Investigation on Anti-diabetic Efficacy of a Cucurbitaceae Food Plant from the North-East Region of India: Exploring the Molecular Mechanism through Modulation of Oxidative Stress and Glycosylated Hemoglobin (HbA1c).

BACKGROUND: The medicinal plants of the Cucurbitaceae family, such as Solena heterophylla Lour. fruits, have significant ethnobotanical value and are readily accessible in North East India. AIMS: We conducted a study on Solena heterophylla Lour. fruits to evaluate their anti-diabetic activity in vivo, standardize their HPTLC, and profile their metabolites using LC-QTOF-MS. We aimed to explore the molecular mechanism behind their effects on oxidative stress and glycosylated hemoglobin (HbA1c). METHODS: Firstly, the ethyl acetate fraction of Solena heterophylla Lour. fruits was standardized using Cucurbitacin B as a standard marker by conducting HPTLC evaluation. Next, we delved into analyzing metabolite profiling. In addition, the standardized fraction was utilized in an experimental study to investigate the molecular mechanism of action in an in vivo high-fat diet and a low dose of streptozotocin-induced diabetic model. RESULTS: We have reportedly identified 52 metabolites in the ethyl acetate fraction of Solena heterophylla (EASH). In the in vitro tests, it has been observed that this extract from plants possesses notable inhibitory properties against α-amylase and α-glucosidase. Solena heterophylla fruits with high levels of Cucurbitacin B (2.29% w/w) helped lower FBG levels in animals with EASH treatment. EASH treatment reduced HbA1c levels and normalized liver lipid peroxidation and antioxidant enzyme levels. SGOT, SGPT, and SALP serum enzyme levels also returned to normal. CONCLUSION: Based on the current evaluation, it was found that EASH exhibited encouraging hypoglycemic effects in diabetic rats induced by a low dose of STZ and high-fat diet, which warrants further investigation.

Protein Kinase C (PKC)-mediated TGF-ß Regulation in Diabetic Neuropathy: Emphasis on Neuro-inflammation and Allodynia.

According to the World Health Organization (WHO), diabetes has been increasing steadily over the past few decades. In developing countries, it is the cause of increased morbidity and mortality. Diabetes and its complications are associated with education, occupation, and income across all levels of socioeconomic status. Factors, such as hyperglycemia, social ignorance, lack of proper health knowledge, and late access to medical care, can worsen diabetic complications. Amongst the complications, neuropathic pain and inflammation are considered the most common causes of morbidity for common populations. This review is focused on exploring protein kinase C (PKC)-mediated TGF-ß regulation in diabetic complications with particular emphasis on allodynia. The role of PKC-triggered TGF-ß in diabetic neuropathy is not well explored. This review will provide a better understanding of the PKC-mediated TGF-ß regulation in diabetic neuropathy with several schematic illustrations. Neuroinflammation and associated hyperalgesia and allodynia during microvascular complications in diabetes are scientifically illustrated in this review. It is hoped that this review will facilitate biomedical scientists to better understand the etiology and target drugs effectively to manage diabetes and diabetic neuropathy.

Influence of rutin and its combination with metformin on vascular functions in type 1 diabetes.

The present work examined the effect of oral administration of rutin and its combination with metformin, an antidiabetic drug on blood glucose, total cholesterol and triglycerides level and vascular function in streptozotocin (STZ) -induced diabetic rats. Male Sprague Dawley rats were rendered diabetic by a single intraperitoneal injection of STZ (50 mg/kg). Rutin and metformin were orally administered to diabetic rats at a dose of 100 mg/kg and 300 mg/kg body weight/day, respectively, for 4 weeks. Plasma analysis was conducted to determine changes in the plasma glucose and lipid levels. Rat aortic ring reactivity in response to endothelium-dependent (acetylcholine, ACh) and endothelium-independent (sodium nitroprusside, SNP) relaxants, and to the α1-adrenergic agonist phenylephrine (PE) were recorded. Histology of pancreas, liver and kidney were evaluated. In results, rutin and metformin alone and in combination has led to significant improvements in blood glucose, cholesterol and triglyceride levels compared to diabetic group. Diabetic aortic rings showed significantly greater contraction in response to PE, and less relaxation in response to ACh and SNP. Treatment with rutin and metformin in combination significantly reduced PE-induced contraction and increased ACh-induced and SNP-induced relaxation in diabetes when compared to rutin or metformin alone. Significant histological improvements were seen with combination therapy. In conclusion, rutin and metformin combination therapy has the most potentiality for restoring blood glucose and lipid level as well as vascular function.

Chitosan nanoparticle toxicity: A comprehensive literature review of in vivo and in vitro assessments for medical applications.

Topic definition: This literature review aims to update the current knowledge on toxicity of chitosan nanoparticles, compare the recent findings and identify the gaps with knowledge that is present for the chitosan nanoparticles. Methods: The publications between 2010 and 2020 were searched in Science Direct, Pubmed.gov, Google Scholar, Research Gate, and ClinicalTrials.gov, according to the inclusion and exclusion criteria. 30 primary research studies were obtained from the literature review to compare the in vitro in vivo toxicity profiles among the chitosan nanoparticles. Major highlights: Chitosan nanoparticles and other types of nanoparticles show cytotoxic effects on cancer cells while having minimal toxicity on normal cells. This apparent effect poses some considerations for use in incorporating cancer therapeutics into chitosan nanoparticles as an administration form. The concentration, duration of exposure, and pH of the solution can influence nanoparticle cytotoxicity, particularly in zebrafish. Different cell lines exhibit varying degrees of toxicity when exposed to nanoparticles, and of note are liver cells that show toxicity under exposure as indicated by increased alanine transaminase (ALT) levels. Aside from ALT, platelet aggregation can be considered a toxicity induced by chitosan nanoparticles. In addition, zebrafish cells experience the most toxicity, including organ damage, neurobehavioral impairment, and developmental abnormalities, when exposed to nanoparticles. However, nanoparticles may exhibit different toxicity profiles in different organisms, with brain toxicity and liver toxicity being present in zebrafish but not rats. Different organs exhibit varying degrees of toxicity, with the eye and mouth apparently having the lowest toxicity, while the brain, intestine, muscles and lung showing mixed results. Cardiotoxicity induced by chitosan nanoparticles was not observed in zebrafish embryos, and nanoparticles may reduce cardiotoxicity when delivering drug. Toxicity found in an organ may not necessarily mean that it is toxic towards all the cells found in that organ, as muscle toxicity was present when tested in zebrafish but not in C2C12 myoblast cells. Some of the studies conducted may have limitations that need to be reconsidered to account for differing results, with some examples being two experiments done on HeLa cells where one study concluded chitosan nanoparticles were toxic to the cells while the other seems to have no toxicity present. With regards to LD50, one study has stated the concentration of 64.21 mg/ml was found. Finally, smaller nanoparticles generally exhibit higher toxicity in cells compared to larger nanoparticles. Scope for future work: This literature review did not uncover any published clinical trials with available results. Subsequent research endeavors should prioritize conducting clinical trials involving human volunteers to directly assess toxicity, rather than relying on cell or animal models.

Development of controlled release silicone adhesive-based mupirocin patch demonstrates antibacterial activity on live rat skin against Staphylococcus aureus.

BACKGROUND: Peritonitis is the most serious complication of peritoneal dialysis. Staphylococcus aureus infections could lead to peritonitis which causes reversal of peritoneal dialysis treatment back to hemodialysis. The aim of this study was to develop a controlled release silicone adhesive-based mupirocin patch for prophylactic effect and analyze its antibacterial effectiveness against S. aureus. METHODS: The matrix patches were prepared by using different polymers, with and without silicone adhesive, dibutyl sebacate and mupirocin. The patches were characterized for mechanical properties, drug content, moisture content, water absorption capacity and Fourier transform infrared spectrum. In vitro release studies were performed by using Franz diffusion cell. In vitro disk diffusion assay was performed on the Mueller-Hinton Agar plate to measure the zone of inhibition of the patches. The in vivo study was performed on four groups of rats with bacterial counts at three different time intervals, along with skin irritancy and histopathologic studies. RESULTS: The patches showed appropriate average thickness (0.63-1.12 mm), tensile strength (5.08-10.08 MPa) and modulus of elasticity (21.53-42.19 MPa). The drug content ranged from 94.5% to 97.4%, while the moisture content and water absorption capacities at two relative humidities (75% and 93%) were in the range of 1.082-3.139 and 1.287-4.148 wt%, respectively. Fourier transform infrared spectra showed that there were no significant interactions between the polymer and the drug. The highest percentage of drug release at 8 hours was 47.94%. The highest zone of inhibition obtained was 28.3 mm against S. aureus. The in vivo studies showed that the bacterial colonies were fewer at 1 cm (7×101 CFU/mL) than at 2 cm (1.3×102 CFU/mL) over a 24-hour period. The patches were nonirritant to the skin, and histopathologic results also showed no toxic or damaging effects to the skin. CONCLUSION: The in vitro and in vivo studies indicated that controlled release patches reduced the migration of S. aureus on the live rat skin effectively, however, a longer duration of study is required to determine the effectiveness of the patch on a suitable peritonitis-induced animal model.

Ethosomes as Novel Vesicular Carrier: An Overview of the Principle, Preparation and its Applications.

BACKGROUND: In the study of lipid vesicular carriers in permeation enhancement of drug molecules across skin after the success story of liposomes, ethosomes are a recent addition. There are a number of published reviews but still, there is a lack of reviews representing various aspects in a systematic way with a detailed description of current research works. This review serves to fill this deficiency along with special emphasize on its preparation methods and applications. METHODS: Information was collected from previously published literatures which were represented after analysis in terms of various aspects such as principles, composition, preparation, mechanism of penetration, modified forms, characterization, marketed preparations and its applications. RESULT: This review is represented in an informative and easily understandable way. Basic principles and background were covered in the introduction section. Composition section contains the basic components of formulations along with the impact of various parameters on the characterization of the ethosome. A detailed discussion of all the methods along with their own utility is elaborately provided. Various aspects of characterization studies of ethosomes are also discussed. Therapeutic and cosmetic applications of ethosomes are also outlined here. CONCLUSION: In spite of having a excellent permeation-enhancing and targeted drug release profile, ethosome suffers from limited commercialization. Various challenges regarding their commercialization and product development are also discussed in this review with an objective of acting as a directional route for the researchers.

Melastoma malabathricum Ethyl Acetate Fraction Induces Secondary Necrosis in Human Breast and Lung Cancer Cell Lines.

BACKGROUND: Melastoma malabathricum (MM) is a traditional plant used in the Borneo region. The cytotoxic effects of methanol extracts from MM leaves have been reported in a number of human cancer cell lines. However, the mode of cell death by MM has not been investigated. OBJECTIVE: We investigated the cytotoxic effects of MM in both human breast and lung cancer cell lines, MCF-7 and A549, respectively, and defined the mode of cell death. MATERIALS AND METHODS: Cell viability was measured using the 3-(4-, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Annexin-V/propidium iodide (PI) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was done to determine the mode of cell death. RESULTS: The MTT assay revealed that MM extract had an IC50 of >400 µg/ml on both cell lines at 24 h posttreatment. Flow cytometric and fluorescence microscopy analysis of Annexin-V/PI stained MM-treated cells revealed that the majority of the cells underwent secondary necrosis/late apoptosis. TUNEL assay showed that little to no DNA nicks were present in MM-treated cells, suggesting that cells have undergone secondary necrosis, not late apoptosis, at that time point. CONCLUSION: MCF-7 and A549 cells undergoes secondary necrosis 24 h post-treatment with MM extract. MM leaf extract could be a potential source for a novel anti-tumor agent for cancer therapy. SUMMARY: Melastoma malabathricum (MM) extract was toxic on human breast and lung cancer cell linesMajority of MM-treated cells died by either secondary necrosis or late apoptosis at 24 h post-treatmentTerminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed that MM-treated cells underwent secondary necrosis, not late apoptosis. Abbreviations used: DMSO: Dimethyl sulfoxide; MM: Melastoma malabathricum; MTT: 3-(4-, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; PI: Propidium iodide; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick-end labeling.

Transdermal delivery of tolterodine tartrate for overactive bladder treatment: In vitro and in vivo evaluation.

The purpose of the study was to develop a transdermal tolterodine tartrate (TT) patch and to analyse its efficacy for overactive bladder (OAB) treatment. Patches were prepared using various polymers and plasticizers via the solvent casting method. The patches were characterized for tensile strength, thickness, moisture content, modulus of elasticity and water absorption capacity. Differential scanning calorimetry and Fourier transform infrared analyses were also performed. To determine patch effectiveness, in vitro release, permeation and animal studies were performed. The patches showed satisfactory percentage of release, up to 89.9 %, and their mechanical properties included thickness (0.10-0.15 mm), tensile strength (4.62-9.98 MPa) and modulus of elasticity (20-29 MPa). There were no significant interactions between TT and other excipients. Animal studies indicated that the TT patch reduced the incidence of side effects; however, studies of longer duration are required to determine the effectiveness in treating OAB.

Oral and transdermal drug delivery systems: role of lipid-based lyotropic liquid crystals.

Liquid crystal (LC) dosage forms, particularly those using lipid-based lyotropic LCs (LLCs), have generated considerable interest as potential drug delivery systems. LCs have the physical properties of liquids but retain some of the structural characteristics of crystalline solids. They are compatible with hydrophobic and hydrophilic compounds of many different classes and can protect even biologicals and nucleic acids from degradation. This review, focused on research conducted over the past 5 years, discusses the structural evaluation of LCs and their effects in drug formulations. The structural classification of LLCs into lamellar, hexagonal and micellar cubic phases is described. The structures of these phases are influenced by the addition of surfactants, which include a variety of nontoxic, biodegradable lipids; these also enhance drug solubility. LLC structure influences drug localization, particle size and viscosity, which, in turn, determine drug delivery properties. Through several specific examples, we describe the applications of LLCs in oral and topical drug formulations, the latter including transdermal and ocular delivery. In oral LLC formulations, micelle compositions and the resulting LLC structures can determine drug solubilization and stability as well as intestinal transport and absorption. Similarly, in topical LLC formulations, composition can influence whether the drug is retained in the skin or delivered transdermally. Owing to their enhancement of drug stability and promotion of controlled drug delivery, LLCs are becoming increasingly popular in pharmaceutical formulations.

Clinacanthus nutans: a review on ethnomedicinal uses, chemical constituents and pharmacological properties.

CONTEXT: Medicinal plants have attracted global attention for their hidden therapeutic potential. Clinacanthus nutans (Burm.f) Lindau (Acanthaceae) (CN) is endemic in Southeast Asia. CN contains phytochemicals common to medicinal plants, such as flavonoids. Traditionally, CN has been used for a broad range of human ailments including snake bites and cancer. OBJECTIVES: This article compiles the ethnomedicinal uses of CN and its phytochemistry, and thus provides a phytochemical library of CN. It also discusses the known pharmacological and biological effects of CN to enable better investigation of CN. METHODS: This literature review was limited to articles and websites published in the English language. MEDLINE and Google Scholar databases were searched from December 2014 to September 2016 using the following keywords: "Clinacanthus nutans" and "Belalai gajah". The results were reviewed to identify relevant articles. Information from relevant selected studies was systematically analyzed from contemporary ethnopharmacological sources, evaluated against scientific literature, and extracted into tables. RESULTS: The literature search yielded 124 articles which were then further scrutinized revealing the promising biological activities of CN, including antimicrobial, antiproliferative, antitumorigenic and anti-inflammatory effects. Few articles discussed the mechanisms for these pharmacological activities. Furthermore, CN was beneficial in small-scale clinical trials for genital Herpes and aphthous stomatitis. CONCLUSION: Despite the rich ethnomedicinal knowledge behind the traditional uses of CN, the current scientific evidence to support these claims remains scant. More research is still needed to validate these medicinal claims, beginning by increasing the understanding of the biological actions of this plant.

Tolterodine Tartrate Proniosomal Gel Transdermal Delivery for Overactive Bladder.

The goal of this study was to formulate and evaluate side effects of transdermal delivery of proniosomal gel compared to oral tolterodine tartrate (TT) for the treatment of overactive bladder (OAB). Proniosomal gels are surfactants, lipids and soy lecithin, prepared by coacervation phase separation. Formulations were analyzed for drug entrapment efficiency (EE), vesicle size, surface morphology, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, and in vivo effects. The EE was 44.87%-91.68% and vesicle size was 253-845 nm for Span formulations and morphology showed a loose structure. The stability and skin irritancy test were also carried out for the optimized formulations. Span formulations with cholesterol-containing formulation S1 and glyceryl distearate as well as lecithin containing S3 formulation showed higher cumulative percent of permeation such as 42% and 35%, respectively. In the in vivo salivary secretion model, S1 proniosomal gel had faster recovery, less cholinergic side effect on the salivary gland compared with that of oral TT. Histologically, bladder of rats treated with the proniosomal gel formulation S1 showed morphological improvements greater than those treated with S3. This study demonstrates the potential of proniosomal vesicles for transdermal delivery of TT to treat OAB.

Parasitic Mistletoes of the Genera Scurrula and Viscum: From Bench to Bedside.

The mistletoes, stem hemiparasites of Asia and Europe, have been used as medicinal herbs for many years and possess sophisticated systems to obtain nutrients from their host plants. Although knowledge about ethnomedicinal uses of mistletoes is prevalent in Asia, systematic scientific study of these plants is still lacking, unlike its European counterparts. This review aims to evaluate the literature on Scurrula and Viscum mistletoes. Both mistletoes were found to have anticancer, antimicrobial, antioxidant and antihypertensive properties. Plants from the genus Scurrula were found to inhibit cancer growth due to presence of phytoconstituents such as quercetin and fatty acid chains. Similar to plants from the genus Viscum, Scurrula also possesses TNFα activity to strengthen the immune system to combat cancer. In line with its anticancer activity, both mistletoes are rich in antioxidants that confer protection against cancer as well as neurodegeneration. Extracts from plants of both genera showed evidence of vasodilation and thus, antihypertensive effects. Other therapeutic effects such as weight loss, postpartum and gastrointestinal healing from different plants of the genus Scurrula are documented. As the therapeutic effects of plants from Scurrula are still in exploration stage, there is currently no known clinical trial on these plants. However, there are few on-going clinical trials for Viscum album that demonstrate the functionalities of these mistletoes. Future work required for exploring the benefits of these plants and ways to develop both parasitic plants as a source of pharmacological drug are explained in this article.

Transdermal delivery of oxybutynin chloride proniosomal gels for the treatment of overactive bladder.

CONTEXT: Overactive bladder (OAB) is a common problem and anticholinergic drugs are first-line therapy, but they have side effects. OBJECTIVE: Development of oxybutynin chloride (OC) proniosomal gels and analyses of its efficacy for OAB treatment. MATERIALS AND METHODS: Phase separation coacervation was used to prepare proniosomal gels using various non-ionic surfactants, lipids, soy lecithin and isopropyl alcohol. Gels were characterized with regard to entrapment efficiency (EE), vesicle size, surface morphology (using environmental scanning electron microscopy [E-SEM]), stability, attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, in vitro skin permeation, in vivo animal studies and histopathology. RESULTS AND DISCUSSION: EE was 87-92%, vesicle size was 0.38-5.0 µm, and morphology showed some loosened pores in proniosomes after hydration. ATR-FTIR spectroscopy showed no significant shifts in peaks corresponding to OC and excipients. Most formulations exhibited >50% permeation but the cholesterol-containing formulations P3 (Span 20:Span 60 [1:1]) and P4 [Tween 20:Tween 80 (1:1)] had the highest percent cumulative permeation. P3 and P4 also showed faster recovery of cholinergic effects on salivary glands than oral formulations. P3 and P4 had pronounced therapeutic effects in reduction of urinary frequency and demonstrated improvements in bladder morphology (highly regenerative surface of the transitional epithelium). CONCLUSION: These results suggest that OC could be incorporated into proniosomal gels for transdermal delivery in the treatment of OAB.

Medicinal Plants: A Potential Source of Compounds for Targeting Cell Division.

Modern medicinal plant drug discovery has provided pharmacologically active compounds targeted against a multitude of conditions and diseases, such as infection, inflammation, and cancer. To date, natural products from medicinal plants remain a solid niche as a source from which cancer therapies can be derived. Among other properties, one favorable characteristic of an anticancer drug is its ability to block the uncontrollable process of cell division, as cancer cells are notorious for their abnormal cell division. There are numerous other documented works on the potential anticancer activity of drugs derived from medicinal plants, and their effects on cell division are an attractive and growing therapeutic target. Despite this, there remains a vast number of unidentified natural products that are potentially promising sources for medical applications. This mini review aims to revise the current knowledge of the effects of natural plant products on cell division.