Synergism of CD28 Immune Molecule in Late Immunosuppressive Phase of COVID-19: Effectiveness in Vaccinated Individuals.

Context: Lymphopenia has been frequently documented and linked to coronavirus disease 2019 (COVID-19) in a severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV-2) attack. A decrease in the T-lymphocyte count has shown promise as a clinical indicator and predictor of COVID-19 severity. Objective: The review intended to examine the relationship of COVID-19 infections in individuals to lost expression of CD28 on naive CD4+/CD8+-mediated, vaccine-specific, neutralizing antibody responses. Design: The research team performed a narrative review by searching eight databases: Medline, Elsevier, Cochrane, PubMed, Google Scholar, Mendeley, and Springer Nature. The search used the following key terms: SARS CoV-2, clinical aspects and pathology of SARS CoV-2, involvement of viral spike (S) protein in SARS CoV-2, immunological changes in COVID-19 infection, basic overview of CD28 immuno-molecule ligand, reduction of vaccine therapeutic efficacy in COVID-19 infection, and immunomodulatory response of lost CD28 ligand. Setting: This study was done in a Maharishi Arvind College of Pharmacy, Jaipur, India. Results: In COVID-19 patients, particularly those with severe disease, had increased levels of IL-2 or IL-2R. Given IL-2's supportive role in the expansion and differentiation of T cells, the authors exhibiting that lymphopenia, particularly in severe COVID-19, could be attributed to nonfunctional and dysfunctional differentiation of CD4+ and CD8+ T cells as a result of low CD28 immuno-molecule expression on naive T cells. Conclusions: The literature review found that independent, early immunological prognostic markers for a poor prognosis, in addition to higher levels of IL-6, include a substantial proportion of large inflammatory monocytes and a small proportion of chronic CD28+ CD4+T cells. The current findings suggest that a combination of COVID-19 vaccination with SARS CoV-2-reactive naive T cells with the CD28 immune-molecule may be a viable method for establishing T-cell-based, adaptive cellular immunotherapy against COVID-19 infection. Further research is needed, especially larger studies to confirm the current findings, to improve early clinical treatment.

Nanomedicine in treatment of breast cancer - A challenge to conventional therapy.

Amongst the various types of cancer, breast cancer is a highly heterogeneous disease and known as the leading cause of death among women globally. The extensive interdisciplinary investigation in nanotechnology and cancer biomedical research has been evolved over the years for its effective treatment. However, the advent of chemotherapeutic resistance in breast cancer is one of the major confront researchers are facing in achieving successful chemotherapy. Research in the area of cancer nanotechnology over the years have now been revolutionized through the development of smart polymers, lipids, inorganic materials and eventually their surface-engineering with targeting ligands. Moreover, nanotechnology further extended and brings in the notice the new theranostic approach which combining the therapy and imaging simultaneously. Currently, research is being envisaged in the area of novel nano-pharmaceutical design viz. liposome, nanotubes, polymer lipid hybrid system, which focuses to make the chemotherapy curative and long-lasting. In this review, we aimed to discuss the recent advancement of different surface-engineered/targeted nanomedicines that improved the drug efficacy in breast cancer.

Molecular explanation of Wnt/ßcatenin antagonist pyrvinium mediated calcium equilibrium changes in aging cardiovascular disorders.

The symptoms of ageing are somewhat different and can lead to the altered role of the cardiovascular system at the levels of genetic, biochemical, tissue, organ, and systems. Ageing is an autonomous cardiovascular risk factor. In the ageing rat heart, oxidative and inflammatory stress, immune cell infiltration, increasing myeloperoxidase function, elevated caspase-3 activity, and protein fibronectins were detected and associated with ageing and cardiovascular disease. The intracellular Ca2 + homeostasis disturbed in an older heart dramatically increases cardiomyopathy, atherosclerosis, stroke, ischemia, myocardial infarction, hypertrophy, remodelling, and hypertension. Evidence shows that suppression of Wnt/ß signals prevents cardiovascular dysfunction, such as remodelling, high blood pressure, and excessive overload stress. However, one study has shown that the pharmacological disruption of Wnt-ß-catenin by decreasing expression of α-smooth muscle actin, fibronectin and collagen I proteins attenuates angiotensin II mediated hypertension cardiac fibrosis. Thus, this review examined the impacts of calcium overload and age-related diseases, including cardiovascular. Energy dysregulation, calcium overloading, and mitochondrial dysfunction are the main activities causing cardiovascular disease linked with age. Therefore, the current study explores that age-associated cardiovascular disease has triggered the WNT/ß-catenin pathway, and pharmacological inhibition can delay pathological changes by attenuating calcium dyshomeostasis.

Effects of the Anthocyanin Hirsutidin on Gastric Ulcers: Improved Healing through Antioxidant Mechanisms.

The goal of this study was to determine the effect of hirsutidin on ethanol-induced stomach ulcers in rats. Rats (n = 24 rats/group) were separated at random into the following groups: normal saline-treated (normal control), ethanol-treated (ethanol control), 10 mg/kg hirsutidin + ethanol-treated (hirsutidin 10), and 20 mg/kg hirsutidin + ethanol-treated (hirsutidin 20). All the groups received the respective treatment orally for 7 days. On day 7, i.e., after 24 h of fasting, except for the normal control group, all the groups orally received 5 mL/kg of ethanol. Four hours later, rats were anaesthetized, serum was isolated from the blood, and biochemical tests were performed. The stomach tissue was utilized for ulcer grading, histology, and biochemical analysis. The rats developed stomach acidity and ulcers after being given ethanol based on increased ulcer score, disturbed cellular architecture, increased oxidative stress, myeloperoxidase and decreased endogenous antioxidants, and nitric oxide and prostaglandin E2 concentration. Ethanol-treated rats also displayed increased tumor necrosis factor-α, aspartate aminotransferase, alanine transaminase, alkaline phosphatase, and inflammatory cytokines. The treatment with hirsutidin protected and significantly restored all serum parameters in ethanol-induced stomach ulcers and may have antiulcer activity.

Rosiridin Attenuates Scopolamine-Induced Cognitive Impairments in Rats via Inhibition of Oxidative and Nitrative Stress Leaded Caspase-3/9 and TNF-α Signaling Pathways.

AIM: A monoterpene and bioactive component of the plant Rhodiola rosea (R. rosea), rosiridin has beneficial effects on the human central nervous system and enhances brain function. The goal of this scientific study was to determine if rosiridin might shield rats from neurocognitive problems induced by scopolamine. METHODS: To track the potential toxicities in rats, the acute toxicity in rats was clarified. Rosiridin at a dose of 10 mg/kg was tested in rats for 14 days. At the conclusion of the investigation, behavioral parameters that were used to identify the rats' cognitive and motor abilities were evaluated. Several biochemical parameters were estimated using the prepared homogenate, including acetylcholine esterase (AChE), choline acetyltransferase (ChAT), radical scavengers produced by the body (Catalase-CAT, superoxide dismutase-SOD, and reduced glutathione-GSH), indicators of oxidative and nitrative burnout, pro-inflammatory (Interleukins- IL-1ß, IL-6, interferon gamma IFN-ꝩ, and tumor necrosis factor-TNF-α), and cell apoptosis caspases 3 and 9. RESULTS AND CONCLUSION: A significant behavioral parameter restoration was seen in the rosiridin-treated group, including reduction in latency time during acquisition and retention trial in the Morris water maze test, and percentage of spontaneous alterations in the y-maze test, when compared to the disease control group that received scopolamine; rosiridin also altered the oxidative stress and neuroinflammatory markers, as well as restoring Ach and ChAT activities and normalizing GSH, SOD, MDA, TNF-α, nitrate, IL-1ß, IL-6, IFN-ꝩ, caspases 3 and 9 levels. The results imply that rosiridin limits the effect of scopolamine on rat cognitive function.

Rosinidin Protects Streptozotocin-Induced Memory Impairment-Activated Neurotoxicity by Suppressing Oxidative Stress and Inflammatory Mediators in Rats.

Background and Objectives: To assess the antioxidant and neuroprotective role of rosinidin on rat memory impairment that is induced by streptozotocin. Materials and Methods: Wistar rats were given an intraperitoneal (i.p) injection of streptozotocin (60 mg/kg) followed by treatment with rosinidin at selective doses (10 and 20 mg/kg) for 30 days. The behavioral parameters were estimated by Y-maze test and Morris water test. Biochemical parameters such as acetylcholinesterase (AChE), choline aacetyltransferase (ChAT), and nitric oxide, and antioxidants such as glutathione transferase (GSH), superoxide dismutase (SOD) IL-6, IL-10, Nrf2, and BDNF, were determined. Results: The study results revealed that rosinidin improved cognition by reverting the behavioral parameters. The treatment with rosinidin restored the antioxidant enzymes and inflammatory cytokines. Conclusions: From the results, it has been proven that rosinidin possesses antioxidant, anti-amnesic, and anti-inflammatory activity. Rosinidin improved the cognitive and behavioral deficits that were induced by streptozotocin. Furthermore, 20 mg/kg rosinidin was found to have strong protective action against streptozotocin-induced toxicity.

Hibiscetin attenuates oxidative, nitrative stress and neuroinflammation via suppression of TNF-α signaling in rotenone induced parkinsonism in rats.

Parkinson's disease (PD) is the gradual and selective degradation of dopamine-releasing neurons in substantia nigra pars compacta (SNpc) and results in postural instability, stiffness, bradykinesia, and resting tremor. The goal of this research was to see how hibiscetin action on PD in rotenone-treated rats. Rats were administered orally with hibiscetin (10 mg/kg) after 1 h rotenone (0.5 mg/kg, s.c.). This therapy regimen was followed on a daily basis for 28 days. Rats were tested for catalepsy and akinesia on day 29 after the last dosage of rotenone. Biochemical parameters were performed to measure reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), nitrite, neuroinflammatory cytokines, and neurotransmitter and their metabolite levels such as dopamine (DA), norepinephrine (NE), serotonin (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). Rotenone-induced akinesia and catatonia in rats decreased endogenous antioxidant (GSH, CAT, and SOD) levels, increased MDA and nitrite levels, and changed neurotransmitter and metabolite levels. Hibiscetin effectively reduced rotenone-induced akinesia and catatonia, improved endogenous antioxidant (GSH, CAT and SOD) levels, and reduced oxidative and nitrative stress in the treated rats. Moreover, hibiscetin restored altered neurotransmitters and their metabolites to normal levels in rotenone-treated rats. The study results showed that hibiscetin has anti-Parkinson's activity against rotenone-induced PD in rats.

Pharmacological evaluation of cardioprotective potential of Berberis orthobotrys Bien.ex Aitch.

The resurgence of scrutiny in plant-based medicine is mainly due to the current widespread belief that "green medicine" is safe and more dependable than the expensive synthetic drugs. The current study was focused to evaluate the anti-myocardial ischemic potential of Berberis orthobotrys Bien ex Aitch against chemically induced myocardial ischemia in animal models. Myocardial ischemia was instigated in Sprague Dawley rats of either sex (250-450g) by administration of Isoproterenol (ISO) and doxorubicin (DOX) at doses of 25mg/kg b.w and 15mg/kg b.w. respectively. The protective effect of the plant extract was explored by pretreating a group of animals with aqueous methanolic extract of Berberis orthobotrys roots at a dose of 50mg/kg b.w. (orally) for 10 days in ISO-ischemic model while for doxorubicin ischemic model; the study was conducted for 14 days. The findings of the study revealed that serum levels of cardiac marker enzymes were significantly increased (p<0.0001) followed by the administration of Isoproterenol and doxorubicin whereas the pretreatment with aqueous methanolic plant extract had significantly (p<0.0001) prevented the rise in the same, as compared to both intoxicated groups. The statistical analysis of the study led to the conclusion that Berberis orthobotrys possesses cardio protective potential against chemically induced myocardial ischemia.

Role of Epithelial-to-Mesenchymal Transition Markers in Different Stages of Endometriosis: Expression of the Snail, Slug, ZEB1, and Twist Genes.

Among various epithelial-to-mesenchymal transition (EMT)-related transcription factors (TFs), altered expression levels of Snail-1, Snail-2/Slug, Twist, and ZEB1 have shown a significant association in different cancers having a higher risk of metastasis. However, their role in the circulation of endometriosis patients is not well understood. Hence, the present study was designed to evaluate the crucial role of these TFs in defining the molecular pathogenesis for endometriosis progression and differentiation from control subjects. The qualitative and quantitative expression analysis of Snail-1, Snail-2/Slug, Twist, and ZEB1 were analyzed in peripheral blood samples of 75 different stages of endometriosis patients and compared with 50 control subjects. Total RNA was extracted and converted into complementary DNA (cDNA) for relative quantification of each gene transcript using SYBRGreen-based reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). The Livak method of relative quantification was used for calculating the fold change in each TF compared with endogenous control. All four selected TFs showed significantly upregulated expression levels in endometriosis patients compared with control subjects. A three-fold increase was observed for Snail-1 (p = 0.0001), and a two-fold increase was observed for Snail-2 (p = 0.01), Twist (p = 0.0002), and ZEB1 (p = 0.001) in stage III and IV compared with stage I and II of endometriosis patients. The present study revealed that EMT-related TFs play a crucial role in the pathogenesis and differentiating different stages of endometriosis patients through expression analysis of specific molecular cascades using non-invasive tools.

Calcium sensing receptor hyperactivation through viral envelop protein E of SARS CoV2: A novel target for cardio-renal damage in COVID-19 infection.

Over the recent decades, a number of new pathogens have emerged within specific and diverse populations across the globe, namely, the Nipah virus, the Ebola virus, the Zika virus, and coronaviruses (CoVs) to name a few. Recently, a new form of coronavirus was identified in the city of Wuhan, China. Interestingly, the genomic architecture of the virus did not match with any of the existing genomic sequencing data of previously sequenced CoVs. This had led scientists to confirm the emergence of a new CoV strain. Originally, named as 2019-nCoV, the strain is now called as SARS-CoV-2. High serum levels of proinflammatory mediators, namely, interleukin-12 (IL-12), IL-1ß, IL-6, interferon-gamma (IFNγ), chemoattractant protein-1, and IFN-inducible protein, have been repeatedly observed in subjects who were infected with this virus. In addition, the virus demonstrated strong coagulation activation properties, leading to further the understanding on the SARS-CoV2. To our understanding, these findings are unique to the published literature. Numerous studies have reported anomalies, namely, decline in the number of lymphocytes, platelets and albumins; and a rise in neutrophil count, aspartate transaminase, alanine aminotransaminase, lactate dehydrogenase, troponins, creatinine, complete bilirubin, D-dimers, and procalcitonin. Supplementation of calcium during the SARS CoV-2 associated hyperactive stage of calcium-sensing receptors (CaSR) may be harmful to the cardio-renal system. Thus, pharmacological inhibition of CaSR may prevent the increase in the levels of intracellular calcium, oxidative, inflammatory stress, and cardio-renal cellular apoptosis induced by high cytokines level in COVID-19 infection.

Formulation of carteolol chitosomes for ocular delivery: formulation optimization, ex-vivo permeation, and ocular toxicity examination.

Background:Conventional delivery systems like solution and suspension are commonly used for the treatment of ocular diseases but have low corneal residence time and hence the duration of effect is limited. These drawbacks of conventional systems can be reduced by preparing bioadhesive chitosan (CH) coated noisome.Methods: Niosomes (NIM) of carteolol (CT) were developed by the thin-film hydration method and optimised by the Box-Behnken statistical design. Further, the optimised CT-NIM was coated with CH to enhance the ocular residence time . The optimised formulation was evaluated for vesicle size, entrapment efficiency, and in-vitro drug release and transcorneal permeation, histopathology, etc.Results: CT-NIM-opt showed the vesicle size and entrapment efficiency of 235 ± 3.54 nm, and 70.45 ± 0.87%, respectively. DSC spectra exhibited that CT was completely encapsulated into the CH-CT-NIM matrix. Drug release from CH-CT-NIM-opt was more sustained (68.28 ± 4.2%) than CT-NIM (75.69 ± 4.5% in 12 h) and CT solution (99.89 ± 2.8% in 4 h). The CH-CT-NIM-opt represented a strong bio-adhesion (89.76 ± 3.6%) than CT-NIM-opt (15.65 ± 3.4%). The permeation flux exhibited 1.13-fold higher permeation than CT-NIM and 3.23 fold than CT solution. The corneal hydration was found to be within the limit value. The histopathology study exhibited no structural damage to the cornea . HET-CAM results showed zero scores indicating no bleeding or haemorrhage. CH-CT-NIM-opt was found to be isotonic and exhibited good stability when stored at 4 °C for the stated duration of time.Conclusion: The above findings suggested that NIM can be a potential carrier for the delivery of CT with better ocular residence time.

Formulation of Chitosan-Coated Piperine NLCs: Optimization, In Vitro Characterization, and In Vivo Preclinical Assessment.

In the present research work, surface-modified nanostructured lipid carriers (NLCs) with chitosan (CH) were prepared to improve the therapeutic efficacy of piperine (PP). NLCs were developed and optimized (CH-PP-NLCs-opt) by design expert software and the selected NLCs surface was coated with chitosan (0.2% w/v). CH-PP-NLCs-opt have shown a particle size of 149.34 ± 4.54 nm and entrapment efficiency of 80.65 ± 1.23%. The results of the solid-state characterization study exhibited that PP enclosed in lipids and present amorphous form. It might be due to the nanoparticle size of NLCs. The drug release study revealed PP-NLCs-opt and CH-PP-NLCs-opt exhibited significant (P < 0.05) difference in PP release (88.87 ± 5.23% and 76.34 ± 4.54%) as compared to pure PP (19.02 ± 2.87%). CH-PP-NLCs-opt exhibited strong bioadhesion than PP-NLCs-opt which has a positive influence the drug permeation and absorption. CH-PP-NLCs-opt showed higher permeation (1083.34 ± 34.15 µg/ cm2) than pure PP (106.65 ± 15.44 µg/cm2) and PP-NLCs-opt (732.45 ± 28.56 µg/ cm2). The significantly enhanced bioavailability of PP was observed from CH-PP-NLCs-opt (3.76- and 1.21-fold) than PP-dispersion and PP-NLCs-opt. The diabetes was induced in rats by a single intraperitoneal administration of streptozotocin (STZ, 40 mg/kg, citrate buffer pH 4.5), and results revealed that PP-NLCs-opt and CH-PP-NLCs-opt reduce the blood glucose level (28.26% and 36.52% respectively) as compared to PP-dispersion (10.87%). It also helps to maintain the altered biochemical parameters. In conclusion, CH-PP-NLC can be a novel oral nanocarrier for the management of diabetes.

Bioactive Apigenin loaded oral nano bilosomes: Formulation optimization to preclinical assessment.

AIM: Diabetic (type-2) is a metabolic disease characterized by increased blood glucose level from the normal level. In the present study, apigenin (AG) loaded lipid vesicles (bilosomes: BIL) was prepared, optimized and evaluated for the oral therapeutic efficacy. EXPERIMENTAL: AG-BIL was prepared by a thin-film evaporation method using cholesterol, span 60 and sodium deoxycholate. The prepared formulation was optimized by 3-factor and 3-level Box-Behnken design using particle size, entrapment efficiency and drug release as a response. The selected formulation further evaluated for ex-vivo permeation, in vivo pharmacokinetic and pharmacodynamics study. RESULTS: The optimized AG bilosomes (AG-BILopt) has shown the vesicle size 183.25 ± 2.43 nm, entrapment efficiency 81.67 ± 4.87%. TEM image showed a spherical shape vesicle with sharp boundaries. The drug release study revealed a significant enhancement in AG release (79.45 ± 4.18%) from AG-BILopt as compared to free AG-dispersion (25.47 ± 3.64%). The permeation and pharmacokinetic studies result revealed 4.49 times higher flux and 4.67 folds higher AUC0-t than free AG-dispersion. The antidiabetic activity results showed significant (P < 0.05) enhancement in therapeutic efficacy than free AG-dispersion. The results also showed marked improvement in biochemical parameters. CONCLUSION: Our findings suggested, the prepared apigenin loaded bilosomes was found to be an efficient delivery in the therapeutic efficacy in diabetes.

Novel 1,2,4-triazole derivatives as apoptotic inducers targeting p53: Synthesis and antiproliferative activity.

A series of novel thiazolo[3,2-b][1,2,4]-triazoles 3a-n has been synthesized and evaluated in vitro as potential antiproliferative. Compounds 3b-d exhibited significant antiproliferative activity. Compound 3b was the most potent with Mean GI50 1.37 µM comparing to doxorubicin (GI50 1.13 µM). The transcription effects of 3b, 3c and 3d on the p53 were assessed and compared with the reference doxorubicin. The results revealed an increase of 15-27 in p53 level compared to the test cells and that p53 protein level of 3b, 3c and 3d was significantly inductive (1419, 571 and 787 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL). The docking study of the new compounds 3a-n revealed high binding scores for the new compounds toward p53 binding domain in MDM2. The docking analyses revealed the highest affinities for compounds 3b-d which induced p53 activity in MCF-7 cancer cells. Compound 3b which exhibited the highest antiproliferative activity and induced the highest increase in p53 level in MCF-7 cells showed also the highest affinity to MDM2.

Beta-catenin non-canonical pathway: A potential target for inflammatory and hyperproliferative state via expression of transglutaminase 2 in psoriatic skin keratinocyte.

Psoriasis is a chronic, local as well as a systemic, inflammatory skin condition. Psoriasis influences the quality of life up to 3.8% of the population and occurs often between 15 and 30 years of age. Specific causes are linked to psoriasis, including the interleukin IL-23/IL-17 Axis, human antigen leucocyte (HLA), and tumor necrosis factor-α (TNF-α). Secukinumab is a monoclonal antibody that specifically binds and neutralizes IL-17A required in the treatment of Psoriasis. The signaling pathways of Wnt govern multiple functions of cell-like fate specification, proliferation, polarity, migration, differentiation with their signaling controlled rigorously, given that dysregulation caused by various stimuli, can lead to alterations in cell proliferation, apoptosis, and human inflammatory disease. Current data has supported non-canonical Wnt signaling pathways in psoriasis development, particularly Wnt5a activated signaling cascades. These interconnected factors are significant in interactions between immune cells, keratinocytes, and inflammatory factors due to a higher degree of transglutaminase 2, mediated by activation of the keratinocyte hyperproliferation of the psoriatic patient's epidermis. This study discusses the pathology of Wnt5a signaling and its involvement in the epidermal inflammatory effects of psoriasis with other related pathways.

Role of rivaroxaban in sunitinib-induced renal injuries via inhibition of oxidative stress-induced apoptosis and inflammation through the tissue nacrosis factor-α induced nuclear factor-κappa B signaling pathway in rats.

Rivaroxaban (RIVA) inhibits factor Xa and exhibits antithrombotic and anti-inflammatory activities by inhibiting several cellular signaling molecules. Sunitinib (SUN) is FDA approved first-line drug for metastatic renal cancers and advanced cancerous states of gastrointestinal tract. Present hypothesis was aimed to examine the nephroprotective potential of RIVA in SUN-induced nephrotoxicity, mediated through the inhibition of oxidative stress-induced apoptosis and inflammation, via the TNF-α/NFk-B signaling pathways. Wistar rats 200-250 g were selected and divided randomely in 5 groups (n = 6): Group 1 kept as normal control; Group 2 as disease control and exposed to SUN 50 mg/kg thrice-weekly upto 21 days; Groups 3 and 4, were treatment groups and administered SUN 50 mg/kg thrice-weekly as of group 2 and treated with RIVA 5 and 10 mg/kg/daily for 21 days, respectively; and Group 5 fed with RIVA alone (10 mg/kg/daily for 21 days). Serum was separated from blood to estimate serum biochemical parameters and kidney tissues were collected to estimate antioxidant enzyme, mRNA and protein expression. SUN exposure significantly elevated levels of creatinine, urea, uric acid, blood urea nitrogen, albumin, and bilirubin, and decreased serum magnesium and iron levels. Malondialdehyde and catalase levels were significantly increased and glutathione and glutathione reductase levels were significantly decreased. Intracellular levels of caspase-3 and TNF-α were significantly increased; RIVA treatment restored the altered levels. In SUN-exposed animals, western blotting revealed significantly elevated NFk-B, IL-17, and MCP-1 expression, and IKBα levels were significantly downregulated; RIVA restored these levels to normal values.RIVA treatment significantly restored the apoptotic and inflammatory parameters in SUN-damaged renal tissues.

Formulation of amorphous ternary solid dispersions of dapagliflozin using PEG 6000 and Poloxamer 188: solid-state characterization, ex vivo study, and molecular simulation assessment.

The present study was designed to prepare dapagliflozin (DFG) loaded ternary solid dispersions (SDs) using the carrier blend polyethylene glycol 6000 (PEG 6000) and poloxamer 188 (PLX 188). The prepared DFG-SDs were evaluated for solubility study, physicochemical characterization and molecular simulation study. The prepared DFG-SDs showed significant higher solubility and dissolution vis-a-vis pure DFG and DFG physical mixture. The composition DFG:PEG:PLX (1:2.25:0.75 mM) showed the highest solubility (0.476 ± 0.016 mg/mL). The physicochemical characterization confirms the polymorphic transition of DFG from crystalline state to stable amorphous form. The prepared DFG-SDs showed a significantly higher dissolution (64.78 ± 2.34% to 78.41 ± 2.39%) than pure DFG (15.70 ± 3.54%). DFG-SD2 showed a significantly enhanced drug permeation (p<.05) (58.76 ± 4.65 µg/cm) as compared to pure DFG (14.97 ± 3.32 µg/cm). The molecular docking study result revealed a good hydrophobic interaction of DFG with the used carrier due to the lowest energy pose. The interaction occurs between the methylene bridges and the central hydrophobic chain of polyoxypropylene of the polymer. Therefore, DFG-SDs prepared by microwave irradiation method using hydrophilic carrier blend might be a promising strategy for improving the solubility and in vitro dissolution performance.

Formulation of Chitosan Polymeric Vesicles of Ciprofloxacin for Ocular Delivery: Box-Behnken Optimization, In Vitro Characterization, HET-CAM Irritation, and Antimicrobial Assessment.

Ciprofloxacin is a commonly used antibiotic for treatment of bacterial conjunctivitis. The conventional eye drop dosage form is the widely used mode of treatment, but it has low corneal residence time. This drawback can be overcome by developing a bioadhesive noisome system (chitosan-coated) for enhanced corneal residence time. The niosomes were prepared by thin-film hydration technique and optimized by using Box-Behnken statistical design software. Cholesterol (A), Span 60 (B), and sonication time (C) were selected as independent variables, whereas vesicle size (Y1 in nm), entrapment efficiency (Y2 in %), and drug release (Y3 in %) were chosen as dependent variables. The vesicle size, entrapment efficiency, and drug release of optimized CIP niosomes (CIP-NSMopt) were found to be 180.34 ± 5.13 nm, 78.32 ± 4.49%, and 82.87 ± 4.01% (in 12 h), respectively. Further CIP-NSMopt was coated with different chitosan concentrations (0.1 to 0.3%) to enhance mucoadhesion. Finally, optimized chitosan-coated niosomes (chitosomes; CIP-CHTopt) showed a vesicle size of 210.65 ± 2.76 nm, zeta potential of - 35.17 ± 2.25Mv, and PDI of 0.221. CIP-CHTopt exhibited sustained release profile (75.31% in 12 h) with the Korsmeyer-Peppas kinetic model (R2 = 0.980). The permeation study showed 1.79-fold enhancements in corneal permeation compared with marketed CIP eye drop. The hen's egg chorioallantoic membrane (HET-CAM) study showed 0 scores (no irritation), and it was further confirmed by corneal hydration and histopathology study. The antimicrobial study exhibited a significant high zone (P < 0.05) of inhibition against tested organism. Our findings demonstrated that chitosan-coated niosomes are a promising drug carrier to enhance corneal contact time and treatment of bacterial conjunctivitis.

Effect of Roflumilast in airways disorders via dual inhibition of phosphodiesterase and Ca2+-channel.

The bronchodilator effects of Roflumilast "a selective phosphodiesterase type-4 (PDE4)" inhibitor studied in this experimental protocol. The spiral strips of isolated guinea-pig tracheal chains mounted in organ bath and maintained in Krebs solution ventilated with carbogen at 32 °C and in Ca++ restricted krebs solution. PDE inhibitory activity was evaluated by recording dose response curves using inhibitory effect of isoprenaline on CCh induced contractions. For confirmation of PDE inhibition the intracellular cAMP levels were also estimated. Roflumilast resulted a sharp inhibition in contractile responses of carbachol (CCh, 1 µM) and K+ (80 mM) and the results were almost similar to verapamil. In Ca++ restricted Krebs solution, a rightward shift in the Ca++ response curves observed in the tracheal chain strips which were pretreated with Roflumilast (0.001-0.003 mg/mL) and the maximum response was suppressed, similarly as with verapamil. PDE inhibitory effect of Roflumilast evaluated by recording dose-dependent (0.03-0.1 mg/mL) responses, the isoprenaline-induced inhibitory dose response curves shifted leftward similar to papaverine (PDE inhibitor). Pretreatment with Roflumilast exhibited elevated intracellular cAMP levels in tracheal strips. Findings of the experiment conclude bronchodilatory influence of Roflumilast via PDE and Ca++ channel inhibition. Results of current experiment offers comprehensive mechanistic background of Roflumilast in future as therapeutic bronchodilator for hyperactive bronchial airway diseases.

Genotoxic potential of a novel PDE-4B inhibitor Apremilast by chromosomal aberration and micronucleus assay in mice.

OBJECTIVE: Researchers have confirmed that chronic administration of drugs at high doses causes genotoxicity which serve as first step in development of cancers. Apremilast, a phosphodiesterase-4 inhibitor is Food and Drug Administration (FDA) approved drug for Psoriatic Arthritis. The present study designed to conduct genotoxicity testing using the genotoxic study which give simple, sensitive, economical and fast tools for the assessment of damage of genetic material. METHODS: To conduct genotoxicity study of Apremilast, 60 Swiss albino male mice divided into 6 groups (n = 10). Group1 served as a normal control group without any treatment, Group 2 treated as a disease control and administered with cyclophosphamide 40 mg/kg, IP. Group 3, 4, 5 and 6 treated as test groups and received 10, 20, 40 and 80 mg/kg/day Apremilast respectively. The total duration of study was 13 weeks. At termination day animals were sacrificed and chromosomal aberration assay (BMCAA) and micronucleus assay (BMMNA) were performed to know the genotoxicity potential of Apremilast. RESULTS: The results indicates significant rise in chromosomal aberrations (CA) frequency in bone marrow cells and decrease in the MI of the disease control animals as well as Apremilast treated groups. Further significant (p < 0.001; p < 0.0001) increase in score of micronucleated polychromatic erythrocytes (MNPCEs) and percentage of micronucleated PCEs per 1000 PCEs and decrease in the ratio of polychromatic/normochromatic erythrocytes (PCE/NCE) was observed in micronucleus assay. Genotoxic effect increases with the increase of Apremilast dose. Conclusion: Finding of present indicates that Apremilast shows genotoxic potential on high administration although further detailed toxicity studies required for confirmations.