Apigenin Alleviates Autistic-like Stereotyped Repetitive Behaviors and Mitigates Brain Oxidative Stress in Mice.

Studying the involvement of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in neuropsychiatric brain disorders such as autism spectrum disorder (ASD) has gained a growing interest. The flavonoid apigenin (APG) has been confirmed in its pharmacological action as a positive allosteric modulator of α7-nAChRs. However, there is no research describing the pharmacological potential of APG in ASD. The aim of this study was to evaluate the effects of the subchronic systemic treatment of APG (10-30 mg/kg) on ASD-like repetitive and compulsive-like behaviors and oxidative stress status in the hippocampus and cerebellum in BTBR mice, utilizing the reference drug aripiprazole (ARP, 1 mg/kg, i.p.). BTBR mice pretreated with APG (20 mg/kg) or ARP (1 mg/g, i.p.) displayed significant improvements in the marble-burying test (MBT), cotton-shredding test (CST), and self-grooming test (SGT) (all p < 0.05). However, a lower dose of APG (10 mg/kg, i.p.) failed to modulate behaviors in the MBT or SGT, but significantly attenuated the increased shredding behaviors in the CST of tested mice. Moreover, APG (10-30 mg/kg, i.p.) and ARP (1 mg/kg) moderated the disturbed levels of oxidative stress by mitigating the levels of catalase (CAT) and superoxide dismutase (SOD) in the hippocampus and cerebellum of treated BTBR mice. In patch clamp studies in hippocampal slices, the potency of choline (a selective agonist of α7-nAChRs) in activating fast inward currents was significantly potentiated following incubation with APG. Moreover, APG markedly potentiated the choline-induced enhancement of spontaneous inhibitory postsynaptic currents. The observed results propose the potential therapeutic use of APG in the management of ASD. However, further preclinical investigations in additional models and different rodent species are still needed to confirm the potential relevance of the therapeutic use of APG in ASD.

Effect of Hydration Forms and Polymer Grades on Theophylline Controlled-Release Tablet: An Assessment and Evaluation.

BACKGROUND: Drug release from controlled release delivery systems is influenced by various factors, including the polymer's grade and the drug's hydration form. This study aimed to investigate the impact of these factors on the controlled release of theophylline (THN). This research compares the monohydrate form found in branded products with the anhydrous form in generic equivalents, each formulated with different polymer grades. METHODS: Quality control assessment was conducted alongside in vitro evaluation, complemented by various analytical techniques such as X-ray diffraction (XRD) and scanning electron microscopy (SEM). Additionally, thermal analyses using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were employed. RESULTS: Quality control assessments demonstrated that the generic tablets exhibited lower average weight and resistance force compared to the branded ones. In vitro tests revealed that generic tablets released contents within 120 min, compared to 720 min for the branded counterpart. Characterization using XRD and SEM identified disparities in crystallinity and particle distribution between the three samples. Additionally, the thermal analysis indicated consistent endothermic peaks across all samples, albeit with minor variations in heat flow and decomposition temperatures between the two products. CONCLUSIONS: This study demonstrated that variations in polymer grade and hydration form significantly impact THN release.

Nanomedicines: Emerging Platforms in Smart Chemotherapy Treatment-A Recent Review.

Cancer continues to pose one of the most critical challenges in global healthcare. Despite the wide array of existing cancer drugs, the primary obstacle remains in selectively targeting and eliminating cancer cells while minimizing damage to healthy ones, thereby reducing treatment side effects. The revolutionary approach of utilizing nanomaterials for delivering cancer therapeutic agents has significantly enhanced the efficacy and safety of chemotherapeutic drugs. This crucial shift is attributed to the unique properties of nanomaterials, enabling nanocarriers to transport therapeutic agents to tumor sites in both passive and active modes, while minimizing drug elimination from delivery systems. Furthermore, these nanocarriers can be designed to respond to internal or external stimuli, thus facilitating controlled drug release. However, the production of nanomedications for cancer therapy encounters various challenges that can impede progress in this field. This review aims to provide a comprehensive overview of the current state of nanomedication in cancer treatment. It explores a variety of nanomaterials, focusing on their unique properties that are crucial for overcoming the limitations of conventional chemotherapy. Additionally, the review delves into the properties and functionalities of nanocarriers, highlighting their significant impact on the evolution of nanomedicine. It also critically assesses recent advancements in drug delivery systems, covering a range of innovative delivery methodologies. Finally, the review succinctly addresses the challenges encountered in developing nanomedications, offering insightful perspectives to guide future research in this field.

Preparation and Characterization of Theophylline Controlled Release Matrix System Incorporating Poloxamer 407, Stearyl Alcohol, and Hydroxypropyl Methylcellulose: A Novel Formulation and Development Study.

BACKGROUND: Theophylline (THN), a bronchodilator with potential applications in emerging conditions like COVID-19, requires a controlled-release delivery system due to its narrow therapeutic range and short half-life. This need is particularly crucial as some existing formulations demonstrate impaired functionality. This study aims to develop a new 12-h controlled-release matrix system (CRMS) in the form of a capsule to optimize dosing intervals. METHODS: CRMSs were developed using varying proportions of poloxamer 407 (P-407), stearyl alcohol (STA), and hydroxypropyl methylcellulose (HPMC) through the fusion technique. Their in vitro dissolution profiles were then compared with an FDA-approved THN drug across different pH media. The candidate formulation underwent characterization using X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Additionally, a comprehensive stability study was conducted. RESULTS: In vitro studies showed that adjusting the concentrations of excipients effectively controlled drug release. Notably, the CRMS formulation 15 (CRMS-F15), which was composed of 30% P-407, 30% STA, and 10% HPMC, closely matched the 12 h controlled-release profile of an FDA-approved drug across various pH media. Characterization techniques verified the successful dispersion of the drug within the matrix. Furthermore, CRMS-F15 maintained a consistent controlled drug release and demonstrated stability under a range of storage conditions. CONCLUSIONS: The newly developed CRMS-F15 achieved a 12 h controlled release, comparable to its FDA-approved counterpart.

Community pharmacists' knowledge and awareness about isotretinoin therapy and its dispensing practice in Jordan.

A validated self-reported questionnaire was used to evaluate pharmacists' knowledge about isotretinoin and their awareness of isotretinoin dispensing practice. The majority were not able to recognize the initial dose of isotretinoin, the potential side effects such as dyslipidemia and liver toxicity, the potential interaction with tetracycline and Vitamin A and the contraindications of isotretinoin. Around 41.3 % of the pharmacists dispensed isotretinoin without a prescription, and the majority did not recognize that isotretinoin should be dispensed for only 30 days, should not be dispensed without an emphasis on the appropriate indication, and did not know the appropriate duration of isotretinoin therapy. Male gender and postgraduate degree were associated with better awareness, while increased work experience and postgraduate degree were associated with better knowledge about isotretinoin therapy. Nevertheless, both male and female pharmacists demonstrated equivalent knowledge levels. The current study demonstrates the need to implement educational programs to improve pharmacists' knowledge and awareness about isotretinoin and its dispensing practice.

α-Bisabolol, a Dietary Sesquiterpene, Attenuates Doxorubicin-Induced Acute Cardiotoxicity in Rats by Inhibiting Cellular Signaling Pathways, Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3ß, NF-κB/p38/MAPK, and NLRP3 Inflammasomes Regulating Oxidative Stress and Inflammatory Cascades.

Cancer chemotherapy with doxorubicin (DOX) may have multiorgan toxicities including cardiotoxicity, and this is one of the major limitations of its clinical use. The present study aimed to evaluate the cardioprotective role of α-Bisabolol (BSB) in DOX-induced acute cardiotoxicity in rats and the underlying pharmacological and molecular mechanisms. DOX (12.5 mg/kg, single dose) was injected intraperitoneally into the rats for induction of acute cardiotoxicity. BSB was given orally to rats (25 mg/kg, p.o. twice daily) for a duration of five days. DOX administration induced cardiac dysfunction as evidenced by altered body weight, hemodynamics, and release of cardio-specific diagnostic markers. The occurrence of oxidative stress was evidenced by a significant decline in antioxidant defense along with a rise in lipid peroxidation and hyperlipidemia. Additionally, DOX also increased the levels and expression of proinflammatory cytokines and inflammatory mediators, as well as activated NF-κB/MAPK signaling in the heart, following alterations in the Nrf2/Keap-1/HO-1 and Akt/mTOR/GSK-3ß signaling. DOX also perturbed NLRP3 inflammasome activation-mediated pyroptosis in the myocardium of rats. Furthermore, histopathological studies revealed cellular alterations in the myocardium. On the contrary, treatment with BSB has been observed to preserve the myocardium and restore all the cellular, molecular, and structural perturbations in the heart tissues of DOX-induced cardiotoxicity in rats. Results of the present study clearly demonstrate the protective role of BSB against DOX-induced cardiotoxicity, which is attributed to its potent antioxidant, anti-inflammatory, and antihyperlipidemic effects resulting from favorable modulation of numerous cellular signaling regulatory pathways, viz., Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3ß, NF-κB/p38/MAPK, and NLRP3 inflammasomes, in countering the cascades of oxidative stress and inflammation. The observations suggest that BSB can be a promising agent or an adjuvant to limit the cardiac injury caused by DOX. Further studies including the role in tumor-bearing animals as well as regulatory toxicology are suggested.

A review of pharmacogenomics studies assessing the knowledge and attitudes of physicians and pharmacists across the Arab and Middle Eastern Region

The principal goal of pharmacogenomics (PGx) is to achieve the highest drug efficacy while maintaining a low toxicity profile. Historically, health care systems used to target treatment for all individuals with the same diagnosis using a standardized medication or dose that fits all. However, a recent pattern in medicine has emerged focusing on personalized and precision medicine. For effective implementation of PGx, there is a need for more collaborations between all the stakeholders in the healthcare system to integrate the pharmacogenetics concept into practice. When it comes to the knowledge and attitudes towards pharmacogenomics, the majority of medical professionals, including pharmacists and physicians, appear to lack appropriate knowledge and training. Across the Middle East and Arab Region, only few studies have addressed this topic. The current review objective is to shed light on pharmacists’ and physicians’ knowledge and attitudes towards PGx practice in the UAE, Arab and the Middle East region as compared to the rest of the world. Moreover, highlighting the role of the pharmacists in the application of PGx services and the educational challenges that are faced. Proposed solutions to improve the knowledge gaps will also be discussed. We also aim to provide the international readers as well as the local researchers with a summary of the trends and distribution of the results across these countries. (AU)

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3ß Signaling Pathway in MK801-Induced Amnesia in Mice.

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3ß proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.

Tannic Acid Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Inhibiting Inflammation, Oxidative Stress, Apoptosis, and Glutamate Toxicity in Rats.

Parkinson's disease (PD), a movement disorder, is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. The etiopathogenesis of PD involves increased oxidative stress, augmented inflammation, impaired autophagy, accumulation of α-synuclein, and α-Glutamate neurotoxicity. The treatment of PD is limited and there is a lack of agents to prevent the disease/delay its progression and inhibit the onset of pathogenic events. Many agents of natural and synthetic origin have been investigated employing experimental models of PD, mimicking human PD. In the present study, we assessed the effect of tannic acid (TA) in a rodent model of PD induced by rotenone (ROT), a pesticide and an environmental toxin of natural origin reported to cause PD in agricultural workers and farmers. Rotenone (2.5 mg/kg/day, i.p.) was administered for 28 days, and TA (50 mg/kg, orally) was administered 30 min before ROT injections. The study results showed an increase in oxidative stress, as evidenced by the depletion of endogenous antioxidants and enhanced formation of lipid peroxidation products, along with the onset of inflammation following a rise in inflammatory mediators and proinflammatory cytokines. ROT injections have also augmented apoptosis, impaired autophagy, promoted synaptic loss, and perturbed α-Glutamate hyperpolarization in rats. ROT injections also induced the loss of dopaminergic neurons subsequent to the activation of microglia and astrocytes. However, TA treatment was observed to reduce lipid peroxidation, prevent loss of endogenous antioxidants, and inhibit the release and synthesis of proinflammatory cytokines, in addition to the favorable modulation of apoptosis and autophagic pathways. Treatment with TA also attenuated the activation of microglia and astrocytes along with preservation of dopaminergic neurons following reduced loss of dopaminergic neurodegeneration and inhibition of synaptic loss and α-Glutamate cytotoxicity. The effects of TA in ROT-induced PD were attributed to the antioxidant, anti-inflammatory, antiapoptotic, and neurogenesis properties. Based on the present study findings, it can be concluded that TA may be a promising novel therapeutic candidate for pharmaceutical as well as nutraceutical development owing to its neuroprotective properties in PD. Further regulatory toxicology and translational studies are suggested for future clinical usage in PD.

Non-adherence to pharmacotherapy and its associated factors in outpatients with rheumatoid arthritis

Background: Despite the availability of effective pharmacotherapy for the management of rheumatoid arthritis (RA), health outcomes are suboptimal due to poor adherence to the prescribed treatment. Limited research has been conducted to investigate medication non-adherence and its associated factors among patients with RA. Objective: This study aimed to assess medication adherence and to explore the factors associated with medication non-adherence among outpatients with RA in Jordan. Methods: The current cross-sectional study was conducted at outpatient rheumatology clinics at two teaching hospitals in Jordan. Variables including socio-demographics and biomedical variables, in addition to disease and medication characteristics, were collected using medical records and custom-designed questionnaire. Medication adherence was assessed using the validated 5-item Compliance Questionnaire for Rheumatology. Stepwise Logistic Regression analysis was performed to identify the factors that are independently and significantly associated with medication non-adherence. Results: A total of 261 patients participated in the study, from which, 43.3% were found non-adherent. Binary regression analysis results revealed that low monthly income (OR= 0.239, CI= 0.130-0.440, P<0.01), the presence of chronic respiratory disease (OR= 2.727, CI= 1.059-7.022, P<0.05), lower medication necessity scores (OR= 1.177, CI= 1.10-1.259, P<0.01) and higher concerns about RA medications (OR= 0.917, CI= 0.860-0.978, P<0.01) were significant and independent predictors of medication non-adherence in patients with RA. Conclusion: Future pharmaceutical care and clinical pharmacy service programs should emphasize medications benefits and minimizing medication-related concerns by selecting safe medications and providing guidance on mitigating side effects, particularly for RA patients who have low income and those who suffer from other comorbid diseases. (AU)

Limonene, a Monoterpene, Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Modulating Neuroinflammation, Hippo Signaling and Apoptosis in Rats.

Rotenone (ROT) is a naturally derived pesticide and a well-known environmental neurotoxin associated with induction of Parkinson's disease (PD). Limonene (LMN), a naturally occurring monoterpene, is found ubiquitously in citrus fruits and peels. There is enormous interest in finding novel therapeutic agents that can cure or halt the progressive degeneration in PD; therefore, the main aim of this study is to investigate the potential neuroprotective effects of LMN employing a rodent model of PD measuring parameters of oxidative stress, neuro-inflammation, and apoptosis to elucidate the underlying mechanisms. PD in experimental rats was induced by intraperitoneal injection of ROT (2.5 mg/kg) five days a week for a total of 28 days. The rats were treated with LMN (50 mg/kg, orally) along with intraperitoneal injection of ROT (2.5 mg/kg) for the same duration as in ROT-administered rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers following activation of glial cells (astrocytes and microglia). ROT treatment enhanced oxidative stress, altered NF-κB/MAPK signaling and motor dysfunction, and enhanced the levels/expressions of inflammatory mediators and proinflammatory cytokines in the brain. There was a concomitant mitochondrial dysfunction followed by the activation of the Hippo signaling and intrinsic pathway of apoptosis as well as altered mTOR signaling in the brain of ROT-injected rats. Oral treatment with LMN corrected the majority of the biochemical, pathological, and molecular parameters altered following ROT injections. Our study findings demonstrate the efficacy of LMN in providing protection against ROT-induced neurodegeneration.

Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1ß) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD.

Enteric-coating film effect on the delayed drug release of pantoprazole gastro-resistant generic tablets.

Background: Enteric coating films in acidic labile tablets protect the drug molecule from the acidic environment of the stomach. However, variations in the excipients used in the coating formulation may affect their ability to provide adequate protection. This study is the first to investigate the potential effects of coating materials on the protective functionality of enteric coating films for pantoprazole (PNZ) generic tablets after their recall from the market. Methods: A comparative analysis was conducted between generic and branded PNZ products, using pure drug powder for identification. The in vitro release of the drug was evaluated in different pH media. The study also utilized various analytical and thermal techniques, including differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR), and confocal Raman microscopy. Results: The in vitro assessment results revealed significant variations in the release profile for the generic product in acidic media at 120 min. DSC and TGA thermal profile analyses showed slight variation between the two products. XRD analysis exhibited a noticeable difference in peak intensity for the generic sample, while SEM revealed smaller particle sizes in the generic product. The obtained spectra profile for the generic product displayed significant variation in peaks and band intensity, possibly due to impurities. These findings suggest that the excipients used in the enteric coating film of the generic product may have affected its protective functionality, leading to premature drug release in acidic media. Additionally, the presence of polysorbate 80 (P-80) in the brand product might improve the properties of the enteric coating film due to its multi-functionality. Conclusions: In conclusion, the excipients used in the brand product demonstrated superior functionality in effectively protecting the drug molecule from acidic media through the enteric coating film, as compared to the generic version.

Effect of citronellol on oxidative stress, neuroinflammation and autophagy pathways in an in vivo model of Parkinson's disease.

Citronellol, a monoterpene found in the essential oils of Cymbopogo plants has been reported to possess various biological properties. In the present study, we investigated the neuroprotective mechanisms of citronellol against rotenone induced neurodegeneration by using rat model of Parkinson's disease (PD). Our results demonstrated that oral administration of citronellol prevented rotenone induced reactive oxygen species production, lipid peroxidation and enhanced Nrf2 expression, catalase, glutathione peroxidase and superoxide dismutase levels in the brain. Enzyme-linked immunosorbent assays showed that citronellol reduced secretion of TNF-α, IL-1ß, IL-6 and decreased MMP-9 expression levels. Further, citronellol prevented rotenone induced microglia (Iba-1 staining) and astrocyte (GFAP staining) activation. Western blot analysis showed that citronellol significantly decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase-2 that are key markers of neuroinflammation. We further evaluated the effect of citronellol on dopaminergic neurons in substantia nigra pars compacta (SNpc) and striatum (ST) which are key anatomical structures in PD. Tyrosine hydroxylase (TH) immunoreactivity showed that citronellol preserved Tyrosine hydroxylase (TH) positive dopaminergic neurons and enhanced TH striatal expression levels significantly compared to rotenone alone group. Further, to understand the effect of citronellol on apoptosis and proteotoxicity, we evaluated apoptotic markers (Bax, Bcl-2), growth regulator (mTOR) and α-synuclein expression. Citronellol attenuated rotenone induced expression of pro-apoptotic protein Bax, reduced α-synuclein expression and enhanced Bcl-2 and mTOR levels. In addition, citronellol modulated autophagy pathway by decreasing LC-3 (Microtubule-associated proteins) and p62 levels. Taken together, our results demonstrate that citronellol protected dopaminergic neurons through its antioxidant, anti-inflammatory, anti-apoptotic and autophagy modulating properties.

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats.

The present study investigated the effects of α-bisabolol on DOX-induced testicular damage in rats. Testicular damage was induced in rats by injecting DOX (12.5 mg/kg, i.p., single dose) into rats. α-Bisabolol (25 mg/kg, i.p.) was administered to the rats along with DOX pre- and co-treatment daily for a period of 5 days. DOX-injected rats showed a decrease in absolute testicular weight and relative testicular weight ratio along with concomitant changes in the levels/expression levels of oxidative stress markers and Nrf2 expression levels in the testis. DOX injection also triggered the activation of NF-κB/MAPK signaling and increased levels/expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and inflammatory mediators (iNOS and COX-2) in the testis. DOX triggered apoptosis, manifested by an increment in the expression levels of pro-apoptotic markers (Bax, Bcl2, cleaved caspase-3 and -9, and cytochrome-C) and a decline in the expression levels of anti-apoptotic markers (Bcl-xL and Bcl2) in the testis. Additionally, light microscopy revealed the changes in testicular architecture. α-Bisabolol rescued alterations in the testicular weight; restored all biochemical markers; modulated the expression levels of Nrf2-mediated antioxidant responses, NF-κB/MAPK signaling, endoplasmic reticulum (ER) stress, and apoptosis markers in DOX-injected testicular toxicity in rats. Based on our findings, it can be concluded that α-bisabolol has the potential to attenuate DOX-induced testicular injury by modifying NF-κB/MAPK signaling and the ER-stress-mediated mitochondrial pathway of apoptosis by invoking Nrf2-dependent antioxidant defense systems in rats. Based on the findings of the present study, α-bisabolol could be suggested for use as an agent or adjuvant with chemotherapeutic drugs to attenuate their deleterious effects of DOX on many organs including the testis. However, further regulatory toxicology and preclinical studies are necessary before making recommendations in clinical tests.

Relationship between lipid profile, inflammatory and endothelial dysfunction biomarkers, and type 1 diabetes mellitus: a case-control study.

OBJECTIVE: Inflammation is a major factor in endothelial dysfunction (ED) which is the earliest predictor of cardiovascular disease and premature mortality in type 1 diabetes mellitus (T1DM) patients. This study aimed to describe the possible relationship between plasma lipids and inflammatory and ED biomarkers in young Emirati patients with and without T1DM. METHODS: This case-control study included 158 patients with T1DM and 157 healthy controls from the local population of the United Arab Emirates (UAE). Anthropometric data, clinical variables, lipid profiles, liver enzymes, HbA1c, inflammatory, and ED biomarkers were measured for all participants using sophisticated techniques and assays. RESULTS: The mean ages ± SD of patients with T1DM and healthy controls was 19.3 ± 6.4 years (59.5% females) and 9.2 ± 6.8 years (61.5% females), respectively. The mean duration of T1DM was 9.3 ± 5.7 years, with HbA1c of 8.9 ± 2.1%. BMI, WC, SBP, and DBP significantly differed between the two groups. The mean lipid profiles (HDL, TG, TC, ApoA, and ApoB), liver enzymes (GGT, ALT), inflammatory (IL-6, adiponectin, TNF-α, hs-CRP), and ED biomarker levels (ICAM-1, VCAM-1, selectin, and ET-1) were also significantly different between patients and controls. Based on Spearman's rank and logistic regression analysis, there was a significant association between elevated lipid profile, liver enzymes, inflammatory markers, and ED markers in T1DM patients compared to controls. Among the biomarkers studied, ApoA, ApoB, and TC were significantly increased in T1DM patients compared to controls. CONCLUSION: This study revealed a strong association between an elevated lipid profile and inflammatory and ED markers with T1DM, which could lead to cardiovascular events in the UAE population.

Effectiveness of BBIBP-CorV vaccine against severe outcomes of COVID-19 in Abu Dhabi, United Arab Emirates.

The effectiveness of the inactivated BBIBP-CorV vaccine against severe COVID-19 outcomes (hospitalization, critical care admission and death due to COVID-19) and its long-term effectiveness have not been well characterized among the general population. We conducted a retrospective cohort study using electronic health records of 3,147,869 adults, of which 1,099,886 vaccinated individuals were matched, in a 1:1 ratio to 1,099,886 unvaccinated persons. A Cox-proportional hazard model with time varying coefficients was used to assess the vaccine effectiveness adjusting for age, sex, comorbidity, ethnicity, and the calendar month of entry into the study. Our analysis showed that the effectiveness was 79.6% (95% CI, 77.7 to 81.3) against hospitalization, 86% (95% CI, 82.2 to 89.0) against critical care admission, and 84.1% (95% CI, 70.8 to 91.3) against death due to COVID-19. The effectiveness against these severe outcomes declined over time indicating the need for booster doses to increase protection against severe COVID-19 outcomes.

Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep-Wake Cycle Disorder.

A relationship appears to exist between dysfunction of brain histamine (HA) and various neuropsychiatric brain disorders. The possible involvement of brain HA in neuropathology has gained attention recently, and its role in many (patho)physiological brain functions including memory, cognition, and sleep-wake cycle paved the way for further research on the etiology of several brain disorders. Histamine H3 receptor (H3R) evidenced in the brains of rodents and humans remains of special interest, given its unique position as a pre- and postsynaptic receptor, controlling the synthesis and release of HA as well as different other neurotransmitters in different brain regions, respectively. Despite several disappointing outcomes for several H3R antagonists/inverse agonists in clinical studies addressing their effectiveness in Alzheimer's disease (AD), Parkinson's disease (PD), and schizophrenia (SCH), numerous H3R antagonists/inverse agonists showed great potentials in modulating memory and cognition, mood, and sleep-wake cycle, thus suggesting its potential role in neurocognitive and neurodegenerative diseases such as AD, PD, SCH, narcolepsy, and major depression in preclinical rodent models. In this review, we present preclinical applications of selected H3R antagonists/inverse agonists and their pharmacological effects on cognitive impairment, anxiety, depression, and sleep-wake cycle disorders. Collectively, the current review highlights the behavioral impact of developments of H3R antagonists/inverse agonists, aiming to further encourage researchers in the preclinical drug development field to profile the potential therapeutic role of novel antagonists/inverse agonists targeting histamine H3Rs.

Clinical characteristics and risk factors for mortality among COVID-19 hospitalized patients in UAE: Does ethnic origin have an impact.

BACKGROUND: The relationship between COVID-19 patient's clinical characteristics and disease manifestation remains incompletely understood. The impact of ethnicity on mortality of patients with COVID-19 infection is poorly addressed in the literature. Emerging evidence suggests that many risk factors are related to symptoms severity and mortality risk, emphasizing the necessity of fulfilling this knowledge gap that may help reducing mortality from COVID-19 infections through tackling the risk factors. AIMS: To explore epidemiological and demographic characteristics of hospitalized COVID-19 patients from different ethnic origins living in the UAE, compare them to findings reported across the globe and determine the impact of these characteristics and ethnicity on mortality during hospitalization. METHODS: A single center, retrospective chart review study of hospitalized COVID-19 patients was conducted in a large COVID-19 referral hospital in UAE. The following outcomes were assessed: patients' clinical characteristics, disease symptoms and severity, and association of ethnicity and other risk factors on 30-day in hospital mortality. RESULTS: A total of 3296 patients were recruited in this study with an average age of 44.3±13.4 years old. Preliminary data analysis indicated that 78.3% (n = 2582) of cases were considered mild. Average duration of hospital stay was 6.0±7.3 days and 4.3% (n = 143) were admitted to ICU. The most frequently reported symptoms were cough (32.6%, n = 1075) and fever (22.2%, n = 731). The 30-day mortality rate during hospitalization was 2.7% (n = 90). Many risk factors were associated with mortality during hospitalization including: age, respiratory rate (RR), creatinine, and C-reactive protein, oxygen saturation (SaO2), hemoglobin, hematocrit, ferritin, creatinine, C-reactive protein, anemia, COPD, Chronic kidney disease, dyslipidemia, Vitamin-D Deficiency, and ethnic origin (p <0.05). Multiple logistic regression analysis showed that higher mortality rates during hospitalization was associated with anemia, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and Middle Eastern origin (p<0.05). CONCLUSION: The results indicated that most COVID-19 cases were mild and morality rate was low compared to worldwide reported mortality. Mortality rate during hospitalization was higher in patients from Middle East origin with preexisting comorbidities especially anemia, COPD, and chronic kidney disease. Due to the relatively small number of mortality cases, other identified risk factors from univariate analysis such as age, respiratory rate, and Vitamin-D (VitD) deficiency should also be taken into consideration. It is crucial to stratify patients on admission based on these risk factors to help decide intensity and type of treatment which, possibly, will reduce the risk of death.

The incidence of COVID-19 infection following emergency use authorization of BBIBP-CORV inactivated vaccine in frontline workers in the United Arab Emirates.

Based on the findings from the Phase III clinical trials of inactivated SARS COV-2 Vaccine, (BBIBP-CORV) emergency use authorization (EUA) was granted for the vaccine to frontline workers in the UAE. A prospective cohort study was conducted among frontline workers to estimate the incidence rate and risk of symptomatic COVID-19 infection 14 days after the second dose of inoculation with BBIBP-CORV inactivated vaccine. Those who received two doses of the BBIBP-CORV vaccine in the period from 14th of September 2020 (first dose) to 21st of December 2020 (second dose) were followed up for COVID-19 infections. 11,322 individuals who received the two-dose BBIBP-CORV vaccine were included and were followed up post the second dose plus fourteen days. The incidence rate of symptomatic infection was 0.08 per 1000-person days (95% CI 0.07, 0.10). The estimated absolute risk of developing symptomatic infection was 0.97% (95% CI 0.77%, 1.17%). The confirmed seroconversion rate was 92.8%. There were no serious adverse events reported and no individuals suffered from severe disease. Our findings show that vaccinated individuals are likely to remain protected against symptomatic infection or becoming PCR positive for SARS COV 2 following the second dose of the vaccination.