Protective activity of hirsutidin in high-fat intake and streptozotocin-induced diabetic rats: In silico and in vivo study.

Background: Type 2 diabetes mellitus (T2DM) is defined by a wide variety of metabolic abnormalities, persistent hyperglycemia, and a slew of other complications. Catharanthus roseus L. (apocyanaceae), remarkably notable as Vinca Rosea, appears to be the source of the active component hirsutidin, which is reported in various diseases. Objective: The study intended to appraise the antidiabetic capability of hirsutidin in a high-fat diet (HFD) and streptozotocin (STZ) induced diabetes in experimental rats. Materials and methods: An experimental rodent T2DM model was elicited by consuming an HFD regimen with STZ 50 mg/kg, i.p. dose formulated in a 0.1 M cold citrate buffer (pH 4.5). The test drug hirsutidin (10 and 20 mg/kg) and the standard drug glimeclamide (5 mg/kg) were administered daily for six weeks. The efficacy of hirsutidin was observed on several diabetes parameters. The average body weight and an array of biochemical markers were determined, including blood glucose, insulin, dyslipidemia (lipid profile), total protein (TP), liver injury [aspartate aminotransferase (AST), alanine aminotransferase (ALT)], inflammation [IL-6, IL-1ß, tumor necrosis factor-α (TNF-α)], oxidative stress [malondialdehyde (MDA)] and antioxidant status [catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD)]. In addition, the concentrations of leptin, adiponectin, and resistin were also assessed. Also, molecular docking studies were undertaken to investigate critical targets associated with diabetes, including TNF-α, insulin, adiponectin, and leptin. Results: Diabetes induction with HFD/STZ resulted in hyperglycemia (significantly reduced blood glucose and increased insulin level), dyslipidemia (significantly reduced TC, TG and increased HDL), total protein (significantly reduced), oxidative stress and antioxidant status (significantly reduced MDA and increased CAT, SOD and GSH levels), inflammation (significantly decreased IL-6, IL-1ß, TNF-α), liver damage (significantly reduced AST, ALT), and specific hormones such as adiponectin, leptin significantly improved and resistin significantly reduced as evidenced by biochemical data in this study. Intermolecular interactions of ligands and docking score, hirsutidin proteins TNF-α (2AZ5), Insulin (4IBM), Adiponectin (6KS1), Leptin (7Z3Q) with binding energy of -6.708, -7.674, -7.2 and -7.547 Kcal/mol. Conclusion: Hirsutidin may have an evidential hypoglycemic outcome and may exhibit potent antidiabetic activity in HFD/STZ-induced T2DM in rats. Treatment with hirsutidin significantly improved glycemic control, lipid metabolism, oxidative stress, inflammation, and liver function. Additionally, it normalized dysregulated levels of adiponectin, leptin, and resistin. Molecular docking confirmed its strong binding affinity to key diabetic targets.

6-Shogaol Abrogates Parkinson's Disease in Rotenone-Induced Rodents: Based on In Silico Study and Inhibiting TNF-α/NF-κB/IL-1ß/MAO-B.

Background/Objectives: 6-Shogaol is a comparatively innovative anti-Parkinson's remedy with antioxidant and anti-inflammatory characteristics. This investigation intended to determine the role of 6-shogaol in the Parkinson's disease (PD) paradigm in rotenone-induced rats. Methods: Thirty male Wistar rats (10-12 weeks old; 180 ± 20 g) were divided into five groups. Animals with rotenone-induced experimental PD were subsequently treated with 6-shogaol-10 at 20 mg/kg for 28 days. After the experimental duration, behavioural investigations were performed, i.e., open field test, forced swim test, rotarod test, and catalepsy test. Biochemical assessments like AChE, GSH, CAT, SOD, MDA, nitrite, ceruloplasmin, proinflammatory markers such as IL-1ß, NF-κB, TNF-α, and catecholamines markers (DA, GABA, and MAO-B) were determined. The docking procedure was conducted using the AutoDock Vina docking protocol. Furthermore, histopathology was performed. Results: Rotenone significantly increased the level of MAO-B, oxidative, nitrative, and pro-inflammatory markers. However, there was a decline in ceruloplasmin, dopamine, and endogenous antioxidants. Treatment with 6-shogaol (10 and 20 mg/kg) considerably sustained the elevation of oxidative stress and inflammatory indicators and decreased AChE activity and dopamine levels. In the histology of the brain, 6-shogaol improved the neuronal structure and reduced the degeneration of neurons. Based on the binding energy values, compound 6-shogaol demonstrates a favourable binding affinity to AChE, MAO-B, DA, and GABA with respective binding energies of -8.214, -8.133, -7.396 and -6.189 kcal/mol. Conclusions: In this study, 6-shogaol exhibited neuroprotective properties against PD, which could be employed as a prospective medication for PD.

Fustin, a Potent Phytochemical, Attenuates Scopolamine-induced Memory Impairment and Neurodegeneration by Modulating Neuroinflammation and Neurotransmitters.

INTRODUCTION: Fustin, a photogenic flavanol found in the plant Rhus verniciflua Stokes, has been involved in multiple disease ailments and has a beneficial pharmacological effect and a history of use in traditional medicine. The present research aimed to study the impact of fustin on scopolamine (SCOP)-induced memory impairment and neurodegeneration by modulating neuroinflammation and neurotransmitters in rats. METHODS: A total of 30 healthy Wistar rats were allocated into five groups (n=6). Group I- served as control and received saline solution (1mL/kg i.p.), group -II- fustin (100 mg/kg, orally), group -III -SCOP (1 mg/kg, i.p.), and group -IV and V were given fustin (50 and 100 mg/kg/p.o.) with SCOP (1 mg/kg, i.p.) for 14-days. After 14 days, 2 hours after SCOP injection, the Y-maze and Morris water maze (MWM) tests were performed. After behavioral tests rats were subsequently euthanized, and brain supernatants were used to estimate choline-acetyltransferase (ChAT), acetylcholinesterase (AChE), antioxidant [superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)], and total protein, oxidative stress markers [nitrate and malondialdehyde (MDA)], pro-inflammatory markers [tumor necrosis factor (TNF-α), and Interleukins-1ß (IL-1ß) and IL-6]. Also, neurotransmitters such as serotonin (5-HT), dopamine (DA), ϒ-amino butyric acid (GABA), acetylcholine (Ach), and noradrenaline (NA) contents were performed. RESULTS: Fustin exhibited substantial behavioral improvement in the Y-maze measures spontaneous alterations percentage (SA%) and decreased latency time following the acquisition and prolonged time spent in the probe trial in the MWM test. Moreover, fustin inhibits enhanced neuroinflammatory cytokines and oxidative stress markers and improves the neurotransmitters. CONCLUSION: The findings of this study suggest that fustin inhibits SCOP impact on cognitive abilities in rats. The present investigation demonstrates that fustin, a potent phytochemical, effectively mitigated the behavioral and physiological changes induced by SCOP in rats. This was primarily achieved by modulating the levels of inflammatory response and neurotransmitters.

Design of in-situ implant for the brain-targeted drug delivery using cross-linked gellan gum polymer through response surface methodology.

The analysis aimed to prepare an in-situ implant (ISFI) formulation holding dimethyl fumarate as (a model drug) using cross-linked gellan gum by homogenization method. Cross-linking of gellan gum was done with L-cysteine to improve its gelation properties. Fourier transform infrared spectroscopy (FTIR) and (DSC) Differential scanning calorimetry were used to test the compatibility of the drug-polymer. The diverse formulations were prepared and tested using Design Expert® ver 8.0.1 software to optimize the experiment technique and employ the response surface. The tissue compatibility of the test verified the existence of non-irritants in the established formulation. All preparations contained the drug content from approximately 97.98 to 99.88%. Viscosities are ideal for injection in the optimized formulation (1,55 percent w/w in water). The optimized formula was monitored, and up to 156hours, it was found to be 95.7%. The result was that ISFI can effectively monitor and control the delivery of several powerful drug products.

Chemical analogue based drug design for cancer treatment targeting PI3K: integrating machine learning and molecular modeling.

Cancer is a generic term for a group of disorders defined by uncontrolled cell growth and the potential to invade or spread to other parts of the body. Gene and epigenetic alterations disrupt normal cellular control, leading to abnormal cell proliferation, resistance to cell death, blood vessel development, and metastasis (spread to other organs). One of the several routes that play an important role in the development and progression of cancer is the phosphoinositide 3-kinase (PI3K) signaling pathway. Moreover, the gene PIK3CG encodes the catalytic subunit gamma (p110γ) of phosphoinositide 3-kinase (PI3Kγ), a member of the PI3K family. Therefore, in this study, PIK3CG was targeted to inhibit cancer by identifying a novel inhibitor through computational methods. The study screened 1015 chemical fragments against PIK3CG using machine learning-based binding estimation and docking to select the potential compounds. Later, the analogues were generated from the selected hits, and 414 analogues were selected, which were further screened, and as most potential candidates, three compounds were obtained: (a) 84,332, 190,213, and 885,387. The protein-ligand complex's stability and flexibility were then investigated by dynamic modeling. The 100 ns simulation revealed that 885,387 exhibited the steadiest deviation and constant creation of hydrogen bonds. Compared to the other compounds, 885,387 demonstrated a superior binding free energy (ΔG = -18.80 kcal/mol) with the protein when the MM/GBSA technique was used. The study determined that 885,387 showed significant therapeutic potential and justifies further experimental investigation as a possible inhibitor of the PIK3CG target implicated in cancer.

A Simple, Sensitive, and Greener HPLC-DAD Method for the Simultaneous Analysis of Two Novel Orexin Receptor Antagonists.

The orexin receptor antagonist (ORA) is one of the new psychopharmacological agents used in the treatment of insomnia. There are currently no documented greener high-performance liquid chromatography-diode array detector (HPLC-DAD) methods for the analysis of ORA antagonists, lemborexant (LMB) and suvorexant (SUV) simultaneously. Therefore, in this study, a simple, sensitive, and greener HPLC-DAD method has been developed for the simultaneous quantitative analysis of LMB and SUV in bulk and laboratory-prepared mixture. The developed method was validated for numerous validation parameters and evaluated for greenness. The C18 Waters Spherisorb CN (4.6 × 250 mm2; 5 µm) column was used for the chromatographic separation. The mobile phase composition was ethanol: 10 mM KH2PO4 buffer in a ratio of (60:40 v/v). The DAD detection was performed at 253 nm using a Waters DAD detector. The greenness was evaluated using the analytical Eco-Scale (AES), ChlorTox, and analytical GREEnness (AGREE) techniques. The calibration curves showed excellent linearity for LMB and SUV between the concentration range of 125-5000 ng/mL and 250-10,000 ng/mL, respectively. In addition, the proposed HPLC-DAD method was accurate, precise, robust, highly sensitive, and greener. AES, ChlorTox, and AGREE scales were predicted by the HPLC-DAD method to be 91, 1.14 g, and 0.79, respectively, showing an excellent greenness profile. The greener HPLC-DAD method was successfully used to analyze both medicines quantitatively in bulk and laboratory-prepared synthetic mixtures. The findings of this study indicated that the proposed HPLC-DAD method may be consistently applied to evaluate LMB and SUV in bulk and dosage forms.

Europinidin Attenuates Methamphetamine-induced Learning and Memory Impairments and Hippocampal Alterations in Rodents: Based on Molecular Docking through a Mechanism of Neuromodulatory Cytokines/ Caspases-3/ CREB/BDNF Pathway.

BACKGROUND: Methamphetamine (MA) is well recognized as a psychostimulant that can cause neurotoxicity and neurodegeneration, which is associated with cognitive decline, has been confirmed experimentally. OBJECTIVE: The research aimed to investigate the neuroprotective properties of europinidin (Eu) in rodents affected by methamphetamine (MA)-induced cognitive impairments and hippocampal alterations. This was achieved by inhibiting lipid peroxidation and pro-inflammatory markers. METHODS: Rats were exposed to cognitive impairment produced by MA. The Morris water maze (MWM) is utilized for evaluating behavioral parameters. Tests were conducted on malondialdehyde (MDA), catalase (CAT), interleukins-1ß (IL-1ß), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), and the expression of neurotransmitters (Norepinephrine [NE], dopamine [DA], glutamate, and gamma-aminobutyric acid [GABA]) as well as cAMP response element-binding protein (CREB), IL-6, brain-derived neurotrophic factor (BDNF), and caspase 3 proteins. An investigation was carried out using docking methodology to ascertain whether Eu interacts with relevant molecular targets. RESULTS: Significant decline in the transfer latency and there were significant changes in the amount of SOD, GSH, CAT, and MDA and alterations in levels of IL-6, IL-1ß, CREB, TNF-α, BDNF, and Caspase 3 proteins expression, as well as considerably alterations in level of neurotransmitters (NE, DA, Glutamate, and GABA) were observed in the Eu-treated rats compared to the MA-induced rats. Eu had a favorable affinity towards BDNF with docking scores of -9.486 kcal/mol. CONCLUSION: The experiment found that administering Eu to rats improved cognitive abilities by changing antioxidant enzymes, reducing cytokines, and modifying neurotransmitter levels, compared to rats in the control group treated with MA.

Formulation and characterization of polymeric nanoparticle of Rivastigmine for effective management of Alzheimer's disease.

Memory loss or dementia is a progressive disorder, and one of its common forms is Alzheimer's disease (AD), effecting mostly middle aged and older adults. In the present study, we developed Rivastigmine (RIV) nanoparticles using poly(lactic-co-glycolic acid) (RIV-loaded PLGA NPs) and polyvinyl alcohol (PVA). The prepared RIV-PLGA nanoparticles was evaluated for the management of Alzheimer's disease (AD). The nanoparticles were prepared by the slightly modified nano-precipitation technique. The developed formulations were evaluated for particle size, zeta potential (ZP), polydispersibility index (PDI) and surface morphology and drug content. The experimental result revealed that prepared RIV-loaded PLGA NPs (F1) was optimized having particle size (61.2 ± 4.6 nm), PDI (0.292), ZP (-11.2 ± 1.2). SEM study confirms the prepared nanoparticles depicted non-aggregated as well smooth surface particles without any fracture. This formulation (F1) was further assessed for in vivo studies on animal model. A pharmacological screening on an animal model of Alzheimer's disease revealed that RIV-loaded PLGA NPs formulations treat CNS disorders like Alzheimer's effectively. In addition to that, an in-vivo brain cholinesterase estimation study found that, animals treated with optimized formulation significantly (p < 0.01) reduced brain cholinesterase activity when compared to scopolamine-treated animals. According to the above results, it can be concluded that RIV-loaded PLGA NPs are ideal carriers for delivering the drug at a specific target site in the brain, thus may treat Alzheimer's disease efficiently and improve patient compliance.

Barbaloin's Chemical Intervention in Aluminum Chloride Induced Cognitive Deficits and Changes in Rats through Modulation of Oxidative Stress, Cytokines, and BDNF Expression.

Alzheimer's disease (AD) is a long-term neurodegenerative condition characterized by impaired cognitive functions, particularly in the domains of learning and memory. Finding promising options for AD can be successful with a medication repurposing strategy. The goal of the research was to examine the neuroprotective characteristics of barbaloin in aluminum chloride (AlCl3)-induced cognitive deficits and changes in rats through modulation of oxidative stress, cytokines, and brain-derived neurotrophic factor (BDNF) expression. Thirty male Wistar rats were subjected to AlCl3 at a dosage of 100 mg/kg via the per oral route (p.o.), which induced cognitive decline. Morris water maze (MWM) is used to assess behavioral metrics. Assays for catalase (CAT), malondialdehyde (MDA), reduced glutathione (GSH), acetylcholinesterase (AChE), choline-acetyltransferase (ChAT), interleukins-1ß (IL-1ß), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), nuclear factor kappa-B (NF-κB), interleukins-6 (IL-6), BDNF, and neurotransmitter levels [dopamine (DA), acetylcholine (Ach), and γ-aminobutyric acid (GABA)] were performed. Results: The transfer latency time was notably decreased, and substantial modifications in the concentrations of GSH, MDA, CAT, SOD, AChE, ChAT and observed modulations in the formation of interleukins-6 (IL-6), TNF-α, IL-1ß, BDNF, and NF-κB were also evidenced after the treatment of rats with barbaloin in comparison to AlCl3-induced control groups. Significant alterations in neurotransmitter levels (DA, Ach, and GABA) were also seen in barbaloin-treated groups in comparison to AlCl3-induced groups. The current investigation has provided evidence that the administration of barbaloin yielded notable enhancements in cognitive function in rats through the inhibition of MDA, enhancing endogenous antioxidant enzymes, reduction of cytokine levels, and enhancement of neurotransmitter contents in the brain. These effects were observed in comparison to a control group treated with AlCl3 and can be attributable to barbaloin's strong anti-inflammatory and antioxidant properties, and metal chelating properties may contribute to its neuroprotective effects. Barbaloin may also promote neuronal survival and enhance learning and memory by upregulating the expression of BDNF.

Oxyphenbutazone ameliorates carfilzomib induced cardiotoxicity in rats via inhibition of oxidative free radical burst and NF-κB/IκB-α pathway.

Carfilzomib (CFZ), a chemotherapeutic agent used for multiple myeloma treatments reported to cause high incidence of cardiac events either new onset and/or exacerbate formerly diagnosed heart failure with ventricular and myocardial dysfunction. Purpose: Current research designed to explore and examine the preventive effect of oxyphenbutazone in the CFZ -instigated cardiotoxicity. Methodology: Female Wistar Rats weighing 200-250 g selected randomly and grouped as follows: Group 1 designated as the Normal control and receive normal saline only. Group 2 served toxic control and exposed to CFZ (4 mg/kg, intraperitoneally [i.p.]). Group 3 & 4 served as treatment groups and administered with CFZ concomitantly orally fed with oxyphenbutazone at doses of 35 and 70 mg/kg/three times a week, respectively. The total duration of experimental protocol was of 21 days. After completion of the experiments animals subjected to blood collection using light ether anesthesia and serum was separated for biochemical analysis further. The serum levels of Mg+2, Ca+2 and cardiac enzymes (aspartate transaminase (AST), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase-MB (CK-MB) levels were estimated. Later animals sacrificed and heart tissue isolated for further examinations. Intracellular proteins NFkB and IkBα were estimated by western blot. Results: The serum analysis revealed that CFZ administration significantly elevated the levels of LDH, CK and CKMB in CFZ exposed animals when compared to normal animals while administration of oxyphenbutazone significantly reduced these biochemical changes, Intracellular antioxidant enzymes and NF-kB in treatment groups as compared to disease control animals. Conclusion: Findings of the research protocol suggests significant injuries to cardiac tissues when animals exposed to CFZ and Oxyphenbutazone protected the cardiac tissues.

Effect of Apremilast on LPS-induced immunomodulation and inflammation via activation of Nrf2/HO-1 pathways in rat lungs.

Lipopolysaccharides (LPS), the lipid component of gram-negative bacterial cell wall, is recognized as the key factor in acute lung inflammation and is found to exhibit severe immunologic reactions. Phosphodiesterase-4 (PDE-4) inhibitor: "apremilast (AP)" is an immune suppressant and anti-inflammatory drug which introduced to treat psoriatic arthritis. The contemporary experiment designed to study the protective influences of AP against LPS induced lung injury in rodents. Twenty-four (24) male experimental Wistar rats selected, acclimatized, and administered with normal saline, LPS, or AP + LPS respectively from 1 to 4 groups. The lung tissues were evaluated for biochemical parameters (MPO), Enzyme Linked Immunosorbent Assay (ELISA), flowcytometry assay, gene expressions, proteins expression and histopathological examination. AP ameliorates the lung injuries by attenuating immunomodulation and inflammation. LPS exposure upregulated IL-6, TNF-α, and MPO while downregulating IL-4 which were restored in AP pretreated rats. The changes in immunomodulation markers by LPS were reduced by AP treatment. Furthermore, results from the qPCR analysis represented an upregulation in IL-1ß, MPO, TNF-α, and p38 whereas downregulated in IL-10 and p53 gene expressions in disease control animals while AP pretreated rats exhibited significant reversal in these expressions. Western blot analysis suggested an upregulation of MCP-1, and NOS-2, whereas HO-1, and Nrf-2 expression were suppressed in LPS exposed animals, while pretreatment with AP showed down regulation in the expression MCP-1, NOS-2, and upregulation of HO-1, and Nrf-2 expression of the mentioned intracellular proteins. Histological studies further affirmed the toxic influences of LPS on the pulmonary tissues. It is concluded that, LPS exposure causes pulmonary toxicities via up regulation of oxidative stress, inflammatory cytokines and stimulation of IL-1ß, MPO, TNF-α, p38, MCP-1, and NOS-2 while downregulation of IL-4, IL-10, p53, HO-1, and Nrf-2 at different expression level. Pretreatment with AP controlled the toxic influences of LPS by modulating these signaling pathways.

Hirsutidin Prevents Cisplatin-Evoked Renal Toxicity by Reducing Oxidative Stress/Inflammation and Restoring the Endogenous Enzymatic and Non-Enzymatic Level.

Recent research has shown that phytocomponents may be useful in the treatment of renal toxicity. This study was conducted to evaluate the renal disease hirsutidin in the paradigm of renal toxicity induced by cisplatin. Male Wistar rats were given cisplatin (3 mg/kg body weight/day, for 25 days, i.p.) to induce renal toxicity. Experimental rats were randomly allocated to four different groups: group I received saline, group II received cisplatin, group III received cisplatin + hirsutidin (10 mg/kg) and group IV (per se) received hirsutidin (10 m/kg) for 25 days. Various biochemical parameters were assessed, oxidative stress (superoxide dismutase (SOD), glutathione transferase (GSH), malonaldehyde (MDA) and catalase (CAT)), blood-chemistry parameters (blood urea nitrogen (BUN) and cholesterol), non-protein-nitrogenous components (uric acid, urea, and creatinine), and anti-inflammatory-tumor necrosis factor-α (TNF-α), interleukin-1ß(IL-1ß). IL-6 and nuclear factor-kB (NFκB) were evaluated and histopathology was conducted. Hirsutidin alleviated renal injury which was manifested by significantly diminished uric acid, urea, urine volume, creatinine, and BUN, compared to the cisplatin group. Hirsutidin restored the activities of several antioxidant enzyme parameters-MDA, CAT, GSH, and SOD. Additionally, there was a decline in the levels of inflammatory markers-TNF-α, IL-1ß, IL-6, and NFκB-compared to the cisplatin group. The current research study shows that hirsutidin may act as a therapeutic agent for the treatment of nephrotoxicity induced by cisplatin.

UPLC-MS/MS Based Identification and Quantification of a Novel Dual Orexin Receptor Antagonist in Plasma Samples by Validated SWGTOX Guidelines.

Lemborexant (LEM) is a novel dual orexin receptor antagonist (DORA), recently approved for the treatment of insomnia. As with other DORAs, LEM has potential of abuse and therefore placed in Schedule IV class by the United States Drug Enforcement Administration (USDEA). In this study, a sensitive and accurate UPLC-MS/MS assay was developed for the quantification of LEM in human plasma sample using losartan as an internal standard (IS). The chromatographic separation was performed by using gradient elution of mobile phase, comprising of 10 mM ammonium acetate and acetonitrile with a flow rate of 0.3 mL/min. An Acquity UPLC BEH C18 (1.7 µm, 2.1 × 50 mm) column was used for separation of LEM and IS by maintaining the oven temperature of 40 °C. The electrospray ionization in positive mode was used for sample ionization. The precursor to product ion transition of 411.12 > 175.09 (qualifier) and 411.1 > 287.14 (quantifier) was used for detection and quantification of LEM, respectively, in multiple reaction monitoring mode. Being a drug of abuse, the assay was validated according to "Scientific Working Group for Toxicology" (SWGTOX) guidelines, including limit of detection (LOD), limit of quantification (LOQ), precision and bias, calibration model, interferences, carry-over effects, matrix effects, and stability parameters. The LOD and LOQ of the assay were 0.35 and 1.0 ng/mL, respectively. The linear range was between 1-300 ng/mL with correlation coefficient of ≥0.995. The method was also cross validated in rat plasma samples with acceptable ranges of precision and accuracy before its application for pharmacokinetic study in rats.

Cathepsin-B inhibitor CA-074 attenuates retinopathy and optic neuritis in experimental autoimmune encephalomyelitis induced in SJL/J mice.

The complicated multiple sclerosis (MS) can exhibit subacute sight deterioration and can lead to total deprivation of vision. In the current work, we explored the therapeutic outcome of Cathepsin B inhibitor (CA-074) against retinopathy and optic neuritis (ON) caused by experimental autoimmune encephalomyelitis (EAE) induced by proteolipid protein peptide (PLP) in female SJL/J mice. A daily dose of 10 mg/kg CA-074 was administered to the EAE mice intraperitoneally for 14 days from day 14 post-immunization until day 28. The Western blot and immunofluorescence analyses show inflammation in the optic nerve through the elevation of iNOS and NFkB markers in EAE mice. Optic neuritis was reported which is a consequence of demyelination and axon injury, estimated with the reduction in myelin basic protein (MBP). The glial fibrillary acidic protein (GFAP) expression level was found to be elevated in the retina of EAE mice which confirmed the retinopathy. The administration of CA-074 ameliorated optic neuritis and retinopathy by reducing inflammation. The treatment with CA-074 also reduced the demyelination and axonal injuries in the EAE mice. The findings of this study have shown the protective effect of CA-074 in the case of retinopathy and ON inflicted by EAE in SJL/J mice.

Protective effect of Apremilast against LPS-induced acute lung injury via modulation of oxidative stress and inflammation.

Lung injuries are attributed due to exposure to Drugs or chemicals. One of the important challenging situations for the clinicians is to manage treatments of different diseases with acute lung injury (ALI). The objective of this study was to investigate the possible protective mechanisms and action of a novel Phosphodiesterase-4 inhibitor "Apremilast" (AP) in lipopolysaccharide (LPS)-induced lung injury. Blood sample from each animals were collected in a vacuum blood collection tube. The rat lungs were isolated for oxidative stress assessment, western blot analysis and their mRNA expressions using RT-PCR. Exposure of LPS in rats causes significant increase in oxidative stress, activates the pro-inflammatory cytokines release like tissue necrotic factor-alpha (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6), modulated gene expression, protein expression and histopathological changes which were reversed by administration of AP. Finding of the research enlighten the protective role of AP against LPS-induced ALI.

Corrigendum to "Protective effect of Apremilast against LPS-induced acute lung injury via modulation of oxidative stress and inflammation" [Saudi J. Biol. Sci. 29(5) (2022) 3414-3424].

[This corrects the article DOI: 10.1016/j.sjbs.2022.02.023.].

6-Shogaol Attenuates Traumatic Brain Injury-Induced Anxiety/Depression-like Behavior via Inhibition of Oxidative Stress-Influenced Expressions of Inflammatory Mediators TNF-α, IL-1ß, and BDNF: Insight into the Mechanism.

Anxiety and depression are among the major traumatic brain injury-induced psychiatric disorders in survivors. The present study was undertaken to investigate the beneficial effects of 6-Shogaol against depression-like behavior and anxiety, induced by traumatic brain injury (TBI), in mice. The mice were administered either fluoxetine, vehicle, or three different doses (10, 20 and 30 mg/kg/day, i.p.) of 6-Shogaol after 10 days of impact-accelerated TBI. The treatment was continued for 14 consecutive days. Elevated plus maze test, marble burying test, staircase test, and social interaction test were employed to investigate the effect of 6-Shogaol on anxiety-like behavior. The impact of treatment on depression-like behavior was assessed using hyper-emotionality behavior or open-field exploration test. The expressions of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and malondialdehyde (MDA) levels in brain tissue and brain water were measured to elucidate possible mechanisms involved. 6-Shogaol treatment (higher dose) was able to attenuate anxiety/depression-like behaviors in mice with TBI. 6-Shogaol treatment also altered MDA formation and expressions of TNF-α and IL-1ß that act as major inflammation-inducing cytokines in brain tissue. Additionally, brain BDNF levels were also affected by 6-Shogaol treatment. Although the lower dose of 6-Shogaol was able to rectify inflammation and BDNF expression in brain tissue, it was unable to improve anxiety/depression-like behaviors. 6-Shogaol treatment produced beneficial effects for TBI-induced anxiety/depression-like behaviors in mice, which could be attributed to the reduction of lipid peroxidation, inflammation, and enhanced BDNF expression.

Toxicological interaction between tobacco smoke toxicants cadmium and nicotine: An in-vitro investigation.

Cigarettes and other tobacco products are used to obtain nicotine that is responsible for their stimulating effects. However, a lot of other organic and inorganic chemicals are also released along with nicotine. Cadmium (Cd) is one of the several heavy metals that are health hazards and is one of the inorganic elements released in tobacco smoke. The in-vitro investigation focused on exploring the effects of nicotine hydrogen tartrate (NHT) and cadmium (Cd) and their toxic interactions in the A549 cell line. In cell viability assay NHT exhibited its IC50 at 11.71 mM concentration, and the IC50 of Cd was found to be 83 µM after a 24 h exposure. Toxic effects of NHT (5 mM and 10 mM), Cd (50 µM and 100 µM), and their combination were also investigated by flowcytometry. The investigation included apoptotic and necrotic events, the effect on different cell cycle phases, and generation of reactive oxygen species by NHT, Cd, and their combination of different concentrations. Data reveal evident toxic effects of NHT, Cd, and NHT + Cd. It also indicates that the toxic interaction of NHT and Cd is not additive and appears to be minimal when compared with NHT or Cd exposures alone.

Protective effect of diosmin against doxorubicin-induced nephrotoxicity.

Doxorubicin (Dox) is an anthracycline antibiotic that is primarily used for treating various solid tumors including that of pulmonary, ovary, breast, uterine, cervix, and several blood cancers. However, nephrotoxicity associated with Dox treatment limits its clinical use. Administration of Dox in combination with compounds exhibiting antioxidant properties are being used to minimize the side effects of Dox. Diosmin is a flavonoid glycoside with numerous beneficial properties that is found in the pericarp of many citrus fruits. Diosmin has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effects in response to various insults, although the exact mechanism remains unknown. Therefore, this study was designed to evaluate the effect of diosmin in preventing kidney damage in response to Dox treatment. Male Wistar rats were randomly divided into four groups: control group, Dox group (20 mg/kg, i.p.), Dox plus low-dose diosmin group (100 mg/kg orally), and Dox plus high-dose diosmin group (200 mg/kg orally). A single intraperitoneal injection of Dox resulted in kidney damage as evidenced by significant alterations in kidney markers, histological abnormalities, and the attenuation of antioxidant defense mechanisms (GSH, SOD, and CAT). Moreover, Dox treatment significantly altered the expression of oxidative stress, inflammatory, and anti-apoptotic protein markers. Diosmin pretreatment alleviated Dox-induced nephrotoxicity by ameliorating the antioxidant mechanism, decreasing inflammation and apoptosis, and restoring kidney architecture. In conclusion, our results indicate that diosmin is a promising therapeutic agent for the prevention of nephrotoxicity associated with DOX.

6-Shogaol attenuated ethylene glycol and aluminium chloride induced urolithiasis and renal injuries in rodents.

The 6-shogaol, is a flavanone type flavonoid that is abundant in citrus fruit and has a wide range of pharmacological effects. The present study attempted to evaluate the antiurolithic effect of 6-shogaol on ethylene glycol (EG) and ammonium chloride (AC)-induced experimental urolithiasis in rats. The efficacy of 6-shogaol 50 mg/kg and 100 mg/kg was studied in EG 0.75% (V/V) and AC 1% (W/V) experimentally induced urolithiasis in rats for 21 days. The weight difference, urine volume, the levels of calcium, phosphate, magnesium, oxalate and uric acid in urine was observed. The blood urea nitrogen, creatinine, uric acid in serum and levels of malondialdehyde (MDA) and glutathione (GSH) were also measured. Histopathological analyses in kidneys were also performed. The rats weights were higher in the 6-shogaol groups than the urolithiasis group. EG caused a significant increase in serum creatinine (p < 0.05), BUN (P < 0.001), and uric acid (p < 0.01) while treatment with Cystone (750 mg/kg), and 6-shogaol (50 and 100 mg/kg) showed the significant reduction in increased serum levels of creatinine (p < 0.001), uric acid (p < 0.01) and BUN (p < 0.001). Administration of EG and AC showed statistically significant (p < 0.001) elevated levels of MDA and reduction in GSH levels. Treatment of Cystone (750 mg/kg), and 6-shogaol (50 and 100 mg/kg) significantly (p < 0.001) reduced MDA levels and an increase GSH levels as compared to EG and AC-treated group. The histological findings further attested antiurolithiatic properties of 6-shogaol. The present study attributed clinical shreds of evidence first time that claiming the significant antiurolithic effect of 6-shogaol and could be a cost-effective candidate for the prevention and treatment of urolithiasis.