Drug permeation enhancement, efficacy, and safety assessment of azelaic acid loaded SNEDDS hydrogel to overcome the treatment barriers of atopic dermatitis.

Atopic dermatitis is one of the most widespread chronic inflammatory skin conditions that can occur at any age, though the prevalence is highest in children. The purpose of the current study was to prepare and optimize the azelaic acid (AzA) loaded SNEDDS using Pseudo ternary phase diagram, which was subsequently incorporated into the Carbopol 940 hydrogel for the treatment of atopic dermatitis. The composition was evaluated for size, entrapment efficiency, in vitro, ex vivo, and in vivo studies. The polydispersity index of the optimized preparation was found to be less than 0.5, and the size of the distributed globules was found to be 151.20 ± 3.67 nm. The SNEDDS hydrogel was characterized for pH, viscosity, spreadability, and texture analysis. When compared to the marketed formulation, SNEDDS hydrogel was found to have a higher rate of permeation through the rat skin. In addition, a skin irritation test carried out on experimental animals showed that the SNEDDS formulation did not exhibit any erythematous symptoms after a 24-h exposure. In conclusion, the topical delivery of AzA through the skin using SNEDDS hydrogel could prove to be an effective approach for the treatment of atopic dermatitis.

Hyaluronic acid-functionalized lipoplexes and polyplexes as emerging nanocarriers for receptor-targeted cancer therapy.

Cancer is an intricate disease that develops as a response to a combination of hereditary and environmental risk factors, which then result in a variety of changes to the genome. The cluster of differentiation (CD44) is a type of transmembrane glycoprotein that serves as a potential biomarker for cancer stem cells (CSC) and viable targets for therapeutic intervention in the context of cancer therapy. Hyaluronic acid (HA) is a linear polysaccharide that exhibits a notable affinity for the CD44 receptor. This characteristic renders it a promising candidate for therapeutic interventions aimed at selectively targeting CD44-positive cancer cells. Treating cancer via non-viral vector-based gene delivery has changed the notion of curing illness through the incorporation of therapeutic genes into the organism. The objective of this review is to provide an overview of various hyaluronic acid-modified lipoplexes and polyplexes as potential drug delivery methods for specific forms of cancer by effectively targeting CD44.

Targeted therapy of breast tumor by PLGA-based nanostructures: The versatile function in doxorubicin delivery.

Breast carcinoma is a molecularly diverse illness, and it is among the most prominent and often reported malignancies in female across the globe. Surgical intervention, chemotherapy, immunotherapy, gene therapy, and endocrine treatment are among the currently viable treatment options for the carcinoma of breast. Chemotherapy is among the most prevalent cancer management strategy. Doxorubicin (DOX) widely employed as a cytostatic medication for the treatment of a variety of malignancies. Despite its widespread acceptance and excellent efficacy against an extensive line up of neoplasia, it has a variety of shortcomings that limit its therapeutic potential in the previously mentioned indications. Employment of nanoparticulate systems has come up as a unique chemo medication delivery strategy and are being considerably explored for the amelioration of breast carcinoma. Polylactic-co-glycolic acid (PLGA)-based nano systems are being utilized in a number of areas within the medical research and medication delivery constitutes one of the primary functions for PLGA given their inherent physiochemical attributes, including their aqueous solubility, biocompatibility, biodegradability, versatility in formulation, and limited toxicity. Herein along with the different application of PLGA-based nano formulations in cancer therapy, the present review intends to describe the various research investigations that have been conducted to enumerate the effectiveness of DOX-encapsulated PLGA nanoparticles (DOX-PLGA NPs) as a feasible treatment option for breast cancer.

Nanomaterials-Based Novel Immune Strategies in Clinical Translation for Cancer Therapy.

Immunotherapy shows a lot of promise for addressing the problems with traditional cancer treatments. Researchers and clinicians are working to create innovative immunological techniques for cancer detection and treatment that are more selective and have lower toxicity. An emerging field in cancer therapy, immunomodulation offers patients an alternate approach to treating cancer. These therapies use the host's natural defensive systems to identify and remove malignant cells in a targeted manner. Cancer treatment is now undergoing somewhat of a revolution due to recent developments in nanotechnology. Diverse nanomaterials (NMs) have been employed to overcome the limits of conventional anti-cancer treatments such as cytotoxic, surgery, radiation, and chemotherapy. Aside from that, NMs could interact with live cells and influence immune responses. In contrast, unexpected adverse effects such as necrosis, hypersensitivity, and inflammation might result from the immune system (IS)'s interaction with NMs. Therefore, to ensure the efficacy of immunomodulatory nanomaterials, it is essential to have a comprehensive understanding of the intricate interplay that exists between the IS and NMs. This review intends to present an overview of the current achievements, challenges, and improvements in using immunomodulatory nanomaterials (iNMs) for cancer therapy, with an emphasis on elucidating the mechanisms involved in the interaction between NMs and the immune system of the host.

Pharmacological Efficacy of Ginseng against Respiratory Tract Infections.

Respiratory tract infections are underestimated, as they are mild and generally not incapacitating. In clinical medicine, however, these infections are considered a prevalent problem. By 2030, the third most comprehensive reason for death worldwide will be chronic obstructive pulmonary disease (COPD), according to the World Health Organization. The current arsenal of anti-inflammatory drugs shows little or no benefits against COPD. For thousands of years, herbal drugs have been used to cure numerous illnesses; they exhibit promising results and enhance physical performance. Ginseng is one such herbal medicine, known to alleviate pro-inflammatory chemokines and cytokines (IL-2, IL-4, IFN-γ, TNF-α, IL-5, IL-6, IL-8) formed by macrophages and epithelial cells. Furthermore, the mechanisms of action of ginsenoside are still not fully understood. Various clinical trials of ginseng have exhibited a reduction of repeated colds and the flu. In this review, ginseng's structural features, the pathogenicity of microbial infections, and the immunomodulatory, antiviral, and anti-bacterial effects of ginseng were discussed. The focus was on the latest animal studies and human clinical trials that corroborate ginseng's role as a therapy for treating respiratory tract infections. The article concluded with future directions and significant challenges. This review would be a valuable addition to the knowledge base for researchers in understanding the promising role of ginseng in treating respiratory tract infections. Further analysis needs to be re-focused on clinical trials to study ginseng's efficacy and safety in treating pathogenic infections and in determining ginseng-drug interactions.

Analgesic, Anti-Inflammatory, Cytotoxic Activity Screening and UPLC-PDA-ESI-MS Metabolites Determination of Bioactive Fractions of Kleinia pendula.

Kleinia pendula (Forssk.) DC. is a prostrate or pendent dark green succulent herb found in the southwestern mountain regions of Saudi Arabia. The literature survey of the plant reveals a lack of phytochemical and pharmacological studies, although traditional uses have been noted. The objective of the present work was to assess the in vivo analgesic and anti-inflammatory activities, as well as, the in vitro cytotoxic potential of the fractions of Kleinia pendula, and correlate these activities to the plant metabolites. The methanolic extract of Kleinia pendula was subjected to fractionation with n-hexane, ethyl acetate, chloroform, n-butanol, and water. The fractions were screened for their analgesic and anti-inflammatory activities, as well as cytotoxic activity against breast, liver, and colon cancer cell lines. The n-hexane and chloroform fractions of Kleinia pendula showed significant cytotoxic activity against all three cancer cell lines tested. The ethyl acetate and chloroform fractions showed significant analgesic and anti-inflammatory activities. The metabolites in these three active fractions were determined using UPLC-PDA-ESI-MS. Thus, the analgesic and anti-inflammatory activities of the plant were attributed to its phenolic acids (caffeoylquinic acid derivatives, protocatechuic, and chlorogenic acids). While fatty acids and triterpenoids such as (tormentic acid) in the hexane fraction are responsible for the cytotoxic activity; thus, these fractions of Kleinia pendula may be a novel source for the development of new plant-based analgesic, anti-inflammatory, and anticancer drugs.

Isolation of anticancer constituents from Cucumis prophetarum var. prophetarum through bioassay-guided fractionation.

BACKGROUND: Cucumis prophetarum var. prophetarum is used in Saudi folk medicine for treating liver disorders and grows widely between Abha and Khamis Mushait City, Saudi Arabia. METHODS: Bioassay-guided fractionation and purification were used to isolate the main active constituents of Cucumis prophetarum var. prophetarum fruits. These compounds were structurally elucidated using NMR spectroscopy, mass spectral analyses and x-ray crystallography. All fractions, sub-fractions and pure compounds were screened for their anticancer activity against six cancer cell lines. RESULTS: The greatest cytotoxic activity was found to be in the ethyl acetate fraction, resulting in the isolation of five cucurbitacin compounds [E, B, D, F-25 acetate and Hexanorcucurbitacin D]. Among the cucurbitacins that were isolated and tested cucurbitacin B and E showed potent cytotoxicity activities against all six human cancer cell lines. CONCLUSION: Human breast cancer cell lines were found to be the most sensitive to cucurbitacins. Preliminary structure activity relationship (SAR) for cytotoxic activity of Cucurbitacins against human breast cancer cell line MDA-MB-231 has been reported.

Targeting CDK6 in hormone receptor-positive breast cancer: inhibitor discovery for precision oncology through dynamics study.

CDK6 is a critical protein involved in the regulation of the cell cycle, playing an important role in the progression from the G1 to S phase. In breast cancer, dysregulation of this protein is involved in tumour development and progression, particularly in hormone receptor-positive (HR+) breast cancers. The upregulation of CDK6 have been observed in a subset of breast cancers, leading to uncontrolled progression of the cell cycle and increased proliferation of cells. The purpose of this abstract is to provide an outline of CDK6's role. In breast cancer and the therapeutic strategies targeting CDK6 using specific selected inhibitors. To discover viable therapeutic candidates after competitive inhibition of CDK6 with a small molecular drug complex, high throughput screening and docking studies were used. Further, we carried the compounds based on ADMET properties and prediction of activity spectra for substances analysis. Finally, two different compounds were selected to carry out MD simulations. CDK6-IMPHY002642 and CDK6-IMPHY005260 are the two compounds that were identified. Overall, our results suggest that the CDK6-IMPHY002642 and CDK6-IMPHY005260 complex was relatively stable during the simulation. The compounds that have been found can also be further examined as potential therapeutic possibilities. The combined findings suggest that CDK6, together with their genetic changes, can be investigated in therapeutic interventions for precision oncology, leveraging early diagnostics and target-driven therapy.Communicated by Ramaswamy H. Sarma.

Design and synthesis of 2-aminothiazole based antimicrobials targeting MRSA.

Privileged structure-based libraries have been shown to provide high affinity lead compounds for a variety of important biological targets. The present study describes the synthesis and screening of a 2-aminothiazole based compound library to determine their utility as antimicrobials, focusing on MRSA. Several of the compounds in this series demonstrated improved antimicrobial activity as compared to ceftriaxone (CTX), a ß-lactam antibiotic. The most potent compound (21) had MICs in the range of 2-4 µg/ml across a panel of Staphylococcus aureus strains. In addition, trifluoromethoxy substituted aminothiazoles and aminobenzothiazoles were found to be potent antimicrobials with MICs of 2-16 µg/ml.

Ameliorative Sexual Behavior and Phosphodiesterase-5 Inhibitory Effects of Spondias mangifera Fruit Extract in Rodents: In Silico, In Vitro, and In Vivo Study.

The ethanolic extracts of Spondias mangifera fruit (SMFE) were evaluated for aphrodisiac activity. The in-vitro phosphodiesterase-5 (PDE-5) inhibition was assessed based on in-silico molecular docking and simulation studies. In addition, the in-vivo sexual behavior was analyzed in the form of mount (MF, ML), intromission (IF, IL), and ejaculation (EF, EL) frequencies and latencies to validate the in-vitro results. Some biochemical parameters, including PDE-5, nitric oxide, and testosterone, were also observed. The above extract constituted ß-amyrin, ß-sitosterol, and oleanolic acid and showed tremendous binding with phosphodiesterase-5 and sildenafil. Both the sildenafil and ethanolic extracts (200 and 400 mg/kg/d bodyweight) significantly (p < 0.1, p < 0.05) increased MF, IF, and EF, respectively. In contrast, ML and IL significantly (p < 0.1) decreased, and EL significantly (p < 0.1) increased compared with a normal group of animals. The ethanolic extracts (200 and 400 mg/kg/d bodyweight) and sildenafil further significantly (p < 0.05, p < 0.1) diminished PDE-5 activity significantly (p < 0.05, p < 0.1) and enhanced nitric oxide and testosterone levels, as compared with normal rodents. Therefore, the S. mangifera ethanolic extract might be a valuable alternate aphrodisiac for erectile dysfunction.

Medicinal Plants of Solanum Species: The Promising Sources of Phyto-Insecticidal Compounds.

Several medicinal plants have the potential to be a promising alternative pharmacological therapy for a variety of human illnesses. Many insects, including mosquitoes, are important vectors of deadly pathogens and parasites, which in the world's growing human and animal populations can cause serious epidemics and pandemics. Medicinal plants continue to provide a large library of phytochemicals, which can be used to replace chemically synthesized insecticides, and utilization of herbal product-based insecticides is one of the best and safest alternatives for mosquito control. Identifying new effective phyto-derived insecticides is important to counter increasing insect resistance to synthetic compounds and provide a safer environment. Solanum genus (Solanaceae family or nightshades) comprises more than 2500 species, which are widely used as food and traditional medicine. All research publications on insecticidal properties of Solanaceae plants and their phytoconstituents against mosquitoes and other insects published up to July 2020 were systematically analyzed through PubMed/MEDLINE, Scopus, EBSCO, Europe PMC, and Google Scholar databases, with focus on species containing active phytoconstituents that are biodegradable and environmentally safe. The current state of knowledge on larvicidal plants of Solanum species, type of extracts, target insect species, type of effects, name of inhibiting bioactive compounds, and their lethal doses (LC50 and LC90) were reviewed in this study. These studies provide valuable information about the activity of various species of Solanum and their phytochemical diversity, as well as a roadmap for optimizing select compounds for botanical repellents against a variety of vectors that cause debilitating and life-threatening human diseases.

Glycyrrhiza glabra (Licorice): A Comprehensive Review on Its Phytochemistry, Biological Activities, Clinical Evidence and Toxicology.

There are more than 30 species of Glycyrrhiza genus extensively spread worldwide. It was the most prescribed herb in Ancient Egyptian, Roman, Greek, East China, and the West from the Former Han era. There are various beneficial effects of licorice root extracts, such as treating throat infections, tuberculosis, respiratory, liver diseases, antibacterial, anti-inflammatory, and immunodeficiency. On the other hand, traditional medicines are getting the attraction to treat many diseases. Therefore, it is vital to screen the medicinal plants to find the potential of new compounds to treat chronic diseases such as respiratory, cardiovascular, anticancer, hepatoprotective, etc. This work comprehensively reviews ethnopharmacological uses, phytochemistry, biological activities, clinical evidence, and the toxicology of licorice, which will serve as a resource for future clinical and fundamental studies. An attempt has been made to establish the pharmacological effect of licorice in different diseases. In addition, the focus of this review article is on the molecular mechanism of licorice extracts and their four flavonoids (isoliquiritigenin, liquiritigenin, lichalocone, and glabridin) pharmacologic activities. Licorice could be a natural alternative for current therapy to exterminate new emerging disorders with mild side effects. This review will provide systematic insights into this ancient drug for further development and clinical use.

Community Pharmacists' Knowledge, Attitudes, and Practice of Herbal Medicines in Asir Region, Kingdom of Saudi Arabia.

BACKGROUND: A dramatic increase in the use of natural products and herbal medicines has been observed globally. Simultaneously, there has been an increase in safety concerns regarding the extensive use of these herbal remedies among health care practitioners. The urban and rural populations of Saudi Arabia still rely on traditional Arabic herbal medicines for the treatment of various diseases. OBJECTIVES: This study aimed to evaluate community pharmacists' knowledge, attitudes, and practices of herbal medicines in the Asir region, Saudi Arabia. METHODS: An online cross-sectional study was conducted among 233 community pharmacists using a structured questionnaire. RESULTS: Pharmacists showed considerable knowledge of the indications of herbal products, with an average score of 84% correct answers, total P value < 0.05 and < 0.001. They were also knowledgeable about contraindications, side effects, and interactions, with an average score of 75% correct answers, total P value < 0.05 and < 0.001. Community pharmacists had a positive attitude towards herbal products, as 71% of them "agreed" or "strongly agreed" that herbal products were efficacious and 77% of them "agreed" or "strongly agreed" that those products should be sold only in a pharmacy. Herbal products were "often" or "always" dispensed by 67.3% of pharmacists in a pharmacy. CONCLUSION: Pharmacists generally exhibited good knowledge, a positive attitude, and effective practice towards herbal products. However, continuing education programs are needed to train pharmacists in providing client counseling on herbal medicine usage and dispensing them.

Ether and Carbamate Derivatives of 3-quinuclidinol and 3- hydroxymethylquinuclidine: Synthesis and Evaluation as Nicotinic Ligands.

BACKGROUND: A lead quinuclidine-based nicotinic ligand (EQA) served as the basis for the design of novel compounds. A new series of 3-substituted quinuclidines was designed, synthesized and evaluated as nicotinic ligands. METHODS: The goal was to improve affinity for nicotinic receptors in the CNS. Interatomic distance calculations were performed on the proposed compounds as well as, known nicotinic ligands. The proposed compounds were then synthesized, characterized and evaluated in in vitro assays as nicotinic receptor ligands. RESULTS: Compounds 9a and 9b were found to inhibit the specific binding of 3H-(S)-Nicotine with Ki values of 48 nM and 42 nM respectively, indicating high affinity interactions with the α4ß2 subtype. Data suggest that several compounds act as partial agonists at CNS receptors with an efficacy between 28 and 40% and are potent partial activators of human muscle type receptors (α1ß1γδ Emax= 80% that of 100 µM nicotine). CONCLUSIONS: Together these results indicate a partial agonism at muscle type receptors (ca. 40%) with no significant activation of rat ganglion-type receptors (α3ß4*: asterisk indicates potential additional subunit that could partner to form the ganglionic receptor). The partial agonism inducing dopamine release from striatal synaptosomes (α4ß2α6α4ß2ß3, and/or α6ß2ß3) suggest that these compounds may in addition be acting at the α4ß2 and/or the α6ß3* receptors. The partial agonists reported herein are interesting nicotinic ligands worthy of further investigation.

Estrogen receptor antagonists are anti-cryptococcal agents that directly bind EF hand proteins and synergize with fluconazole in vivo.

UNLABELLED: Cryptococcosis is an infectious disease of global significance for which new therapies are needed. Repurposing previously developed drugs for new indications can expedite the translation of new therapies from bench to beside. Here, we characterized the anti-cryptococcal activity and antifungal mechanism of estrogen receptor antagonists related to the breast cancer drugs tamoxifen and toremifene. Tamoxifen and toremifene are fungicidal and synergize with fluconazole and amphotericin B in vitro. In a mouse model of disseminated cryptococcosis, tamoxifen at concentrations achievable in humans combines with fluconazole to decrease brain burden by ~1 log10. In addition, these drugs inhibit the growth of Cryptococcus neoformans within macrophages, a niche not accessible by current antifungal drugs. Toremifene and tamoxifen directly bind to the essential EF hand protein calmodulin, as determined by thermal shift assays with purified C. neoformans calmodulin (Cam1), prevent Cam1 from binding to its well-characterized substrate calcineurin (Cna1), and block Cna1 activation. In whole cells, toremifene and tamoxifen block the calcineurin-dependent nuclear localization of the transcription factor Crz1. A large-scale chemical genetic screen with a library of C. neoformans deletion mutants identified a second EF hand-containing protein, which we have named calmodulin-like protein 1 (CNAG_05655), as a potential target, and further analysis showed that toremifene directly binds Cml1 and modulates its ability to bind and activate Cna1. Importantly, tamoxifen analogs (idoxifene and methylene-idoxifene) with increased calmodulin antagonism display improved anti-cryptococcal activity, indicating that calmodulin inhibition can be used to guide a systematic optimization of the anti-cryptococcal activity of the triphenylethylene scaffold. IMPORTANCE: Worldwide, cryptococcosis affects approximately 1 million people annually and kills more HIV/AIDS patients per year than tuberculosis. The gold standard therapy for cryptococcosis is amphotericin B plus 5-flucytosine, but this regimen is not readily available in regions where resources are limited and where the burden of disease is highest. Herein, we show that molecules related to the breast cancer drug tamoxifen are fungicidal for Cryptococcus and display a number of pharmacological properties desirable for an anti-cryptococcal drug, including synergistic fungicidal activity with fluconazole in vitro and in vivo, oral bioavailability, and activity within macrophages. We have also demonstrated that this class of molecules targets calmodulin as part of their mechanism of action and that tamoxifen analogs with increased calmodulin antagonism have improved anti-cryptococcal activity. Taken together, these results indicate that tamoxifen is a pharmacologically attractive scaffold for the development of new anti-cryptococcal drugs and provide a mechanistic basis for its further optimization.