An Insight into the Structural Requirements and Pharmacophore Identification of Carbonic Anhydrase Inhibitors to Combat Oxidative Stress at High Altitudes: An In-Silico Approach.

Carbonic anhydrases (CA) inhibitory action could be linked to the treatment of a number of ailments, including cancer, osteoporosis, glaucoma, and several neurological problems. For the development of effective CA inhibitors, a variety of heterocyclic rings have been investigated. Furthermore, at high altitudes, oxygen pressure drops, resulting in the formation of reactive oxygen and nitrogen species, and CA inhibitors having role in combating this oxidative stress. Acetazolamide contains thiadiazole ring, which has aroused researchers' interest because of its CA inhibitory action. In the present study, we used a number of drug design tools, such as pharmacophore modeling, 3D QSAR, docking, and virtual screening on twenty-seven 1,3,4-thiadiazole derivatives that have been described as potential CA inhibitors in the literature. An atom-based 3D-QSAR analysis was carried out to determine the contribution of individual atoms to model generation, while a pharmacophore mapping investigation was carried out to find the common unique pharmacophoric properties required for biological activity. The coefficient of determination for both the training and test sets were statistically significant in the generated model. The best QSAR model was chosen based on the values of R2 (0.8757) and Q2 (0.7888). A molecular docking study was also conducted against the most potent analogue 4m, which has the highest SP docking score (-5.217) (PDB ID: 6g3v). The virtual screening revealed a number of promising compounds. The screened compound ZINC77699643 interacted with the amino acid residues, Pro201 and Thr199, in the virtual screening study (PDB ID: 6g3v). These interactions demonstrated the significance of the CA inhibitory activity of the compound. Furthermore, ADME study revealed useful information regarding compound's drug-like properties. Therefore, the findings of the present investigation could aid in the development of more potent CA inhibitors, which could benefit the treatment of oxidative stress at high altitudes.

Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase.

For decades, carbonic anhydrase (CA) inhibitors, most notably the acetazolamide-bearing 1,3,4-thiadiazole moiety, have been exploited at high altitudes to alleviate acute mountain sickness, a syndrome of symptomatic sensitivity to the altitude characterized by nausea, lethargy, headache, anorexia, and inadequate sleep. Therefore, inhibition of CA may be a promising therapeutic strategy for high-altitude disorders. In this study, co-crystallized inhibitors with 1,3,4-thiadiazole, 1,3-benzothiazole, and 1,2,5-oxadiazole scaffolds were employed for pharmacophore-based virtual screening of the ZINC database, followed by molecular docking and molecular dynamics simulation studies against CA to find possible ligands that may emerge as promising inhibitors. Compared to the co-crystal ligands of PDB-1YDB, 6BCC, and 6IC2, ZINC12336992, ZINC24751284, and ZINC58324738 had the highest docking scores of -9.0, -9.0, and -8.9 kcal/mol, respectively. A molecular dynamics (MD) simulation analysis of 100 ns was conducted to verify the interactions of the top-scoring molecules with CA. The system's backbone revealed minor fluctuations, indicating that the CA-ligand complex was stable during the simulation period. Simulated trajectories were used for the MM-GBSA analysis, showing free binding energies of -16.00 ± 0.19, -21.04 ± 0.17, and -19.70 ± 0.18 kcal/mol, respectively. In addition, study of the frontier molecular orbitals of these compounds by DFT-based optimization at the level of B3LYP and the 6-311G(d,p) basis set showed negative values of the HOMO and LUMO, indicating that the ligands are energetically stable, which is essential for forming a stable ligand-protein complex. These molecules may prove to be a promising therapy for high-altitude disorders, necessitating further investigations.

Green Synthesis of Oxoquinoline-1(2H)-Carboxamide as Antiproliferative and Antioxidant Agents: An Experimental and In-Silico Approach to High Altitude Related Disorders.

At high altitudes, drops in oxygen concentration result in the creation of reactive oxygen and nitrogen species (RONS), which cause a variety of health concerns. We addressed these health concerns and reported the synthesis, characterization, and biological activities of a series of 10 oxoquinolines. N-Aryl-7-hydroxy-4-methyl-2-oxoquinoline-1(2H)carboxamides (5a-j) were accessed in two steps under ultrasonicated irradiation, as per the reported method. The anticancer activity was tested at 10 µM against a total of 5 dozen cancer cell lines obtained from nine distinct panels, as per the National Cancer Institute (NCI US) protocol. The compounds 5a (TK-10 (renal cancer); %GI = 82.90) and 5j (CCRF-CEM (Leukemia); %GI = 58.61) showed the most promising anticancer activity. Compound 5a also demonstrated promising DPPH free radical scavenging activity with an IC50 value of 14.16 ± 0.42 µM. The epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), two prospective cancer inhibitor targets, were used in the molecular docking studies. Molecular docking studies of ligand 5a (docking score = -8.839) against the active site of EGFR revealed two H-bond interactions with the residues Asp855 and Thr854, whereas ligand 5a (docking = -5.337) interacted with three H-bond with the residues Gln92, Gln67, and Thr200 against the active site CA. The reported compounds exhibited significant anticancer and antioxidant activities, as well as displayed significant inhibition against cancer targets, EGFR and CA, in the molecular docking studies. The current discovery may aid in the development of novel compounds for the treatment of cancer and oxidative stress, and other high altitude-related disorders.

Phage Therapy in Bacterial Pneumonia Models: A Systematic Review and Meta-Analysis.

BACKGROUND: Phage therapy could play an important role in the bacterial pneumonia. However, the exact role of phage therapy in bacterial pneumonia is unclear to date. AIM: The current study aims to find out the role of phage therapy in preclinical models of bacterial pneumonia. METHODS: The studies were searched in databases with proper MeSH terms along with Boolean operators and selected based on eligibility criteria as per the PRISMA guidelines. The Odd Ratio (OR) was calculated with a 95% confidence interval and the heterogeneity was also calculated. The funnel plot was used to conduct a qualitative examination of publication bias. RESULTS: The OR was observed to be 0.11 (0.04, 0.27)] after 24 hrs, 0.11 [0.03, 0.34] after 7 days and 0.04 [0.01, 0.15] after 10 days that showed a significant role of phage therapy in reduction of deaths in the bacterial pneumonia models as compared to the placebo group. However, after 48hrs, a non-significant reduction was observed. CONCLUSION: There was a significant role of phage therapy in the reduction of deaths in the bacterial pneumonia models.

Fermented formulation of Silybum marianum seeds: Optimization, heavy metal analysis, and hepatoprotective assessment.

BACKGROUND: Fermented formulations are extensively used in Ayurveda due to several benefits like improved palatability, bioavailability, pharmacological potential, and shelf life. These formulations can also quench the heavy metals from the plant material and thus reduce the toxicity. Seeds of Silybum marianum (L.) Gaertn. are widely used for the management of many liver diseases. STUDY DESIGN AND METHODS: In the present study, we developed a novel fermented formulation of S. marianum seeds and evaluated parameters like safety (heavy metal analysis) and effectiveness (hepatoprotective). As the developed formulation's validation is crucial, the critical process variables (time, pH, and sugar concentration) are optimized for alcohol and silybin content using the Box-Behnken design (BBD). RESULTS: The response surface methodology coupled with BBD predicted the optimized conditions (fermentation time (28 days), pH 5.6, and sugar concentration (22.04%)) for the development of a fermented formulation of the selected herb. Moreover, the alcohol content (6.5 ± 0.9%) and silybin concentration (26.1 ± 2.1%) were confirmed in optimized formulation by GC-MS and HPTLC analysis. The optimized formulation was also analyzed for heavy metals (Pb, As, Hg, and Cd); their concentration is significantly less than the decoction of herbs. Further, the comparative evaluation of the developed formulation with the marketed formulation also confirmed that the fermented formulation's silybin concentration and percentage release were significantly enhanced. In addition, the developed fermented formulation's percentage recovery of HepG2 cell lines after treatment with CCl4 was significantly improved compared with the marketed formulation. CONCLUSION: It can be summarized that the developed fermented formulation improves safety and effectiveness compared to other market formulations. Finally, it can be concluded that the developed fermented formulation could be further explored as a better alternative for developing Silybum marianum preparation.

Co-Delivery of Naringin and Ciprofloxacin by Oleic Acid Lipid Core Encapsulated in Carboxymethyl Chitosan/Alginate Nanoparticle Composite for Enhanced Antimicrobial Activity.

A novel combination of antibiotic, ciprofloxacin (CIP) with herbal counterpart naringin (NAR) was encapsulated by an oleic acid lipid core and carboxymethyl chitosan (CM-CS)/Alginate (AG) nanoparticle composite (CIP + NAR-CM-CS/AG-NPs) for improved antimicrobial efficacy of antibiotic. Herein, this study explored the design and preparation of a composite system that enables to deliver both CIP and NAR from the oleic acid lipid core of CM-CS/AG nanoparticles using a nonsolvent ionic gelation technique. The nanoparticles (NPs) were fabricated with improved long-acting antimicrobial activity against E. coli and S. aureus. The optimized composition was investigated for physicochemical properties particle size, particle distribution, and ζ-potential. A diverse array of analytical tools was employed to characterize the optimized formulation including DSC, XRD, Malvern Zetasizer for particle size, ζ-potential, TEM, and SEM. Further, the preparation was investigated for % drug release, flux determination, antioxidant, and antimicrobial activity. The formulation stability was tested for 90 days and also evaluated formulation stability in fetal bovine serum to inspect the modification in physicochemical characteristics. NPs size was determined at 85 nm, PDI, and ζ-potential was recorded at 0.318, and 0.7 ± 0.4 mV. The % CIP and NAR entrapment efficiency and % loading were incurred as 91 ± 1.9, and 89.5 ± 1.2; 11.5 ± 0.6, and 10.8 ± 0.5%, respectively. The drug release erupted in the beginning phase followed by sustained and prolonged release for 48 h. The analytical experiments by DSC ensured the noninteracting and safe use of excipients in combination. X-ray studies demonstrated the amorphous state of the drug in the formulation. The insignificant alteration of formulation characteristics in FBS suggested stable and robust preparation. Storage stability of the developed formulation ensured consistent and uniform stability for three months. The DPPH assays demonstrated that NAR had good antioxidant capacity and supported improving antimicrobial activity of CIP. The hemolytic test suggested the developed formulation was compatible and caused insignificant RBC destruction. The in-house built formulation CIP + NAR-CM-CS/AG-NPs significantly improved the antimicrobial activity compared to CIP alone, offering a novel choice in antimicrobial application.

Identification of Novel Signals Associated with US-FDA Approved Drugs (2013) Using Disproportionality Analysis.

BACKGROUND: Drugs are related with various adverse drug reactions (ADRs), however, many unexpected ADRs of drugs are reported through post-marketing surveillance. AIM: The current study's goal is to uncover potential signals connected with FDA-approved medications in the United States (2013). METHODOLOGY: Open Vigil 2.1-MedDRA-v24 (data 20004Q1-2021Q3) was used as a tool to query the FAERS data. To find possible signals, disproportionality measures such as Proportional Reporting Ratio (PRR 2) with associated Chi-square value, Reporting Odds Ratio (ROR 2) with 95% confidence interval, and case count (3) were calculated. RESULTS: A total of eight potential signals were identified with five drugs. Positive signals were found with pomalidomide, canagliflozin, dolutegravir sodium, macitentan and ibrutinib. CONCLUSION: However, further causality assessment is required to confirm the association of these drugs with identified potential signals.

Development and Antibacterial Investigation of Linezolid-Loaded SPIONs and HPLC Method Development for Quantitative Analysis of Linezolid.

BACKGROUND: Linezolid (LNZ) is extremely prone to resistance. The development of resistance to LNZ should be taken into consideration when selecting this drug as a therapeutic option. It is well established that reactive oxygen species (ROS) generated by iron oxide nanoparticles (MNPs) could kill the infecting bacteria. So, we hypothesized the synergistic antibacterial effect of iron oxide nanoparticles and LNZ. OBJECTIVE: To study the release and antibacterial effects of LNZ-loaded superparamagnetic iron oxide nanoparticles (SPIONs) on Staphylococcus aureus and Streptococcus pneumoniae. METHOD: Ferrofluid containing SPIONs was synthesized via chemical co-precipitation method and stabilized by sodium lauryl sulphate (SLS). SPIONs were then loaded with LNZ and characterized for particle size, FT-IR, XRD, and entrapment efficiency. Further antibacterial activity of SPIONs and LNZ-loaded SPIONs was investigated. For the in vitro release findings, HPLC analytical method development and validation were performed. RESULTS: Isolation of LNZ was accomplished on a C-18 column with methanol-TBHS (tetra butyl ammonium hydrogen sulphate, 50:50, v/v). The eluate was monitored at 247 nm with a retention time of 4.175 min. The MNP's DLS measurement revealed monodispersed particles with an average size of 16.81 ± 1.07 nm and PDI 0.176 ± 0.012. In optimized formulation, 25 ± 1.75% (w/w) of the drug was found to be entrapped. XRD revealed uniform coating of oleic acid covering the entire magnetic particles' surface with no change in its crystallinity. An effective antimicrobial activity was observed at the lowered dose of drug. CONCLUSIONS: A robust HPLC method was developed to quantify the LNZ in MNPs, and outcomes showed that the reduced dose of LNZ incorporated in SPIONs was able to show similar activity as the marketed product. HIGHLIGHTS: Successfully reduction of the dose of LNZ was established with the aid of biocompatible MNPs to attain the equivalent antibacterial activity.

Nanomedicine-driven therapeutic interventions of autophagy and stem cells in the management of Alzheimer's disease.

Drug-loaded, brain-targeted nanocarriers could be a promising tool in overcoming the challenges associated with Alzheimer's disease therapy. These nanocargoes are enormously flexible to functionalize and facilitate the delivery of drugs to brain cells by bridging the blood-brain barrier and into brain cells. To date, modifications have included nanoparticles (NPs) coating with tunable surfactants/phospholipids, covalently attaching polyethylene glycol chains (PEGylation), and tethering different targeting ligands to cell-penetrating peptides in a manner that facilitates their entry across the BBB and downregulates various pathological hallmarks as well as intra- and extracellular signaling pathways. This review provides a brief update on drug-loaded, multifunctional nanocarriers and the therapeutic intervention of autophagy and stem cells in the management of Alzheimer's disease.

Fabrication of Sustained Release Curcumin-Loaded Solid Lipid Nanoparticles (Cur-SLNs) as a Potential Drug Delivery System for the Treatment of Lung Cancer: Optimization of Formulation and In Vitro Biological Evaluation.

The goal of current research was to develop a new form of effective drug, curcumin-loaded solid lipid nanoparticles (Cur-SLNs) and test its efficacy in the treatment of lung cancer. Different batches of SLNs were prepared by the emulsification-ultrasonication method. For the optimization of formulation, each batch was evaluated for particle size, polydispersity index (PI), zeta potential (ZP), entrapment efficiency (EE) and drug loading (DL). The formulation components and process parameters largely affected the quality of SLNs. The SLNs obtained with particle size, 114.9 ± 1.36 nm; PI, 0.112 ± 0.005; ZP, -32.3 ± 0.30 mV; EE, 69.74 ± 2.03%, and DL, 0.81 ± 0.04% was designated as an optimized formulation. The formulation was freeze-dried to remove excess water to improve the physical stability. Freeze-dried Cur-SLNs showed 99.32% of drug release and demonstrated a burst effect trailed by sustained release up to 120 h periods. The erythrocyte toxicity study of Cur-SLNs and its components demonstrated moderate hemolytic potential towards red blood cells (RBCs). The cytotoxic potential of the formulation and plain curcumin was estimated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against A549 cell line. After 48 h of incubation, Cur-SLNs demonstrated more cytotoxicity (IC50 = 26.12 ± 1.24 µM) than plain curcumin (IC50 = 35.12 ± 2.33 µM). Moreover, the cellular uptake of curcumin was found to be significantly higher from Cur-SLNs (682.08 ± 6.33 ng/µg) compared to plain curcumin (162.4 ± 4.2 ng/µg). Additionally, the optimized formulation was found to be stable over the period of 90 days of storage. Hence, curcumin-loaded SLNs can be prepared using the proposed cost effective method, and can be utilized as an effective drug delivery system for the treatment of lung cancer, provided in vivo studies warrant a similar outcome.

Enhanced drug delivery and wound healing potential of berberine-loaded chitosan-alginate nanocomposite gel: characterization and in vivo assessment.

Berberine-encapsulated polyelectrolyte nanocomposite (BR-PolyET-NC) gel was developed as a long-acting improved wound healing therapy. BR-PolyET-NC was developed using an ionic gelation/complexation method and thereafter loaded into Carbopol gel. Formulation was optimized using Design-Expert® software implementing a three-level, three-factor Box Behnken design (BBD). The concentrations of polymers, namely, chitosan and alginate, and calcium chloride were investigated based on particle size and %EE. Moreover, formulation characterized in vitro for biopharmaceutical performances and their wound healing potency was evaluated in vivo in adult BALB/c mice. The particle distribution analysis showed a nanocomposite size of 71 ± 3.5 nm, polydispersity index (PDI) of 0.45, ζ-potential of +22 mV, BR entrapment of 91 ± 1.6%, and loading efficiency of 12.5 ± 0.91%. Percentage drug release was recorded as 89.50 ± 6.9% with pH 6.8, thereby simulating the wound microenvironment. The in vitro investigation of the nanocomposite gel revealed uniform consistency, well spreadability, and extrudability, which are ideal for topical wound use. The analytical estimation executed using FT-IR, DSC, and X-ray diffraction (XRD) indicated successful formulation with no drug excipients and without the amorphous state. The colony count of microbes was greatly reduced in the BR-PolyET-NC treated group on the 15th day from up to 6 CFU compared to 20 CFU observed in the BR gel treated group. The numbers of monocytes and lymphocytes counts were significantly reduced following healing progression, which reached to a peak level and vanished on the 15th day. The observed experimental characterization and in vivo study indicated the effectiveness of the developed BR-PolyET-NC gel toward wound closure and healing process, and it was found that >99% of the wound closed by 15th day, stimulated via various anti-inflammatory and angiogenic factors.

Development of UPLC-MS/MS method and its pharmacokinetic application for estimation of sertraline in rat plasma.

The current research aims to develop a rapid, sensitive and robust UPLC-MS/MS method for quantitative estimation of sertraline in rat plasma following oral administration of lipid-based formulation. Different types of isocratic systems were tried for optimization of mobile phase to attain good resolution and appropriate retention time. The multiple reaction monitoring transitions of m/z 306.3 â†’ 159.1 and 515.2 â†’ 276.1 were used to quantify sertraline and internal standard, respectively. The method was validated for different parameters as per the guideline of the United States Food and Drug administration (USFDA). The validated linearity range of sertraline was found to be 1-1,00 ng/mL in rat plasma with 0.1 ng/mL as lower limit of quantification. The intra-day and inter-day precision (RSD%) were within 7.6-10.6% and the accuracies(RE%) were ± 8.0%. The results showed a good percentage recovery of analytes within acceptance limit. No significant degradation of drug in plasma was observed during the stability study. The method demonstrated short analytical run time (< 3 min), low sensitivity (0.1 ng/mL) and requirement of small amount of plasma (50 µL) for extraction procedure. Overall, this method•Results in an optimized and validated assay for estimation of sertraline in plasma.•Offers a cost effective mobile phase with excellent linearity, sensitivity, accuracy, and precision. The method suggested its application in pharmacokinetic study of sertraline administered via oral route.•The method can be used for therapeutic drug monitoring in drug designing. The method can also be used for toxicity and bioequivalence studies.

Carbon-based Nanomaterials: Carbon Nanotubes, Graphene, and Fullerenes for the Control of Burn Infections and Wound Healing.

Burn injuries are extremely debilitating, resulting in high morbidity and mortality rates around the world. The risk of infection escalates in correlation with impairment of skin integrity, creating a barrier to healing and possibly leading to sepsis. With its numerous advantages over traditional treatment methods, nanomaterial-based wound healing has an immense capability of treating and preventing wound infections. Carbon-based nanomaterials (CNMs), owing to their distinctive physicochemical and biological properties, have emerged as promising platforms for biomedical applications. Carbon nanotubes, graphene, fullerenes, and their nanocomposites have demonstrated broad antimicrobial activity against invasive bacteria, fungi, and viruses causing burn wound infection. The specific mechanisms that govern the antimicrobial activity of CNMs must be understood in order to ensure the safe and effective incorporation of these structures into biomaterials. However, it is challenging to decouple individual and synergistic contributions of the physical, chemical, and electrical effects of CNMs on cells. This review reported significant advances in the application of CNMs in burn wound infection and wound healing, with a brief discussion on the interaction between different families of CNMs and microorganisms to assess antimicrobial performance.

ß-Artemether and Lumefantrine Dual Drug Loaded Lipid Nanoparticles: Physicochemical Characterization, Pharmacokinetic Evaluation and Biodistribution Study.

BACKGROUND: ß-artemether (BAT) and lumefantrine (LFT) combination therapies are well recognized for the treatment of malaria. However, the current conventional formulations have several drawbacks. OBJECTIVE: The study aims to develop novel lipid nanoparticles (LNP) for efficient delivery of BAT and LFT. METHODS: The LNP were prepared by solvent injection method and optimized by the Box-Behnken experimental design to achieve the desired particle size, maximum entrapment efficiency (EE), and percentage drug release. BAT and LFT in rat plasma were estimated by liquid chromatographytandem mass spectrometry (LC-MS/MS). RESULTS: Freeze-dried LNP comprised of 78.74% (w/w) lipid, 15.74% (w/w) surfactant, 3.93% (w/w) co-surfactant and 1.57% mannitol with respect to the total inactive components. Mean particle size and zeta potential were found to be 140.22 ± 1.36 nm and -35.23 mv, respectively. EE was 80.60 ± 3.85% for BAT and 69.64 ± 2.63% for LFT. The optimized formulation exhibited a biphasic release profile in phosphate buffer (pH 7.2). In vivo study revealed an increased bioavailability of BAT and LFT from dual drug loaded LNP compared to the pure drug solution. Moreover, the tissue distribution study confirmed the high uptake of both the drugs in the liver and spleen. CONCLUSION: The study demonstrated the potential use of the developed formulation for oral administration in the treatment of malaria.

Development of Nanogel Loaded with Lidocaine for Wound-Healing: Illustration of Improved Drug Deposition and Skin Safety Analysis.

A wound refers to a cut or blow that may result in primary or secondary infection or even death, if untreated. In the current study, we have explored the wound-healing properties of lidocaine nanogel, owing to its antioxidant and neutrophilic modulatory potential. Initially, the pre-formulation study was performed and then using central composite design (CCD) fabrication and the characterization of lidocaine-loaded nanoemulsion was carried out. After the preparation of a nanogel of lidocaine-loaded nanoemulsion, it was evaluated on various parameters, such as pH, spreadability, extrudability, drug content, in vitro drug release, dermatokinetic study and in vivo skin safety. Based on the pre-formulation study, the maximum solubility of lidocaine was found in oleic acid (324.41 ± 4.19 mg/mL) and in Tween 20 (192.05 ± 8.25 mg/mL), selected as a suitable emulsifier. The refractive index of the optimized nanoemulsion was found to be 1.35 ± 0.04, the electrokinetic potential was recorded as −15.47 ± 0.95 mV. The pH, spreadability and extrudability of nanogel was found to be 6.87 ± 0.51, 73.32 ± 4.59 gm.cm/sec and 107.41 ± 6.42 gm/cm2, respectively. The percentage of the cumulative drug content and drug release from nanogel was found to be 99.94 ± 1.70% and 93.00 ± 4.67%, respectively. Moreover, dermatokinetic study showed significantly (p < 0.0005) improved drug deposition and the in vivo skin safety study showed no sign of dermal erythematous lesion or any visible damage. Stability studies also testified the secureness of nanogel after storage in a prescribed environmental condition. Thus, this study provides substantial evidence for healing wounds effectively and the further evaluation of the in vivo model. The patent related to this work was published in the Indian Official Journal of the Patent Office (Issue number: 20/2022).

Intravenous Nanocarrier for Improved Efficacy of Quercetin and Curcumin against Breast Cancer Cells: Development and Comparison of Single and Dual Drug-Loaded Formulations Using Hemolysis, Cytotoxicity and Cellular Uptake Studies.

The present work highlights the suitability of an oil-based nanocarrier to deliver quercetin (Q) and curcumin (C) through the intravenous route for treatment of breast cancer. The nanoemulsion prepared by the modified emulsification-solvent evaporation method resulted in particle size (<30 nm), polydispersity index (<0.2), zeta potential (<10 mV), optimum viscosity, high encapsulation efficiency and drug loading for both drugs. The pH and osmolarity of the nanoemulsion were about 7.0 and 280 mOsm, respectively, demonstrated its suitability for intravenous administration. In-vitro release of drugs from all the formulations demonstrated initial fast release followed by sustained release for a period of 48 h. The fabricated single and dual drug−loaded nanoemulsion (QNE, CNE, QC-NE) exhibited moderate hemolysis at a concentration of 50 µg/mL. The % hemolysis caused by all the formulations was similar to their individual components (p ˃ 0.05) and demonstrated the biocompatibility of the nanoemulsion with human blood. In vitro cytotoxic potential of single and dual drug−loaded nanoemulsions were determined against breast cancer cells (MF-7). The IC50 value for QNE and CNE were found to be 40.2 ± 2.34 µM and 28.12 ± 2.07 µM, respectively. The IC50 value for QC-NE was 21.23 ± 2.16 µM and demonstrated the synergistic effect of both the drugs. The internalization of the drug inside MF-7 cells was detected by cellular uptake study. The cellular uptake of QNE and CNE was approximately 3.9-fold higher than free quercetin and curcumin (p < 0.0001). This strategically designed nanoemulsion appears to be a promising drug delivery system for the proficient primary preclinical development of quercetin and curcumin as therapeutic modalities for the treatment of breast cancer.

Neurobehavioral and Biochemical Evidences in Support of Protective Effect of Marrubiin (Furan Labdane Diterpene) from Marrubium vulgare Linn. and Its Extracts after Traumatic Brain Injury in Experimental Mice.

Traumatic brain injuries due to sudden accidents cause major physical and mental health problems and are one of the main reasons behind the mortality and disability of patients. Research on alternate natural sources could be a boon for the rehabilitation of poor TBI patients. The literature indicates the Marrubium vulgare Linn. and its secondary metabolite marrubiin (furan labdane diterpene) possess various pharmacological properties such as vasorelaxant, calcium channel blocker, antioxidant, and antiedematogenic activities. Hence, in the present research, both marrubiin and hydroalcoholic extracts of the plant were evaluated for their neuroprotective effect after TBI. The neurological severity score and oxidative stress parameters are significantly altered by the test samples. Moreover, the neurotransmitter analysis indicated a significant change in GABA and glutamate. The histopathological study also supported the observed results. The improved neuroprotective potential of the extract could be attributed to the presence of a large number of secondary metabolites including marrubiin.

Novel Therapeutic Approach in PEGylated Chitosan Nanoparticles of Apigenin for the Treatment of Cancer via Oral Nanomedicine.

The goal of this study was to optimize and formulate apigenin (APG)-loaded pegylated chitosan nanoparticles (PEGylated-CNPs) via ionic gelation techniques using the Box-Behnken design (BBD). Three individual variables, X1(chitosan: TPP concentration), X2 (PEG-400 concentration), and X3 (sonication time), were investigated for their influence on response variables (Y1-particle size (PS); Y2-drug entrapment efficiency (DEE); and Y3-zeta potential (ZP). The optimized formula of APG-PEGylated CNPs was picked from the statistical design and was then examined for physical, morphological, release characterization, anti-oxidant, and anti-tumor potential. The average PS, PDI, %DEE, and ZP were found to be 139.63 ± 5.67 nm, 0.296 ± 0.014, 79.55 ± 3.12%, and 24.68 ± 1.84 mV, respectively. The optimized APG formulation was chosen and reformulated based on the desirability function. Results of the observed and predicted values of responses through the BBD process were found to be nearly identical. The resulting APG-PEGylated CNPs were spherical and smooth, according to surface morphology studies. The release study revealed that PEGylated-CNPs exhibited biphasic release patterns distinguished by an initial burst release of APG only at early phases accompanied by a delayed release near 24 h. Furthermore, APG-PEGylated CNPs demonstrated statistically increased antioxidant activities and cytotoxicity against MCF-7 cells compared to pure APG. Based on the findings, it is possible to conclude that BBD was efficient in optimizing the PEGylated CNPs formulation and recognizing the impacts of formulation variables. In conclusion, the developed formulation has a significant potential for anticancer therapy.

Chitosan-modified nanocarriers as carriers for anticancer drug delivery: Promises and hurdles.

With the advent of drug delivery, various polymeric materials are being explored to fabricate numerous nanocarriers. Each polymer is associated with a few characteristics attributes which further facilitate its usage in drug delivery. One such polymer is chitosan (CS), which is extensively employed to deliver a variety of drugs to various targets, especially to cancer cells. The desired properties like biological origin, bio-adhesive, biocompatibility, the scope of chemical modification, biodegradability and controlled drug release make it a highly rough after polymer in pharmaceutical nanotechnology. The present review attempts to compile various chemical modifications on CS and showcase the outcomes of the derived nanocarriers, especially in cancer chemotherapy and drug delivery.

Pharmacological Efficacy of Probiotics in Respiratory Viral Infections: A Comprehensive Review.

Mortality and morbidity from influenza and other respiratory viruses are significant causes of concern worldwide. Infections in the respiratory tract are often underappreciated because they tend to be mild and incapacitated. On the other hand, these infections are regarded as a common concern in clinical practice. Antibiotics are used to treat bacterial infections, albeit this is becoming more challenging since many of the more prevalent infection causes have acquired a wide range of antimicrobial resistance. Resistance to frontline treatment medications is constantly rising, necessitating the development of new antiviral agents. Probiotics are one of several medications explored to treat respiratory viral infection (RVI). As a result, certain probiotics effectively prevent gastrointestinal dysbiosis and decrease the likelihood of secondary infections. Various probiotic bacterias and their metabolites have shown immunomodulating and antiviral properties. Unfortunately, the mechanisms by which probiotics are effective in the fight against viral infections are sometimes unclear. This comprehensive review has addressed probiotic strains, dosage regimens, production procedures, delivery systems, and pre-clinical and clinical research. In particular, novel probiotics' fight against RVIs is the impetus for this study. Finally, this review may explore the potential of probiotic bacterias and their metabolites to treat RVIs. It is expected that probiotic-based antiviral research would be benefitted from this review's findings.