Beneficial Effects of Natural Alkaloids from Berberis glaucocarpa as Antidiabetic Agents: An In Vitro, In Silico, and In Vivo Approach.

Diabetes, also known as diabetes mellitus (DM), is a metabolic disorder characterized by an abnormal rise in blood sugar (glucose) levels brought on by a complete or partial lack of insulin secretion along with corresponding changes in the metabolism of lipids, proteins, and carbohydrates. It has been reported that medicinal plants play a pivotal role in the treatment of various ailments such as diabetes mellitus, dyslipidemia, and hypertension. The current study involved exploring the acute toxicity and in vivo antidiabetic activity of berberine (WA1), palmatine (WA2), and 8-trichloromethyl dihydroberberine (WA3) previously isolated from Berberis glaucocarpa Stapf using a streptozotocin (STZ)-induced diabetic rat model. Body weight and blood glucose level were assessed on a day interval for 4 weeks. Biochemical parameters, antioxidant enzymes, and oxidative stress markers were also determined. In an acute toxicity profile, the WA1, WA2, and WA3 were determined to be nontoxic up to 500 mg/kg (b.w). After the second and third weeks of treatment (14 and 21 days), the blood glucose levels in the WA1-, WA2-, and WA3-treated groups were significantly lower than those in the diabetic control group (476.81 ± 8.65 mg/dL, n = 8, P < 0.001). On the 21st day, there was a decrease in the blood glucose level and the results obtained were 176.33 ± 4.69, 197.21 ± 4.80, and 161.99 ± 4.75 mg/dL (n = 8, P < 0.001) for WA1, WA2, and WA3 at 12 mg/kg, respectively, as opposed to the diabetic control group (482.87 ± 7.11 mg/dL, n = 8, P < 0.001). Upon comparison with the diabetic group at the end of the study (28 days), a substantial drop in the glucose level of WA3 at 12 mg/kg (110.56 ± 4.11 mg/dL, n = 8, P < 0.001) was observed that was almost near the values of the normal control group. The treated groups (WA1, WA2, and WA3) treated with the samples displayed a significant decline in the levels of HbA1c. Treatment of the samples dramatically lowered the lipid level profile. In groups treated with samples, plasma levels of triglycerides, total cholesterol, and LDL were significantly lowered [F (5, 42) = 100.6, n = 8, P < 0.001]; these levels were also significantly decreased [F (5, 42) = 129.6 and 91.17, n = 8, P < 0.001]. In contrast to the diabetes group, all treated groups had significantly higher HDL levels [F (5, 42) = 15.46, n = 8, P < 0.001]. As a result, hypolipidemic activity was anticipated in the samples. In addition to that, the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was considerably elevated in the groups treated with the sample compared to the diabetic control group (n = 8, P < 0.001).

RETRACTED: Khan et al. Poly (N-vinylcaprolactam-grafted-sodium alginate) Based Injectable pH/Thermo Responsive In Situ Forming Depot Hydrogels for Prolonged Controlled Anticancer Drug Delivery; In Vitro, In Vivo Characterization and Toxicity Evaluation. Pharmaceutics 2022, 14, 1050.

The journal retracts the article, "Poly (N-vinylcaprolactam-grafted-sodium alginate) Based Injectable pH/Thermo Responsive In Situ Forming Depot Hy-drogels for Prolonged Controlled Anticancer Drug Delivery; In Vitro, In Vivo Characterization and Toxicity Evaluation" [...].

Unveiling the therapeutic potential: Evaluation of anti-inflammatory and antineoplastic activity of Magnolia champaca Linn's stem bark isolate through molecular docking insights.

Magnolia champaca Linn. has traditionally been used for medicinal activity in Asia for treating various chronic diseases as well as a source of food, medicines, and other commodities. Due to the long-used history of this plant, the present study was designed to explore the in vitro, in vivo and in silico anti-inflammatory and antineoplastic properties of the methanolic extract and fractions and the pure compound isolated from the most active chloroform fraction (CHF) of the stem bark of the plant. The isolated compound from the most active CHF was characterized and identified as a glycoside, trans-syringin, through chromatographic and spectroscopic (1H-NMR and 13C-NMR) analyses. In the in vitro anti-inflammatory assay, CHF was most effective in inhibiting inflammation and hemolysis of RBCs by 73.91 ± 1.70% and 75.92 ± 0.14%, respectively, induced by heat and hypotonicity compared to standard acetylsalicylic acid. In the egg albumin denaturation assay, CME and CHF showed the highest inhibition by 56.25 ± 0.82% and 65.82 ± 3.52%, respectively, contrasted with acetylsalicylic acid by 80.14 ± 2.44%. In an in vivo anti-inflammatory assay, statistically significant (p < 0.05) decreases in the parameters of inflammation, such as paw edema, leukocyte migration and vascular permeability, were recorded in a dose-dependent manner in the treated groups. In the antineoplastic assay, 45.26 ± 2.24% and 68.31 ± 3.26% inhibition of tumor cell growth for pure compound were observed compared to 73.26 ± 3.41% for standard vincristine. Apoptotic morphologic alterations, such as membrane and nuclear condensation and fragmentation, were also found in EAC cells after treatment with the isolated bioactive pure compound. Such treatment also reversed the increased WBC count and decreased RBC count to normal values compared to the untreated EAC cell-bearing mice and the standard vincristine-treated mice. Subsequently, in silico molecular docking studies substantiated the current findings, and the isolated pure compound and standard vincristine exhibited -6.4 kcal/mol and -7.3 kcal/mol binding affinities with topoisomerase-II. Additionally, isolated pure compound and standard diclofenac showed -8.2 kcal/mol and -7.6 kcal/mol binding affinities with the COX-2 enzyme, respectively. The analysis of this research suggests that the isolated bioactive pure compound possesses moderate to potent anti-inflammatory and antineoplastic activity and justifies the traditional uses of the stem bark of M. champaca. However, further investigations are necessary to analyze its bioactivity, proper mechanism of action and clinical trials for the revelation of new drug formulations.

Multi-cavity molecular descriptor interconnections: Enhanced protocol for prediction of serum albumin drug binding.

The role of human serum albumin (HSA) in the transport of molecules predicates its involvement in the determination of drug distribution and metabolism. Optimization of ADME properties are analogous to HSA binding thus this is imperative to the drug discovery process. Currently, various in silico predictive tools exist to complement the drug discovery process, however, the prediction of possible ligand-binding sites on HSA has posed several challenges. Herein, we present a strong and deeper-than-surface case for the prediction of HSA-ligand binding sites using multi-cavity molecular descriptors by exploiting all experimentally available and crystallized HSA-bound drugs. Unlike previously proposed models found in literature, we established an in-depth correlation between the physicochemical properties of available crystallized HSA-bound drugs and different HSA binding site characteristics to precisely predict the binding sites of investigational molecules. Molecular descriptors such as the number of hydrogen bond donors (nHD), number of heteroatoms (nHet), topological polar surface area (TPSA), molecular weight (MW), and distribution coefficient (LogD) were correlated against HSA binding site characteristics, including hydrophobicity, hydrophilicity, enclosure, exposure, contact, site volume, and donor/acceptor ratio. Molecular descriptors nHD, TPSA, LogD, nHet, and MW were found to possess the most inherent capacities providing baseline information for the prediction of serum albumin binding site. We believe that these associations may form the bedrock for establishing a solid correlation between the physicochemical properties and Albumin binding site architecture. Information presented in this report would serve as critical in provisions of rational drug designing as well as drug delivery, bioavailability, and pharmacokinetics.

Management of COPD and Comorbidities in COPD patients by Dispensing Pharmaceutical Care following Global Initiative for chronic Obstructive Lung Disease-Guidelines (GOLD guidelines 2020): A study protocol for a Prospective Randomized Clinical Trial.

COPD (chronic obstructive pulmonary disease) is a medical condition that encompasses several chronic, progressive, and severe respiratory illnesses, such as emphysema and chronic bronchitis. COPD is the 4th most deadly disease in the world and its prevalence is expected to increase. Despite the abundance of information on the disease's etiology, pathophysiology, and treatment possibilities, it has long been underdiagnosed and underreported for a long time, particularly in developing countries. The symptoms of COPD result in significant impairments and significant impact on quality of life. COPD is the third leading cause of death in Pakistan. According to the published literature, COPD has been found to be associated with a serious economic burden, either the direct cost to healthcare systems in the form of frequent hospital admissions or indirect costs to patients suffering from COPD. Despite the availability of excellent medication, COPD treatment goals are frequently not achieved resulting in poor management of COPD. The recent studies revealed that due to the missing role of Pharmacists in most of the public sector hospitals of Pakistan, the COPD disease management protocols are not being properly followed. Pharmacists can help the healthcare system by implementing these management protocols that focus on patient education about the disease, prescribed medications, and proper inhalation techniques. Furthermore, the pharmacists as an effective healthcare's team member properly educate the patients about the ongoing assessments and their willingness to follow treatment recommendations and quit smoking, while referring them to smoking cessation programs as needed, following the GOLD guidelines. This aim of this clinical trial is to evaluate the impact of implementing standard treatment guidelines and the role of pharmacists in implementing GOLD guidelines for COPD management.

Nano-residronate loaded κ-carrageenan-based injectable hydrogels for bone tissue regeneration.

Bone tissue possesses intrinsic regenerative capabilities to address deformities; however, its ability to repair defects caused by severe fractures, tumor resections, osteoporosis, joint arthroplasties, and surgical reconsiderations can be hindered. To address this limitation, bone tissue engineering has emerged as a promising approach for bone repair and regeneration, particularly for large-scale bone defects. In this study, an injectable hydrogel based on kappa-carrageenan-co-N-isopropyl acrylamide (κC-co-NIPAAM) was synthesized using free radical polymerization and the antisolvent evaporation technique. The κC-co-NIPAAM hydrogel's cross-linked structure was confirmed using Fourier transform infrared spectra (FTIR) and nuclear magnetic resonance (1H NMR). The hydrogel's thermal stability and morphological behavior were assessed using thermogravimetric analysis (TGA) and scanning electron microscopy (SEM), respectively. Swelling and in vitro drug release studies were conducted at varying pH and temperatures, with minimal swelling and release observed at low pH (1.2) and 25 °C, while maximum swelling and release occurred at pH 7.4 and 37oC. Cytocompatibility analysis revealed that the κC-co-NIPAAM hydrogels were biocompatible, and hematoxylin and eosin (H&E) staining demonstrated their potential for tissue regeneration and enhanced bone repair compared to other experimental groups. Notably, digital x-ray examination using an in vivo bone defect model showed that the κC-co-NIPAAM hydrogel significantly improved bone regeneration, making it a promising candidate for bone defects.

Doctors' Perception Regarding Bariatric Surgery and Major Barriers in Referral of Morbidly Obese Patients for Surgery in Khyber Pakhtunkhwa.

INTRODUCTION: Obesity is on the rise worldwide and has emerged as a global health concern. It has presented itself as the leading cause of morbidity, disability, and healthcare utilization. Bariatric surgery is a viable treatment option that offers sustained weight loss and improvement in comorbidities. The aim of this study is to determine the perception of doctors regarding bariatric surgery and the major barriers to the referral of morbidly obese for surgery. METHOD: This study is a cross-sectional descriptive study conducted from November 1, 2022, to December 31, 2022. It involved prospective data collection through online questionnaires filled by doctors practicing in Peshawar. The sampling technique was non-probability convenience-based sampling. The sample size was 152. Doctors from all age groups and both genders were included in our study. Non-consenting doctors and those who were practicing bariatric surgery were excluded. Data were analyzed using a statistical package for social sciences (SPSS) version 25.0 (IBM Inc., Armonk, NY). Categorical variables have been presented as frequencies and percentages. Numerical variables have been presented as mean ± SD. RESULTS: A total of 152 doctors participated in our research study; 92 were physicians and 60 were surgeons. The majority of our study participants' patient load per week was >75. Around 47% believed bariatric surgery was a valuable tool in the treatment of morbid obesity. The most commonly reported barrier to referral was surgical complications or side effects (28.9%). CONCLUSION: The study concluded that the awareness regarding bariatric and metabolic surgery remains flimsy among the doctor community. Most of the physicians were unaware of the benefits of the surgical management of obesity. They also had doubts regarding the safety of the procedure. We need proper utilization of awareness strategies to overcome these barriers.

Apprehensions of Morbidly Obese People Regarding Bariatric Surgery.

Introduction Obesity has emerged as a major public health issue in both developed and developing countries. The prevalence of obesity is on the rise. Bariatric surgery is acknowledged as the most effective and safe solution for this problem. It has been shown to be effective in sustained weight loss and improving quality of life. The aim of this study was to identify the causes of reluctance to have surgery among patients who were potential candidates for weight loss procedures. Method Morbidly obese people who were enrolled at Khyber Teaching Hospital, Peshawar, from December 2021 to August 2022 were included in the study. It included hospitalized as well as outpatient appointments. A questionnaire was adopted as the data collection tool. Result A total of 107 patients (58 men and 49 women) were enrolled in the study. The median age was 42. Of the 107 patients, 5% (n=5) of the patients were super morbidly obese (BMI >50kg/m2). Seventy-two percent (n=77) of the population considered themselves morbidly obese. Only 22% (n=24) were physically active. Twenty percent (n=21) of the patients reported that they have or are currently trying dietary modifications for weight loss. Young females were most likely to be on dieting programs. Importantly, 56% (n=60) had never heard of bariatric surgery. Exploring the reasons for reluctance among patients revealed that the concern for surgical mortality was the major hindrance. This was followed by being not interested in committing to surgery and recovery. Concerns regarding cost and financing were also the reasons candidates didn't opt for surgical procedures to treat obesity. Conclusion The study concluded that there is a serious lack of knowledge and awareness among physicians and the general public regarding bariatric surgery. Most of the patients who were potential candidates for the procedure weren't aware that obesity had a surgical and definitive treatment. Patients who were aware of the surgical procedure were hesitant to undergo surgery for the management of their weight as they harbored misconceptions, particularly regarding the safety and efficacy of the procedure.

Formulation and Optimization of Repaglinide Nanoparticles Using Microfluidics for Enhanced Bioavailability and Management of Diabetes.

The technologies for fabrication of nanocrystals have an immense potential to improve solubility of a variety of the poor water-soluble drugs with subsequent enhanced bioavailability. Repaglinide (Rp) is an antihyperglycemic drug having low bioavailability due to its extensive first-pass metabolism. Microfluidics is a cutting-edge technique that provides a new approach for producing nanoparticles (NPs) with controlled properties for a variety of applications. The current study's goal was to engineer repaglinide smart nanoparticles (Rp-Nc) utilizing microfluidic technology (Dolomite Y shape), and then to perform in-vitro, in-vivo, and toxicity evaluations of them. This method effectively generated nanocrystals with average particle sizes of 71.31 ± 11 nm and a polydispersity index (PDI) of 0.072 ± 12. The fabricated Rp's crystallinity was verified by Differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD). In comparison to the raw and commercially available tablets, the fabricated Rp's nanoparticles resulted in a higher saturation solubility and dissolving rate (p < 0.05). Rp nanocrystals had a considerably lower (p < 0.05) IC50 value than that of the raw drug and commercial tablets. Moreover, Rp nanocrystals at the 0.5 and 1 mg/kg demonstrated a significant decrease in blood glucose level (mg/dL, p < 0.001, n = 8) compared to its counterparts. Rp nanocrystals at the 0.5 mg/kg demonstrated a significant decrease (p < 0.001, n = 8) in blood glucose compared to its counterparts at a dose of 1 mg/kg. The selected animal model's histological analyses and the effect of Rp nanocrystals on several internal organs were determined to be equivalent to those of the control animal group. The findings of the present study indicated that nanocrystals of Rp with improved anti-diabetic properties and safety profiles can be successfully produced using controlled microfluidic technology, an innovative drug delivery system (DDS) approach.

Polymeric Nanoparticles as Tunable Nanocarriers for Targeted Delivery of Drugs to Skin Tissues for Treatment of Topical Skin Diseases.

The topical route is the most appropriate route for the targeted delivery of drugs to skin tissues for the treatment of local skin diseases; however, the stratum corneum (SC), the foremost layer of the skin, acts as a major barrier. Numerous passive and active drug delivery techniques have been exploited to overcome this barrier; however, these modalities are associated with several detrimental effects which restrict their clinical applicability. Alternatively, nanotechnology-aided interventions have been extensively investigated for the topical administration of a wide range of therapeutics. In this review, we have mainly focused on the biopharmaceutical significance of polymeric nanoparticles (PNPs) (made from natural polymers) for the treatment of various topical skin diseases such as psoriasis, atopic dermatitis (AD), skin infection, skin cancer, acute-to-chronic wounds, and acne. The encapsulation of drug(s) into the inner core or adsorption onto the shell of PNPs has shown a marked improvement in their physicochemical properties, avoiding premature degradation and controlling the release kinetics, permeation through the SC, and retention in the skin layers. Furthermore, functionalization techniques such as PEGylation, conjugation with targeting ligand, and pH/thermo-responsiveness have shown further success in optimizing the therapeutic efficacy of PNPs for the treatment of skin diseases. Despite enormous progress in the development of PNPs, their clinical translation is still lacking, which could be a potential future perspective for researchers working in this field.

Complex Fistula-in-Ano Extending From the Anal Canal to Mid-Thigh Treated With Combine Fistulectomy and Video-Assisted Anal Fistula Treatment (VAAFT): A Case Report.

An anal fistula is abnormal, chronic epithelial-lined communication between the anorectal lumen and the skin of the perineum or buttock. A complex fistula-in-ano is difficult to diagnose and treat; it requires careful approaches because of the high risk of complications and recurrences. We report a case of a 60-year-old male who presented with a discharging sinus on the posteromedial aspect of his left thigh for the past two years. On examination, there were two external openings on the posteromedial aspect of the left thigh, 20 cm away from the anal verge, extending toward the left buttock, with an internal opening on the right side of the anal canal at 11 o'clock in the lithotomy position. The MRI showed a fluid-filled marginally enhancing tract ascending obliquely from the skin of the posterior left thigh, passing through the left gluteus maximus to the bilateral ischioanal fossae. The distal 7 cm tract was excised, as the rest of the tract was deep, passing through the gluteus maximus. Therefore, a video-assisted anal fistula treatment (VAAFT) procedure was done for the remaining tract. The wound was left open for healing by secondary intention. The patient was monitored for six months during which time the wound healed completely.

Biodegradable Polymers-Based Smart Nanocrystals for Loxoprofen Delivery with Enhanced Solubility: Design, Fabrication and Physical Characterizations.

Nanocrystals are carrier-free, submicron-sized, colloidal drug delivery systems with particle sizes in the mean nanometer range. Nanocrystals have high bioavailability and fast absorption because of their high dissolution velocity and enhanced adhesiveness to cell membranes. Loxoprofen, a nonsteroidal anti-inflammatory drug belonging to the Biopharmaceutical Classification System (BCS) II drug class, was selected as the model drug. The aim of this study was to formulate nanocrystals of loxoprofen. A total of 12 formulations (F1 to F12) were prepared. An antisolvent technique was used to determine the effects of various stabilizers and processing conditions on the optimization of formulations. The various stabilizers used were hydroxypropyl methylcellulose (0.5%), polyvinylpyrrolidone (0.5%), and sodium lauryl sulfate (0.1%). The various characterizations conducted for this research included stability studies at 25 °C and 4 °C, scanning electron microscopy, transmission electron microscopy (TEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), zeta potentials, polydispersity indexes, and dissolution studies. F10 was the optimized formulation that showed stability at room temperature, as well as at a refrigerated temperature, for 30 days. A high dissolution rate (100% within the first 10 min) was shown by comparative dissolution studies of nano-suspensions with the micro-suspension and raw loxoprofen. F10 formulation had a non-porous and crystalline morphology on evaluation by TEM and XRPD, respectively, and the average particle size was 300 ± 0.3 nm as confirmed by TEM. DSC recorded a reduction in the melting point (180 °C processed and 200 °C unprocessed melting points). The dissolution rate and solubility of the formulated loxoprofen nanocrystals were significantly enhanced. It can be concluded that selecting suitable stabilizers (i.e., polymers and surfactants) can produce stable nanocrystals, and this can potentially lead to a scaling up of the process for commercialization.

Silymarin nanocrystals-laden chondroitin sulphate-based thermoreversible hydrogels; A promising approach for bioavailability enhancement.

Hydrogels has gained tremendous interest as a controlled release drug delivery. However, currently it is a big challenge to attain high drug-loading as well as stable and sustained release of hydrophobic drugs. The poor aqueous solubility and low bioavailability of many drugs have driven the need for research in new formulations. This manuscript hypothesized that incorporation of nanocrystals of hydrophobic drug, such as silymarin into thermoreversible hydrogel could be a solution to these problems. Herein, we prepared nanocrystals of silymarin by antisolvent precipitation technique and characterized for morphology, particle size, polydispersity index (PDI) and zeta potential. Moreover, physical cross-linking of hydrogel formulations based on chondroitin sulphate (CS), kappa-Carrageenan (κ-Cr) and Pluronic® F127 was confirmed by Fourier transformed infrared spectroscopy (FT-IR). The hydrogel gelation time and temperature of optimized hydrogel was 14 ± 3.2 s and 34 ± 0.6 °C, respectively. The release data revealed controlled release of silymarin up to 48 h and in-vivo pharmacokinetic profiling was done in rabbits and further analyzed by high-performance liquid chromatography (HPLC). It is believed that the nanocrystals loaded thermoreversible injectable hydrogel system fabricated in this study provides high drug loading as well as controlled and stable release of hydrophobic drug for extended period.

Core-shell Pluronic F127/chitosan based nanoparticles for effective delivery of methotrexate in the management of rheumatoid arthritis.

This study was designed to improve oral bioavailability of the methotrexate (MTX) by sustaining its release profile and integration into core-shell polymeric nanoparticles. The self-micellization and ionotropic gelation technique was employed which resulted into spherical shaped nanoparticles (181-417 nm) with encapsulation efficiency of 80.14% to 85.54%. Furthermore, Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry analyses were carried out to investigate physicochemical and thermal stability of the produced engineered core shell nanoparticles of the methotrexate. . Entrapment of drug in polymeric core was confirmed by X-ray diffraction analysis. In-vitro sustained release behavior of nanoparticles was observed at pH 6.8 for 48 h while low drug release was observed at pH 1.2 due to pH-responsive nature of Pluronic F127. Acute toxicity study confirmed safety and biocompatible profile of nanoparticles. MTX loaded polymeric nanoparticles ameliorated the pharmacokinetic profile (8 folds greater half-life, 6.26 folds higher AUC0-t and 3.48 folds higher mean residence time). In vivo study conducted in rat model depicted the improved therapeutic efficacy and healing of arthritis through MTX loaded polymeric nanoparticles, preferentially attributable to high accretion of MTX in the inflamed site. In conclusion, MTX loaded polymeric nanoparticles is an attractive drug delivery strategy for an effective management and treatment of rheumatoid arthritis.

Poly (N-Vinylcaprolactam-Grafted-Sodium Alginate) Based Injectable pH/Thermo Responsive In Situ Forming Depot Hydrogels for Prolonged Controlled Anticancer Drug Delivery; In Vitro, In Vivo Characterization and Toxicity Evaluation.

This study was aimed to develop novel in situ forming gels based on N-vinylcaprolactam, sodium alginate, and N,N-methylenebisacrylamide. The in situ Poly (NVRCL-g-NaAlg) gels were developed using the cold and free radical polymerization method. The structure formation, thermal stability, and porous nature of gels was confirmed by FTIR, NMR, DSC, TGA, and SEM. The tunable gelation temperature was evaluated by tube titling and rheological analysis. Optical transmittance showed that all formulations demonstrated phase transition around 33 °C. The swelling and release profile showed that gels offered maximum swelling and controlled 5-FU release at 25 °C and pH (7.4), owing to a relaxed state. Porosity and mesh size showed an effect on swelling and drug release. The in vitro degradation profile demonstrated a controlled degradation rate. An MTT assay confirmed that formulations are safe tested against Vero cells. In vitro cytotoxicity showed that 5-FU loaded gels have controlled cytotoxic potential against HeLa and MCF-7 cells (IC50 = 39.91 µg/mL and 46.82 µg/mL) compared to free 5-FU (IC50 = 50.52 µg/mL and 53.58 µg/mL). Histopathological study demonstrated no harmful effects of gels on major organs. The in vivo bioavailability in rabbits showed a controlled release in gel form (Cmax, 1433.59 ± 45.09 ng/mL) compared to a free drug (Cmax, 2263.31 ± 13.36 ng/mL) after the subcutaneous injection.

Interaction Analysis of Adenovirus L5 Protein With Pancreatic Cancer Cell Surface Receptor to Analyze Its Affinity for Oncolytic Virus Therapy.

This study seeks to investigate the interaction profile of the L5 protein of oncolytic adenovirus with the overexpressed surface receptors of pancreatic cancer. This is an important area of research because pancreatic cancer is one of the most fatal malignancies with a very low patient survival rate. Multiple therapies to date to improve the survival rate are reported; however, they show a comparatively low success rate. Among them, oncolytic virus therapy is a type of immunotherapy that is currently under deliberation by researchers for multiple cancer types in various clinical trials. Talimogene laherparepvec (T-VEC) is the first oncolytic virus approved by the US Food and Drug Administration (FDA) for melanoma. The oncolytic virus not only kills cancer cells but also activates the anticancer immune response. Therefore, it is preferred over others to deal with aggressive pancreatic cancer. The efficacy of therapy primarily depends on how effectively the oncolytic virus enters and infects the cancer cell. Cell surface receptors and their interactions with virus coat proteins are a crucial step for oncolytic virus entry and a pivotal determinant. The L5 proteins of the virus coat are the first to interact with host cell surface receptors. Therefore, the objective of this study is to analyze the interaction profile of the L5 protein of oncolytic adenovirus with overexpressed surface receptors of pancreatic cancer. The L5 proteins of three adenovirus serotypes HAdV2, HAdV5, and HAdV3 were utilized in this study. Overexpressed pancreatic cancer receptors include SLC2A1, MET, IL1RAP, NPR3, GABRP, SLC6A6, and TMPRSS4. The protein structures of viral and cancer cell protein were docked using the High Ambiguity Driven protein-protein DOCKing (HADDOCK) server. The binding affinity and interaction profile of viral proteins against all the receptors were analyzed. Results suggest that the HAdV3 L5 protein shows better interaction as compared to HAdV2 and HAdV5 by elucidating high binding affinity with 4 receptors (NPR3, GABRP, SLC6A6, and TMPRSS4). The current study proposed that HAdV5 or HAdV2 virus pseudotyped with the L5 protein of HAdV3 can be able to effectively infect pancreatic cancer cells. Moreover, the current study surmises that the affinity maturation of HAdV3 L5 can enhance virus attachment with all the receptors of cancer cells.

Simulation Models for Prediction of Bioavailability of Medicinal Drugs-the Interface Between Experiment and Computation.

The oral drug bioavailability (BA) problems have remained inevitable over the years, impairing drug efficacy and indirectly leading to eventual human morbidity and mortality. However, some conventional lab-based methods improve drug absorption leading to enhanced BA, and the recent experimental techniques are up-and-coming. Nevertheless, some have inherent drawbacks in improving the efficacy of poorly insoluble and low impermeable drugs. Drug BA and strategies to overcome these challenges were briefly highlighted. This review has significantly unravelled the different computational models for studying and predicting drug bioavailability. Several computational approaches provide mechanistic insights into the oral drug delivery system simulation of descriptors like solubility, permeability, transport protein-ligand interactions, and molecular structures. The in silico techniques have long been known still are just being applied to unravel drug bioavailability issues. Many publications have reported novel applications of the computational models towards achieving improved drug BA, including predicting gastrointestinal tract (GIT) drug absorption properties and passive intestinal membrane permeability, thus maximizing time and resources. Also, the classical molecular simulation models for free solvation energies of soluble-related processes such as solubilization, dissolutions, supersaturation, and precipitation have been used in virtual screening studies. A few of the tools are GastroPlusTM that supports biowaiver for drugs, mainly BCS class III and predicts drug compounds' absorption and pharmacokinetic process; SimCyp® simulator for mechanistic modelling and simulation of drug formulation processes; pharmacodynamics analysis on non-linear mixed-effects modelling; and mathematical models, predicting absorption potential/maximum absorption dose. This review provides in silico-experiment annexation in the drug bioavailability enhancement, possible insights that lead to critical opinion on the applications and reliability of the various in silico models as a growing tool for drug development and discovery, thus accelerating drug development processes.

Biofunctional Hyaluronic Acid/κ-Carrageenan Injectable Hydrogels for Improved Drug Delivery and Wound Healing.

The in situ injectable hydrogel system offers a widespread range of biomedical applications in prompt chronic wound treatment and management, as it provides self-healing, maintains a moist wound microenvironment, and offers good antibacterial properties. This study aimed to develop and evaluate biopolymer-based thermoreversible injectable hydrogels for effective wound-healing applications and the controlled drug delivery of meropenem. The injectable hydrogel was developed using the solvent casting method and evaluated for structural changes using proton nuclear magnetic resonance, Fourier transforms infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the self-assembly of hyaluronic acid and kappa-carrageenan and the thermal stability of the fabricated injectable hydrogel with tunable gelation properties. The viscosity assessment indicated the in-situ gelling ability and injectability of the hydrogels at various temperatures. The fabricated hydrogel was loaded with meropenem, and the drug release from the hydrogel in phosphate buffer saline (PBS) with a pH of 7.4 was 96.12%, and the simulated wound fluid with a pH of 6.8 was observed to be at 94.73% at 24 h, which corresponds to the sustained delivery of meropenem. Antibacterial studies on P. aeruginosa, S. aureus, and E. coli with meropenem-laden hydrogel showed higher zones of inhibition. The in vivo studies in Sprague Dawley (SD) rats presented accelerated healing with the drug-loaded injectable hydrogel, while 90% wound closure with the unloaded injectable hydrogel, 70% in the positive control group (SC drug), and 60% in the negative control group was observed (normal saline) after fourteen days. In vivo wound closure analysis confirmed that the developed polymeric hydrogel has synergistic wound-healing potential.