplasia (BPH). The inhibition of the cannabinoid 1 (CB1) receptor has been used to treat metabolic disorders in animal models. This study reports the use of a peripherally restricted CB1 antagonist (AM6545) and a neutral CB1 antagonist (AM4113) to improve MetS-related BPH in rats. Animals were divided into three control groups to receive either a normal rodent diet, AM6545, or AM4113. MetS was induced in the fourth, fifth, and sixth groups using a concentrated fructose solution and high-salt diet delivered as food pellets for eight weeks. The fifth and sixth groups were further given AM6545 or AM4113 for additional four weeks. Body and prostate weights were measured and prostate sections were stained with hematoxylin eosin. Cyclin D1, markers of oxidative stress and inflammation, and levels of the endocannabinoids were recorded. BPH in rats with MetS was confirmed through increased prostate weight and index, as well as histopathology. Treatment with either AM6545 or AM4113 significantly decreased prostate weight, improved prostate histology, and reduced cyclin D1 expression compared with the MetS group. Groups treated with CB1 antagonists experienced reduced lipid peroxidation, recovered glutathione depletion, restored catalase activity, and had lower inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). MetS rats treated with either AM6545 or AM4113 showed reduced concentrations of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the prostate compared with the MetS group. In conclusion, the CB1 antagonists AM6545 and AM4113 protect against MetS-induced BPH through their anti-proliferative, antioxidant, and anti-inflammatory effects.

The Endocannabinoid System as a Therapeutic Target in Diabetic Peripheral Neuropathic Pain: A Review.

Diabetic peripheral neuropathy (DPN) is characterized by progressive loss of peripheral nerves, which causes numbness, weakness, and severe pain. The medications available currently provide only modest relief from the pain of DPN and are associated with various side effects, which has generated an enormous demand for research on new therapeutic approaches. Dysregulation of the endocannabinoid system has been reported in DPN. Cannabinoid-based medications have gained increasing attention as a potential therapy to alleviate DPN pain. Endocannabinoids and cannabinoids' actions are mediated primarily by cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). Cannabinoids that activate CB1R have demonstrated a profound antinociceptive effect, although CB1R is associated with undesirable psychoactive effects. Peripherally restricted CB1R agonists help overcome this problem; however, adverse metabolic and cardiovascular effects limit its therapeutic use. In contrast, CB1R antagonists, selective CB2R agonists, and endocannabinoid metabolizing enzymes inhibitors alleviate DPN pain effectively with minimal side effects. This article provides a concise overview of the preclinical and clinical studies that have tested the therapeutic potential of targeting the endocannabinoid system to treat painful DPN.