Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches.

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation.Communicated by Ramaswamy H. Sarma.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: An Emerging Diagnostic and Therapeutic Biomolecules for Neurodegenerative Disabilities.

Mesenchymal stem cells (MSCs) are a type of versatile adult stem cells present in various organs. These cells give rise to extracellular vesicles (EVs) containing a diverse array of biologically active elements, making them a promising approach for therapeutics and diagnostics. This article examines the potential therapeutic applications of MSC-derived EVs in addressing neurodegenerative disorders such as Alzheimer's disease (AD), multiple sclerosis (MS), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Furthermore, the present state-of-the-art for MSC-EV-based therapy in AD, HD, PD, ALS, and MS is discussed. Significant progress has been made in understanding the etiology and potential treatments for a range of neurodegenerative diseases (NDs) over the last few decades. The contents of EVs are carried across cells for intercellular contact, which often results in the control of the recipient cell's homeostasis. Since EVs represent the therapeutically beneficial cargo of parent cells and are devoid of many ethical problems connected with cell-based treatments, they offer a viable cell-free therapy alternative for tissue regeneration and repair. Developing innovative EV-dependent medicines has proven difficult due to the lack of standardized procedures in EV extraction processes as well as their pharmacological characteristics and mechanisms of action. However, recent biotechnology and engineering research has greatly enhanced the content and applicability of MSC-EVs.

Gastro-protective effect of l-arginine against nitric oxide deficiency-related mucosal injury induced by indomethacin: Does age matter?

Gastric ulcer is a common disease with increased prevalence in the aged population. Aged gastric mucosa has increased susceptibility to injury along with nonsteroidal anti-inflammatory drugs use due to impaired mucosal defense and decreased vasodilator release. We investigated whether l-arginine could protect against age-related gastric ulceration induced by indomethacin. Aged and adult male Wistar rats were administered sole and combined treatment of  l-arginine and Nω -nitro-l-arginine methyl ester ( l-NAME) before induction of gastric ulceration by indomethacin. The gastroprotective effect of  l-arginine was displayed only in adult rats with indomethacin-induced gastric ulceration, as evidenced by a significant decrease in ulcer index, oxidative stress parameters, and mucosal myeloperoxidase activity along with increased mucosal PGE2 levels. Interestingly, the mucosal gene expressions of NF-кB, iNOS, and COX-2 were significantly suppressed by  l-arginine pretreatment and aggregated upon pretreatment with  l-NAME in both adult and aged rats treated with indomethacin. In conclusion,  l-arginine protected the rats' gastric mucosa against indomethacin-induced gastric ulceration, possibly, at least in part, by enhancement of mucosal nitric oxide/PGE2 content along with suppressing gastric inflammation and oxidative stress. This study supposed that the gastroprotective effect of  l-arginine depends on aging, and even so, the adoption of a new approach to gastric ulcer treatment for the aged population is warranted.

Synthesis, biological evaluation, and computational investigation of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates as potential larvicidal agents against Anopheles arabiensis.

Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.

A century of "Camel Research": a bibliometric analysis.

Introduction: Bibliometrics is a quantitative analytic strategy used to assess the unit of publications per each field of research. Bibliometric studies are commonly employed to examine the current research climate, potential developments, and development trends in certain domains. In this work, the major contributors to camel research throughout the past century are discussed, along with the funding sources, academic institutions, scientific disciplines, and countries that contributed to "Camel Research". Methods: The Web of Science (WOS) database was used to retrieve the publications based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) instructions. Results: There are 7,593 articles dedicated to camel research on the Web of Science (as of August 1st, 2022). Three stages were involved in the publication of a study on camels. At the beginning, from 1877 to 1965, there were fewer than ten new publications per year. The second stage comprised 100 publications per year (1968-2005). Since 2010, nearly 200 new papers have been published each year. King Saud and King Faisal universities contributed > (0.08) of the total publications. While more than 1,000 funding agents were retrieved, the Natural Science Foundation of China (NSFC) showed the greatest rate of funded projects (0.17). Camel research was included in 238 scientific disciplines. The top disciplines were Veterinary Sciences (0.39), Agriculture Dairy Animal Science (0.144), and Food Science Technology (0.087). Conclusion: There has been an increase in interest in camels in recent years, but the research trends in camel health and production need greater support.

A century of "anticoccidial drugs": bibliometric analysis.

Publications are an important measure of scientific and technological progress. The quantitative examination of the number of publications in a certain research topic is known as bibliometrics. Bibliographic studies are widely used to analyse the condition of research, future potential, and current growth patterns in a certain topic. It can serve as a basis for making decisions and implementing strategies to achieve long-term development goals. To our knowledge, no research has been conducted in these domains; so, this work aims to employ bibliometric analysis to provide comprehensive data on publications related to anticoccidial drugs. As a result, the current study uses bibliometric analysis to track the evolution of anticoccidial drugs and its consequences in the academic and public worlds via a survey of relevant scientific and popular publications. The Dimensions database was used to retrieve the bibliographical statistics, which were then cleaned and analyzed. The data was also loaded into the VOS viewer, which generated a network visualization of the authors with the most joint articles. The investigation discovered three stages of publications and citations since the first article on anticoccidial drugs in 1949. The first stage, which ran from 1920 to 1968, was characterized by a scarcity of research articles on anticoccidial drugs. From 1969 to 2000, the second stage was marked by a stable and marginally increased number of articles. The scientific field was characterized by an increasing trend in the number of publications and their citations from 2002 to 2021. The study gave a complete list of the top anticoccidial drugs funding agents, countries, research institutes, most cited publications, and important co-authorship and partnerships. The outcomes of the study will help veterinary practitioners and researchers understand the trends and best sources of knowledge in the field of anticoccidial medications.

Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis-Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1.

The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

Design, Development, and Evaluation of Constant Voltage Iontophoresis for the Transungual Delivery of Efinaconazole.

The efficacy of topical antifungal therapy in onychomycosis has been hindered by the failure of the antimycotic to permeate the nail plate. This research aims to design and develop a transungual system for the effective delivery of efinaconazole utilizing constant voltage iontophoresis. Seven prototype drug-loaded hydrogel formulations (E1-E7) were prepared to assess the influence of solvent (ethanol) and cosolvent (Labrasol®) on transungual delivery. Optimization was performed to evaluate the effect of three independent variables; voltage, solvent-to-cosolvent ratio, and penetration enhancer (PEG 400) concentration on critical quality attributes (CQAs), such as drug permeation and loading into the nail. The selected hydrogel product was characterized for pharmaceutical properties, efinaconazole release from the nail, and antifungal activity. Preliminary data indicates ethanol, Labrasol®, and voltage influence the transungual delivery of efinaconazole. Optimization design indicates a significant impact by applied voltage (p-0.0001) and enhancer concentration (p-0.0004) on the CQAs. Excellent correlation between selected independent variables and CQAs was confirmed by the high desirability value (0.9427). A significant (p < 0.0001) enhancement in the permeation (~78.59 µg/cm2) and drug loading (3.24 µg/mg) was noticed in the optimized transungual delivery with 10.5 V. FTIR spectral data indicates no interaction between the drug and excipients, while the DSC thermograms confirmed the amorphous state of the drug in the formulation. Iontophoresis produces a drug depot in the nail that releases above the minimum inhibitory concentration level for an extended period, potentially reducing the need for frequent topical treatment. Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte. Overall, the promising results obtained here demonstrate the prospective of this non-invasive method for the effective transungual delivery of efinaconazole, which could improve the treatment of onychomycosis.

Safety and immunogenicity of the ChAdOx1, MVA-MERS-S, and GLS-5300 DNA MERS-CoV vaccines.

BACKGROUND: The Middle East respiratory syndrome coronavirus (MERS-CoV) is a pathogen associated with an acute respiratory infection that has a high mortality rate in humans. It was first identified in June of 2012 in the Arabian Peninsula. The success of the COVID-19 vaccines has shown that it is possible to take advantage of medical and scientific advances to produce safe and effective vaccines for coronaviruses. This study aimed to examine the safety and immunogenicity of MERS-CoV vaccines. METHODS: The research method Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was used as the guideline for this study. RevMan 5.4 software was used to perform a meta-analysis of the included studies. The safety was assessed by recording adverse events following vaccination, and the immunogenicity was assessed by using seroconversion. RESULTS: The study included five randomized controlled trials that met the inclusion criteria after screening. The studies had 173 participants and were performed in four countries. The vaccines examined were the ChAdOx1 MERS vaccine, MVA-MERS-S vaccine, and GLS-5300 DNA MERS-CoV vaccine. The meta-analysis showed no significant differences in local adverse effects (all local adverse effects and pain) or systemic adverse effects (all systemic adverse effects, fatigue, and headache) among participants in groups receiving a high-dose vaccine or a low-dose vaccine. There were, however, higher levels of seroconversion in high-dose groups than in low-dose groups (OR 0.16 [CI 0.06, 0.42, p = 0.0002]). CONCLUSION: The findings showed that high doses of current MERS-CoV vaccine candidates conferred better immunogenicity than low doses and that there were no differences in the safety of the vaccines.

Efficacy of the modified vaccinia Ankara virus vaccine and the replication-competent vaccine ACAM2000 in monkeypox prevention.

BACKGROUND: Recently, there has been an uptick in reported cases of monkeypox (Mpox) in Africa and across the globe. This prompted us to investigate the efficacy of the two vaccines that can prevent Mpox, the modified vaccinia Ankara virus (MVA) vaccine and ACAM2000 vaccine. We analyzed them to determine their rates of humoral cell responses, adverse events, and rash reactions and used these factors as the primary indicators. METHODS: This study adapted primary data obtained from the Medline, Google Scholar, and Cochrane Library databases. We included a total of eight studies, three of which explored the ACAM2000 vaccine and five of which explored the JYNNEOS MVA vaccine. RESULTS: There were significant differences in the rates of humoral responses after inoculation by the two vaccines. JYNNEOS MVA vaccine immunization resulted in a statistically significant increased humoral immune response with an effect size of 81.00 (42.80, 119.21) at a 95% CI and a rash reaction with an effect size of 96.50 (42.09, 235.09.21) at a 95% CI. ACAM2000 resulted in a lesser increase in neutralizing antibodies than JYNNEOS MVA vaccine. Similar findings were identified for the rates of adverse reactions, but the difference was not statistically significant. The differences in rash reaction rates in the two vaccination groups were also not statistically significant. CONCLUSION: ACAM2000 and JYNNEOS vaccines have proven to be efficient in preventing Mpox even though variations exist in their modes of action and associated significant effects. The nonreplicating nature of JYNNEOS prevents the occurrence of the adverse effects seen with other vaccines.

Cognitive- and memory-enhancing effects of Augmentin in Alzheimer's rats through regulation of gene expression and neuronal cell apoptosis.

Introduction: Alzheimer's disease (AD) is the most common type of dementia among older persons. This study looked at how Augmentin affected behavior, gene expression, and apoptosis in rats in which AD had been induced by scopolamine. Methods: The rats were divided into five groups: control, sham, memantine, Augmentin, and pre-Augmentin (the last group received Augmentin before scopolamine administration and was treated with memantine). A Morris water maze was utilized to measure spatial memory in the animals, and real-time quantitative reverse transcription PCR (qRT-PCR) and flow cytometry were employed to analyze gene expression and neuronal cell apoptosis, respectively. Results: Memantine and Augmentin increased spatial memory in healthy rats. The use of scopolamine impaired spatial memory. Both Augmentin and memantine improved spatial memory in AD rats, particularly in the group that received memantine; however, the outcomes were more substantial when Augmentin was administered before scopolamine was given to induce AD. Furthermore, the expression of presenilin-2 (PSEN2) and inositol-trisphosphate 3-kinase B (ITPKB) increased, whereas the expression of DEAD-box helicase 5 (DDX5) fell in the AD-treated groups; however, the results were more substantial after combination therapy. According to flow cytometry studies, Augmentin pre-treatment reduced apoptosis in AD rats. Discussion: The results showed that administering Augmentin to AD rats before memantine improved their spatial memory, reduced neuronal cell death, upregulated protective genes, and suppressed genes involved in AD pathogenesis.

Qbd-Based Approach to Optimize Niosomal Gel of Levosulpiride for Transdermal Drug Delivery.

Poor aqueous solubility besides extensive hepatic first effect significantly decreases the oral absorption of levosulpiride, which in turn minimizes its therapeutic effectiveness. Niosomes have been extensively investigated as a transdermal vesicular nanocarrier to increase the delivery of low permeable compounds into and across the skin. This research work was to design, develop and optimize levosulpiride-loaded niosomal gel and to evaluate its prospects for transdermal delivery. The Box-Behnken design was used to optimize niosomes by analyzing the impact of three factors (cholesterol; X1, Span 40; X2, and sonication time; X3) on the responses (particle size, Y1, and entrapment efficiency, Y2). Optimized formulation (NC) was incorporated into gel and evaluated for pharmaceutical properties, drug release study, ex vivo permeation, and in vivo absorption. The design experiment data suggest that all three independent variables influence both response variables significantly (p < 0.01). Pharmaceutical characteristics of NC vesicles showed the absence of drug excipient interaction, nanosize (~102.2 nm), narrow distribution (~0.218), adequate zeta potential (-49.9 mV), and spherical shape, which are suitable for transdermal therapy. The levosulpiride release rates varied significantly (p < 0.01) between niosomal gel formulation and control. Greater flux (p < 0.01) was observed with levosulpiride-loaded niosomal gel than with control gel formulation. Indeed, the drug plasma profile of niosomal gel was significantly higher (p < 0.005), with ~3 folds higher Cmax and greater bioavailability (~500% higher; p < 0.0001) than its counterpart. Overall, these findings imply that the use of an optimized niosomal gel formulation can increase the therapeutic efficacy of levosulpiride and may represent a promising alternative to conventional therapy.

Carnosine Potentiates Doxorubicin-Induced Cytotoxicity in Resistant NCI/ADR-RES Cells by Inhibiting P-Glycoprotein-In Silico and In Vitro Evidence.

The activity of the P-glycoprotein (P-gp) transporter encoded by the ABCB1 gene confers resistance to anticancer drugs and contributes to cancer-related mortality and morbidity. Recent studies revealed the cytotoxic effects of the endogenous dipeptide carnosine. The current study aimed to investigate the role of carnosine as a potential inhibitor of P-gp activity. We used molecular docking and molecular dynamic simulations to study the possible binding and stability of carnosine-P-gp interactions compared with verapamil. In vitro assays using doxorubicin-resistant NCI/ADR-RES cells were established to test the effects of carnosine (10-300 µM) on P-gp activity by the rhodamine-123 efflux assay and its effect on cell viability and doxorubicin-induced cytotoxicity. Verapamil (10 µM) was used as a positive control. The results showed that carnosine binding depends mainly on hydrogen bonding with GLU875, GLN946, and ALA871, with a higher average Hbond than verapamil. Carnosine showed significant but weaker than verapamil-induced rhodamine-123 accumulation. Carnosine and verapamil similarly inhibited cell viability. However, verapamil showed a more significant potentiating effect on doxorubicin-induced cytotoxicity than a weaker effect of carnosine at 300 µM. These results suggest that carnosine inhibits P-gp activity and potentiates doxorubicin-induced cytotoxicity at higher concentrations. Carnosine might be a helpful lead compound in the fight against multidrug-resistant cancers.

Tocotrienol in the Treatment of Topical Wounds: Recent Updates.

Healing wounds is an important attempt to keep the internal higher organs safe. Complications in topical wound healing may lead to the formation of scars, which can affect the patient's quality of life. Although several approaches are ongoing in parallel in the exploration of natural compounds via advanced delivery, in this article, an attempt has been made to highlight tocotrienol. Tocotrienol is a natural form of vitamin E and has shown its potential in certain pharmacological activities better than tocopherol. Its antioxidant, anti-inflammatory, cell signal-mediating effects, angiogenic properties, management of scar, and promotion of wound environment with essential factors have shown potential in the management of topical wound healing. Therefore, this review has aimed to focus on recent advances in topical wound healing through the application of tocotrienols. Challenges in delivering tocotrienols to the topical wound due to its large molecular weight and higher logP have also been explored using nanotechnological-based carriers, which has made tocotrienol a potential tool to facilitate the closure of wounds. Exploration of tocotrienol has also been made in human volunteers for biopsy wounds; however, the results are yet to be reported. Overall, based on the current findings in the literature, it could be inferred that tocotrienol would be a viable alternative to the existing wound dressing components for the management of topical wounds.

Computational Design, Synthesis, and Pharmacological Evaluation of Naproxen-Guaiacol Chimera for Gastro-Sparing Anti-Inflammatory Response by Selective COX2 Inhibition.

The 4-allyl guaiacol is a natural phenolic molecule that has been widely studied for its antioxidant capacity against reactive-oxygen-species-mediated cellular damage. Therefore, we hypothesized that concomitant use of an antioxidant and NSAID may decrease the risk of gastrointestinal toxicity and make the therapy safer. To address the gastrointestinal toxicity of conventional NSAIDs, a new S-naproxen-4-allyl guaiacol chimera (MAS-1696) was computationally developed, chemically synthesized, and tested for anti-inflammatory effectiveness and gastrointestinal safety. The inhibitory potency of MAS-1696 tested against cyclooxygenase-2 (COX2), 15-lipoxygenase-2 (15-LOX2), and lipoxygenase-5 (5-LOX) in vitro revealed a stronger inhibition of COX2. Furthermore, the MAS-1696 chimera increased the COX selectivity index by 23% as compared to the parent compound naproxen, implying higher efficacy and gastric safety. In vivo data showed that MAS-1696 was less likely to cause gastrointestinal harm than naproxen while also exerting anti-inflammatory and analgesic effects equivalent to or superior to naproxen. In conclusion, MAS-1696 is orally active, bio-labile, and crystalline, making it a medication that may be administered orally.

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis-The Role of Drug Efflux Transporters.

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.

Paeonol Attenuates Hepatic Ischemia/Reperfusion Injury by Modulating the Nrf2/HO-1 and TLR4/MYD88/NF-κB Signaling Pathways.

Hepatic ischemia/reperfusion (HIR) is the most common type of liver injury following several clinical situations. Modulating oxidative stress and inflammation by Nrf2/HO-1 and TLR4/MYD88/NF-κB pathways, respectively, is involved in alleviating HIR injury. Paeonol is a natural phenolic compound that demonstrates significant antioxidant and anti-inflammatory effects. The present study explored the possible protective effect of paeonol against HIR injury and investigated its possible molecular mechanisms in rats. Rats were randomly divided into four groups: sham-operated control, paeonol-treated sham-operated control, HIR untreated, and HIR paeonol-treated groups. The results confirmed that hepatic injury was significantly aggravated biochemically by elevated serum levels of alanine transaminase and aspartate transaminase, as well as by histopathological alterations, while paeonol reduced the increase in transaminases and alleviated pathological changes induced by HIR. Additionally, paeonol inhibited the HIR-induced oxidative stress in hepatic tissues by decreasing the upraised levels of malondialdehyde and nitric oxide and enhancing the suppressed levels of reduced glutathione and superoxide dismutase activity. Furthermore, paeonol activated the protective antioxidative Nrf2/HO-1 pathway. The protective effect of paeonol was associated with inhibiting the expression of the inflammatory key mediators TLR4, MYD88, NF-κB, and TNF-α. Finally, paeonol inhibited the increased mRNA levels of the pro-apoptotic marker Bax and enhanced the reduced mRNA levels of the anti-apoptotic marker Bcl-2. Taken together, our results proved for the first time that paeonol could protect against HIR injury by inhibiting oxidative stress, inflammation, and apoptosis.

Ameliorative Effect of Dabigatran on CFA-Induced Rheumatoid Arthritis via Modulating Kallikrein-Kinin System in Rats.

Rheumatoid arthritis is an autoimmune disease that affects joints, leading to swelling, inflammation, and dysfunction in the joints. Recently, research efforts have been focused on finding novel curative approaches for rheumatoid arthritis, as current therapies are associated with adverse effects. Here, we examined the effectiveness of dabigatran, the antithrombotic agent, in treating complete Freund's adjuvant (CFA)-induced arthritis in rats. Subcutaneous injection of a single 0.3 mL dosage of CFA into the rat's hind leg planter surface resulted in articular surface deformities, reduced cartilage thickness, loss of intercellular matrix, and inflammatory cell infiltration. There were also increased levels of the Anti-cyclic citrullinated peptide antibody (ACPA), oxidative stress, and tissue Receptor activator of nuclear factor-kappa B ligand (RANKL). Proteins of the kallikrein-kinin system (KKS) were also elevated. The inhibitory effects of dabigatran on thrombin led to a subsequent inhibition of KKS and reduced Toll-like receptor 4 (TLR4) expression. These effects also decreased RANKL levels and showed anti-inflammatory and antioxidant effects. Therefore, dabigatran could be a novel therapeutic strategy for arthritis.

Semi-automated EPR system for direct monitoring the photocatalytic activity of TiO2 suspension using TEMPOL model compound.

The photocatalytic activity of TiO2 nanoparticles in aqueous solutions is commonly evaluated by monitoring the rate of methylene blue bleaching and phenols degradation, but both substrates suffer from many drawbacks, e.g., the high capacity of dark adsorption, self-degradation, and photosensitization. Besides, filtration is always required to separate the particulate photocatalyst before the analysis. Herein, we investigated the potential use of electron paramagnetic resonance (EPR) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) to directly monitor the photocatalytic activity of TiO2 suspensions without the need for filtration. The results showed that TEMPOL aqueous solution is in the dark and under UV-A illumination, does not absorb UV-A and visible light, and has negligible dark adsorption. The influence of TEMPOL concentration, light intensity, and TiO2 loading on the photocatalytic deactivation rate has been investigated. The mechanisms of TEMPOL deactivation in the presence and absence of oxygen as well as in the presence of methanol •OH radicals' scavenger have been discussed. The photocatalytic deactivation products have been analyzed using EPR, 1H-NMR, and 13C-NMR spectroscopies. It is found that the deactivation of TEMPOL is initiated by •OH radicals and α-H abstraction from the 4-piperidine position followed by the formation of TEMPONE (4-oxo-2,2,6,6-tetramethylpiperidine-1-oxyl) and 4-oxo-2,2,6,6-tetramethylpiperidine). In the presence of methanol, the formed α-hydroxyl radicals (•CH2OH) attack the nitroxide side of TEMPOL and produce 4-hydroxy-tetramethylpiperidine. Same activity trends have been observed for the photocatalytic methanol oxidation and TEMPOL deactivation over different types of TiO2 photocatalysts evincing that the proposed method has a potential for direct monitoring of the activities of photocatalyst suspensions.

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives.

A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a-3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k-3m. Thus, compounds 3k-3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.