Exploration of Succinimide Derivative as a Multi-Target, Anti-Diabetic Agent: In Vitro and In Vivo Approaches.

Diabetes mellitus (DM) is counted among one of the leading challenges in the recent era, and it is a life-threatening disorder. Compound 4-hydroxy 3-methoxy phenylacetone (compound 1) was previously isolated from Polygonum aviculare. This compound was reacted with N-benzylmaleimide to synthesize the targeted compound 3. The purpose of this research is to exhibit our developed compound 3's ability to concurrently inhibit many targets that are responsible for hyperglycemia. Compound 3 was capable of inhibiting α-amylase, α-glucosidase, and protein tyrosine phosphatase 1 B. Even so, outstanding in vitro inhibition was shown by the compound against dipeptidyl peptidase-4 (DPP-4) with an IC50 value of 0.07 µM. Additionally, by using DPPH in the antioxidant activity, it exhibited good antioxidant potential. Similarly, in the in vivo activity, the experimental mice proved to be safe by treatment with compound 3. After 21 days of examination, the compound 3 activity pattern was found to be effective in experimental mice. Compound 3 decreased the excess peak of total triglycerides, total cholesterol, AST, ALT, ALP, LDL, BUN, and creatinine in the STZ-induced diabetic mice. Likewise, the histopathology of the kidneys, liver, and pancreas of the treated animals was also evaluated. Overall, the succinimde moiety, such as compound 3, can affect several targets simultaneously, and, finally, we were successful in synthesizing a multi-targeted preclinical therapy.

Resveratrol regulates inflammation and improves oxidative stress via Nrf2 signaling pathway: Therapeutic and biotechnological prospects.

Usually, in aerobic metabolism, natural materials including nucleic acids, proteins, and lipids can experience auxiliary injury by oxidative responses. This damage produced by reactive oxygen/nitrogen species has been identified as "oxidative stress." As a natural polyphenol got from red wine and peanuts, resveratrol is one of the most eminent anti-aging mixtures. Based on many studies', resveratrol hinders destructive effects of inflammatory causes and reactive oxygen radicals in several tissues. The nuclear erythroid 2-related factor 2 is a factor related to transcription with anti-inflammatory, antioxidant possessions which is complicated by enzyme biotransformation and biosynthesis of lipids and carbohydrates. This review provides current understanding and information about the character of resveratrol against oxidative stress and regulation of inflammation via Nrf2 signaling pathway.

How Curcumin Targets Inflammatory Mediators in Diabetes: Therapeutic Insights and Possible Solutions.

Diabetes mellitus is a multifactorial chronic metabolic disorder, characterized by altered metabolism of macro-nutrients, such as fats, proteins, and carbohydrates. Diabetic retinopathy, diabetic cardiomyopathy, diabetic encephalopathy, diabetic periodontitis, and diabetic nephropathy are the prominent complications of diabetes. Inflammatory mediators are primarily responsible for these complications. Curcumin, a polyphenol derived from turmeric, is well known for its anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The regulation of several signaling pathways effectively targets inflammatory mediators in diabetes. Curcumin's anti-inflammatory and anti-oxidative activities against a wide range of molecular targets have been shown to have therapeutic potential for a variety of chronic inflammatory disorders, including diabetes. Curcumin's biological examination has shown that it is a powerful anti-oxidant that stops cells from growing by releasing active free thiol groups at the target location. Curcumin is a powerful anti-inflammatory agent that targets inflammatory mediators in diabetes, and its resistant form leads to better therapeutic outcomes in diabetes complications. Moreover, Curcumin is an anti-oxidant and NF-B inhibitor that may be useful in treating diabetes. Curcumin has been shown to inhibit diabetes-related enzymes, such as a-glucosidase, aldose reductase and aldose reductase inhibitors. Through its anti-oxidant and anti-inflammatory effects, and its suppression of vascular endothelial development and nuclear transcription factors, curcumin has the ability to prevent, or reduce, the course of diabetic retinopathy. Curcumin improves insulin sensitivity by suppressing phosphorylation of ERK/JNK in HG-induced insulin-resistant cells and strengthening the PI3K-AKT-GSK3B signaling pathway. In the present article, we aimed to discuss the anti-inflammatory mechanisms of curcumin in diabetes regulated by various molecular signaling pathways.

Antimicrobial Potential of Curcumin: Therapeutic Potential and Challenges to Clinical Applications.

Curcumin is a bioactive compound that is extracted from Curcuma longa and that is known for its antimicrobial properties. Curcuminoids are the main constituents of curcumin that exhibit antioxidant properties. It has a broad spectrum of antibacterial actions against a wide range of bacteria, even those resistant to antibiotics. Curcumin has been shown to be effective against the microorganisms that are responsible for surgical infections and implant-related bone infections, primarily Staphylococcus aureus and Escherichia coli. The efficacy of curcumin against Helicobacter pylori and Mycobacterium tuberculosis, alone or in combination with other classic antibiotics, is one of its most promising antibacterial effects. Curcumin is known to have antifungal action against numerous fungi that are responsible for a variety of infections, including dermatophytosis. Candidemia and candidiasis caused by Candida species have also been reported to be treated using curcumin. Life-threatening diseases and infections caused by viruses can be counteracted by curcumin, recognizing its antiviral potential. In combination therapy with other phytochemicals, curcumin shows synergistic effects, and this approach appears to be suitable for the eradication of antibiotic-resistant microbes and promising for achieving co-loaded antimicrobial pro-regenerative coatings for orthopedic implant biomaterials. Poor water solubility, low bioavailability, and rapid degradation are the main disadvantages of curcumin. The use of nanotechnologies for the delivery of curcumin could increase the prospects for its clinical application, mainly in orthopedics and other surgical scenarios. Curcumin-loaded nanoparticles revealed antimicrobial properties against S. aureus in periprosthetic joint infections.

Regulation of endoplasmic reticulum stress by hesperetin: Focus on antitumor and cytoprotective effects.

BACKGROUND: Cancer is still an all-times issue due to a large and even increasing number of deaths. Impaired genes regulating cell proliferation and apoptosis are targets for the development of novel cancer treatments. HYPOTHESIS: Increased transcription of NADPH oxidase activator (NOXA), Bcl2-like11 (BIM), BH3-only proteins and p53 unregulated apoptosis modulator (PUMA) is caused by the imbalance between pro- and anti-apoptotic Bcl-2 proteins due to endoplasmic reticulum (ER) stress. The membranous network of ER is present in all eukaryotic cells. ER stress facilitates the interaction between Bax and PUMA, triggering the release of cytochrome C. As a main intracellular organelle, ER is responsible for translocation as well as post-translation modification and protein folding. RESULTS: Hesperetin is a cytoprotective flavonone, which acts against ER stress and protects from cell damage induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hesperetin inhibits lipid peroxidation induced by Fe2+ and l-ascorbic acid in rat brain homogenates. CONCLUSION: This review deals with the anticancer effects of hesperetin regarding the regulation of ER stress as a principal mechanism in the pathogenesis of tumors.

Nanoscale delivery of phytochemicals targeting CRISPR/Cas9 for cancer therapy.

BACKGROUND: With growing global prevalence, cancer is a major cause of disease-related deaths. The understanding of the fundamental tumor pathology has contributed to the development of agents targeting oncogenic signaling pathways. Although these agents have increased survival for defined cancers, the therapeutic choices are still limited due to the development of drug resistance. CRISPR/Cas9 is a powerful new technology in cancer therapy by facilitating the identification of novel treatment targets and development of cell-based treatment strategies. PURPOSE: We focused on applications of the CRISPR/Cas9 system in cancer therapy and discuss nanoscale delivery of cytotoxic phytochemical targeting the CRISPR/Cas9 system. RESULTS: Genome engineering has been significantly accelerated by the advancement of the CRISPR/Cas9 technique. Phytochemicals play a key role in treating cancer by targeting various mechanisms and pathways. CONCLUSIONS: The use of CRISPR/Cas9 for nanoscale delivery of phytochemicals opens new avenues in cancer therapy. One of the main obstacles in the clinical application of CRISPR/Cas9 is safe and efficient delivery. As viral delivery methods have certain drawbacks, there is an urgent need to develop non-viral delivery systems for therapeutic applications.

Evaluation of hepatoprotective effects of crude methanolic extract of Datura metel L. in mice.

Datura metel has been recommended in several human disorders including a remedy for liver toxicity. The current study was designed to evaluate the hepatoprotective effect of methanolic extract of D. metel in animal model. Acute toxicity of methanolic crude extract of Datura metel (MEDM) was studied in animals in various doses 500-2000 mg/kg. Mice of either sex were divided into groups (n=6). One group received normal saline intraperitonially as negative control, while other gentamicin 100mg/kg for 8 days as positive control. 3rd group received 50mg/kg silymarin as standard, 4th group received 100mg/kg of MEDM, 5th group received 200mg/kg MEDM while 6th group received 300mg/kg MEDM and gentamicin 100mg/kg for 8 days. The blood samples were collected on 9th day and the animals were then dissected and the liver of all the animals were isolated. MEDM was found safe in acute toxicity test at various doses up to 2000 mg/kg. The levels of serum glutamic pyruvic transaminase and alkaline phosphatase were elevated significantly with gentamicin treatment which significantly down-regulated by MEDM (100, 200 and 300 mg/kg) in a dose dependent manner.. The histological examination showed that the MEDM has markedly treated the inflammatory infiltrate, fatty changes and congested blood vessels which were induced by gentamicin.  The findings of our study thus proved the absolute of MEDM in acute toxicity test; followed by significant hepatoprotective effect in gentamicin induced hepatotoxic mice.

In vivo acute toxicity, laxative and antiulcer effect of the extract of Dryopteris Ramose.

Dryopteris ramosa (D. ramosa) is one of the most traded medicinally important plants of Himalayan region. Apart from other uses, D. ramosa is traditionally also used to treat gastric ulcers and as a laxative. The present study was designed to investigate the role of methanolic crude extract of Dryopteris Ramosa (MEDR) in acute toxicity, against loperamide induced constipated mice model, antiulcer effect of methanolic extract of D. Ramosa and cholinomimetic like effect of methanolic extract of D. Ramosa. The crude extract was investigated for the presence of active compounds (secondary metabolites) such as alkaloids, flavonoids, carbohydrates, glycosides, terpenoids, phenolic compounds, saponins, and tannins following the standard methods. The antiulcer effect was investigated in mice using the ethanol induced ulcer model at various doses i.e. 50 mg/kg, 100 mg/kg and 200 mg/kg doses. Constipation was induced in the mice via loperamide (3mg/kg body weight). The control group received normal saline. Different doses of plant extracts (50, 100, 150 and 200 mg/kg body weight/day) were administered for 7 days. Various parameters like feeding characteristics, gastrointestinal transit ratio, body weight, fecal properties and the possible mechanism of action of D. Ramosa on intestinal motility were monitored. Various Phytochemicals like saponins, glycosides, flavonoids, tannins, phenols, carbohydrate, alkaloids and triterpenes were found in D. Ramosa. The acute toxicity study showed that MEDR was associated with no mortality except mild and moderate sedation at the highest tested doses (1500 and 2000 mg/kg). MEDR also showed significant antiulcer activity against ethanol-induced ulcerogenesis. The extract enhanced the intestinal motility, normalized the body weight of constipated mice and increased the fecal volume which are indications of laxative property of the herb. The 200 mg/kg body weight dose of the extract was found effective. The presence of various Phytochemicals such as flavonoids, glycosides and tannins might be responsible for the antiulcer activity of D. Ramosa. This study provides the scientific background for the folkloric use of D. Ramosa as antiulcer agent. The laxative action of the extract compares positively with Duphalac, (standard laxative drug). These findings have therefore evidence scientific background to the folkloric use of the herb as a laxative agent.

Current Status and Future Perspectives on Therapeutic Potential of Apigenin: Focus on Metabolic-Syndrome-Dependent Organ Dysfunction.

Metabolic syndrome and its associated disorders such as obesity, insulin resistance, atherosclerosis and type 2 diabetes mellitus are globally prevalent. Different molecules showing therapeutic potential are currently available for the management of metabolic syndrome, although their efficacy has often been compromised by their poor bioavailability and side effects. Studies have been carried out on medicinal plant extracts for the treatment and prevention of metabolic syndrome. In this regard, isolated pure compounds have shown promising efficacy for the management of metabolic syndrome, both in preclinical and clinical settings. Apigenin, a natural bioactive flavonoid widely present in medicinal plants, functional foods, vegetables and fruits, exerts protective effects in models of neurological disorders and cardiovascular diseases and most of these effects are attributed to its antioxidant action. Various preclinical and clinical studies carried out so far show a protective effect of apigenin against metabolic syndrome. Herein, we provide a comprehensive review on both in vitro and in vivo evidence related to the promising antioxidant role of apigenin in cardioprotection, neuroprotection and renoprotection, and to its beneficial action in metabolic-syndrome-dependent organ dysfunction. We also provide evidence on the potential of apigenin in the prevention and/or treatment of metabolic syndrome, analysing the potential and limitation of its therapeutic use.

Micronutrient Food Supplements in Patients with Gastro-Intestinal and Hepatic Cancers.

Colorectal carcinogenesis is the second most common cause of mortality across all types of malignancies, followed by hepatic and stomach cancers. Chemotherapy and radiotherapy are key approaches to treating cancer patients, but these carry major concerns, such as a high risk of side effects, poor accessibility, and the non-selective nature of chemotherapeutics. A number of natural products have been identified as countering various forms of cancer with fewer side effects. The potential impact of vitamins and minerals on long-term health, cognition, healthy development, bone formation, and aging has been supported by experimental and epidemiological studies. Successful treatment may thus be highly influenced by the nutritional status of patients. An insufficient diet could lead to detrimental effects on immune status and tolerance to treatment, affecting the ability of chemotherapy to destroy cancerous cells. In recent decades, most cancer patients have been taking vitamins and minerals to improve standard therapy and/or to decrease the undesirable side effects of the treatment together with the underlying disease. On the other hand, taking dietary supplements during cancer therapy may affect the effectiveness of chemotherapy. Thus, micronutrients in complementary oncology must be selected appropriately and should be taken at the right time. Here, the potential impact of micronutrients on gastro-intestinal and hepatic cancers is explored and their molecular targets are laid down.

Nrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects.

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc-curcumin Zn (II)-curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc-curcumin Zn (II)-curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

Datura metel: A Review on Chemical Constituents, Traditional Uses and Pharmacological Activities.

Datura metel (Solanaceae) which is commonly known as thorn's apple, Indian apple or devil's trumpet isan annual herb of temperate zones which is distributed all over the world. D. metel belongs to the family solanaceae. From a longer period of time (37 A.D), species of this family had therapeutic uses. This article is based on the review of different scientific backgrounds and studies regarding the traditional uses, phytochemistry, biochemical constituents and pharmacological uses of D. metel. This review is based on the facts of the available literature review. Different researchers conducted researches and studies on D. metel and confirmed the presence of enormous chemical compounds like flavonoids, tropane alkaloids, tannins, saponins and withanolides. D. metel has been found to be pharmacologically important species because of its different pharmacological and traditional uses, such as hepatoprotective, antiviral effect, antibacterial effect, anti-asthmatic, analgesic, antipyretic and nephroprotective effect, anticancer and antifungal effect. However, further in vivo and in vitro advanced studies are required to carried out for the exact pharmacological mechanisms and for basis of clinical utility.

Kaempferol as a Dietary Anti-Inflammatory Agent: Current Therapeutic Standing.

Inflammation is a physiological response to different pathological, cellular or vascular damages due to physical, chemical or mechanical trauma. It is characterized by pain, redness, heat and swelling. Current natural drugs are carefully chosen as a novel therapeutic strategy for the management of inflammatory diseases. Different phytochemical constituents are present in natural products. These phytochemicals have high efficacy both in vivo and in vitro. Among them, flavonoids occur in many foods, vegetables and herbal medicines and are considered as the most active constituent, having the ability to attenuate inflammation. Kaempferol is a polyphenol that is richly found in fruits, vegetables and herbal medicines. It is also found in plant-derived beverages. Kaempferol is used in the management of various ailments but there is no available review article that can summarize all the natural sources and biological activities specifically focusing on the anti-inflammatory effect of kaempferol. Therefore, this article is aimed at providing a brief updated review of the literature regarding the anti-inflammatory effect of kaempferol and its possible molecular mechanisms of action. Furthermore, the review provides the available updated literature regarding the natural sources, chemistry, biosynthesis, oral absorption, metabolism, bioavailability and therapeutic effect of kaempferol.

Nephroprotective effects of Datura metel extract in gentamicin induced mice model: biochemical and histological evidences.

Datura metel is traditionally used as a remedy for renal toxicity. However, the nephroprotection has not been scientifically validated yet. To evaluate the nephroprotective like effect of methanolic extract of D. metel in gentamicin induced mice model, mice of either sex were divided into groups. One group received normal saline as negative control. The 2nd group received gentamicin 100mg/kg for 8 days as positive control, 3rd group received 50mg/kg silymarin as standard, while the reaming groups received 100, 200 and 300 mg/kg of MEDM and gentamicin 100mg/kg, for 8 days. The blood and urine samples were collected on 9th day, animals were then dissected and whole kidneys were removed and preserved in formalin for later histological examinations. The level of serum creatinine, blood urea nitrogen, urine creatinine and urine urea were significantly (P<0.05) elevated and the renal MDA level was also elevated significantly (P<0.05) by gentamicin in mice. After the treatment of test animals with MEDM, the elevated level of serum and urine biomarkers by gentamicin were reversed by MEDM. The nephroprotective effect was found in dose dependent manner. As the MEDM significantly protected the nephrotoxicity via its antioxidant effect. The findings of our study thus proved the scientific background for the nephroprotective effect of MEDM.