A review on the nexus of autophagy genes from the perspective of polycystic ovary syndrome.

Polycystic ovary syndrome or PCOS is an endocrine disorder in women of reproductive age. It is a diversified multi factorial disorder and diagnosis is very complicated because of its overlapping symptoms some of which are irregular menstrual cycle, acne in face, excess level of androgen (AE), insulin resistance, obesity, cardiovascular disease, mood disorder and type 2 diabetes (T2DM). PCOS may be caused by hormonal imbalance, genetic and epigenetic vulnerability, hypothalamic and ovarian troubles. PCOS is essentially hyperandrogenimia with oligo-anovulation. This review explains the abnormal regulation of autophagy related genes and proteins in different cells at various stages which leads to the genesis of PCOS. During nutrient starvation cells face stress condition, which it tries to overcome by activating its macroautophagy mechanism and by degrading the cytoplasmic material. This provides energy to the cell facilitating its survival. Downregulation of autophagy related genes in endometria has been observed in PCOS women. PCOS can be managed by maintaining proper lifestyle and medical treatment. Healthy meals and regular exercise can prevent the excessive weight and also reduce the PCOS complications. Medicines such as metformin, clomiphene, and the oral contraceptive pill can also balance the hormonal level. The imbalance in regulation of autophagy genes has been discussed with correlation to PCOS. The different management strategies for PCOS have also been summarized.

A zwitterionic probe for ratiometric fluorescent detection of aluminium(III) ion in aqueous medium and its application in bioimaging.

In the present study, we have synthesized an aminobenzoic acid containing Schiff base (compound 1) and its structure was confirmed through single crystal X-ray study. Importantly, the compound 1 crystallizes in the zwitterionic form, with an anionic carboxylate group (-COO-) and a cationic iminium group (-C = NH+-). The compound 1 is highly soluble in water due to its zwitterionic feature in the solid state. Interestingly, compound 1 acts as a ratiometric fluorescent probe for the selective detection of Al3+ ion in aqueous solution without organic cosolvent. It can also detect Al3+ ion by visual colour change to bluish-green fluorescence under 365 nm UV light. The association constant between compound 1 with Al3+ ion was estimated to be 1.67 × 104 M-1. The lowest detection limit for Al3+ ion was calculated to be 7.05 × 10-8 M in water. Compound 1 in combination with Al3+ ion demonstrated fluorescent imaging potential of the nucleus of in RAW 264.7 murine macrophage cell line. In addition, the sensing model is developed as paper based sensor ''Test Kit' 'for its practical applicability.

Implications of Three-Dimensional Cell Culture in Cancer Therapeutic Research.

Replicating the naturalistic biomechanical milieu of cells is a primary requisite to uncover the fundamental life processes. The native milieu is significantly not replicated in the two-dimensional (2D) cell cultures. Alternatively, the current three-dimensional (3D) culture techniques can replicate the properties of extracellular matrix (ECM), though the recreation of the original microenvironment is challenging. The organization of cells in a 3D manner contributes to better insight about the tumorigenesis mechanism of the in vitro cancer models. Gene expression studies are susceptible to alterations in their microenvironment. Physiological interactions among neighboring cells also contribute to gene expression, which is highly replicable with minor modifications in 3D cultures. 3D cell culture provides a useful platform for identifying the biological characteristics of tumor cells, particularly in the drug sensitivity area of translational medicine. It promises to be a bridge between traditional 2D culture and animal experiments and is of great importance for further research in tumor biology. The new imaging technology and the implementation of standard protocols can address the barriers interfering with the live cell observation in a natural 3D physiological environment.

Oncotherapeutic Application of Resveratrol-based Inorganic Nanoparticles.

BACKGROUND: Potential therapeutic benefits of natural phytoconstituents and the emergence of nano-structured drug delivery systems have expanded the scope of enhanced chemotherapy with minimal adverse effects. Various in vivo and in vitro studies have revealed Resveratrol to be a potent anti-carcinogenic agent. Researchers are currently applying the concept of nano-science for enhancing the delivery of phyto-drugs like resveratrol, in order to carry the drug to the affected tissues and organs of cancer patients with much ease and efficiency. METHODS: The current review emphasizes the use of inorganic nanoparticles for enhancing the delivery and efficacy of resveratrol into otherwise inaccessible tumorigenic tissues. CONCLUSION: The present review work summarizes a comprehensive update on the mechanism of actions of the resveratrol-based inorganic nanocomposite particles that are currently being studied against various cancer models. This work may be significant in laying the foundation for the future of metallic nanoparticles-based delivery and efficacy of phytochemicals in general and resveratrol in specific against non-invasive metastatic cancer.

In-silico comparison of inhibition of wild and drug-resistant Haemonchus contortus ß-tubulin isotype-1 by glycyrrhetinic acid, thymol and albendazole interactions.

ABSTRACT: Haemonchus contortus is among the most prevalent pathogenic gastrointestinal nematodes that poses significant health issues in small ruminants. Control of Haemonchus contortus relies on benzimidazoles. However, most small ruminants have started showing benzimidazole resistance due to prolonged and intensive drug consumption It is postulated that single nucleotide polymorphism of specific amino acids, Phe200Tyr, Phe167Tyr and Glu198Ala in ß-tubulin is the causal factor of this resistance. Hence, a plethora of alternative anthelmintic drug is currently being investigated. The present study intends to investigate in silico anthelmintic potential of glycyrrhetinic acid and thymol against wild and mutant ß-tubulin protein of Haemonchus contortus. Based on binding energies obtained in docking studies using AutoDock 4.0, mutant ß-tubulin at Phe200Tyr, Phe167Tyr and Glu198Ala illustrates insignificant changes in binding affinity of albendazole in comparison to the wild ß-tubulin. However, glycyrrhetinic acid and thymol exhibited significantly greater binding affinities towards mutant ß-tubulin in comparison to the albendazole-wild ß-tubulin binding affinity. Hence, these phytocompounds can potentially inhibit both wild and mutant Haemonchus contortus ß-tubulin polymerization. If established by in vitro and in vivo experiments, glycyrrhetinic acid could be an alternative anthelmintic compound, thus, further motivating the concept of reverse pharmacognosy. SUPPLEMENTARY INFORMATION: is available for this paper at 10.1007/s12639-020-01274-w.

Potential Alternatives to Conventional Cancer Therapeutic Approaches: The Way Forward.

onventional cancer therapeutic approaches broadly include chemotherapy, radiation therapy and surgery. These established approaches have evolved over several decades of clinical experience. For a complex disease like cancer, satisfactory treatment remains an enigma for the simple fact that the causal factors for cancer are extremely diverse. In order to overcome existing therapeutic limitations, consistent scientific endeavors have evolved several potential therapeutic approaches, majority of which focuses essentially on targeted drug delivery, minimal concomitant ramification, and selective high cytotoxicity. The current review focuses on highlighting some of these potential alternatives that are currently in various stages of in vitro, in vivo, and clinical trials. These include physical, chemical and biological entities that are avidly being explored for therapeutic alternatives. Some of these entities include suicide gene, micro RNA, modulatory peptides, ultrasonic waves, free radicals, nanoparticles, phytochemicals, and gene knockout, and stem cells. Each of these techniques may be exploited exclusively and in combination with conventional therapeutic approaches thereby enhancing the therapeutic efficacy of the treatment. The review intends to briefly discuss the mechanism of action, pros, and cons of potential alternatives to conventional therapeutic approaches.

Molecular mechanisms of action of resveratrol in modulation of diabetic and non-diabetic cardiomyopathy.

Cardiomyopathy is among the major clinical manifestations of heart diseases that triggers malfunctioning of the cardiovascular system. Some of the major causal factors of cardiomyopathy includes myocardial ischemia, drug-toxicity, genetic aberrations, abnormal depositions of essential elements, and redox imbalance. Diabetes, being the major comorbid of cardiovascular diseases and vice versa, further contributes to the progression of cardiomyopathy. The molecular mechanisms of action suggest that oxidative stress is among the primary factors that triggers cascading impact on cardiomyopathy. Resveratrol, a phenolic antioxidant, has the potential to quench the excessive free radicals. It is a potent antioxidant supplement that may as well be a therapeutic molecule. The review focuses on the various molecular mechanisms of action that resveratrol potentiates in reversing or attenuating the progress of diabetic and non-diabetic cardiomyopathy triggered by wide range of factors. Additionally, resveratrol also tends to preserve the healthy heart from potential damage that may be triggered by oxidative stress.

Enhanced drug retention, sustained release, and anti-cancer potential of curcumin and indole-curcumin analog-loaded polysorbate 80-stabilizied PLGA nanoparticles in colon cancer cell line SW480.

The major therapeutic limitation of curcumin and indole-incorporated curcumin analog is its low bioavailability. We hypothesized that nano-encapsulation of indole-incorporated curcumin analog and curcumin as a biodegradable polymeric nanoparticle may enhance its bioavailability with extended drug retention time. Indole-incorporated curcumin analog and curcumin loaded PLGA nanoparticles were synthesized by solvent evaporation technique. Physicochemical characterizations and anti-cancer potential of the nanoparticles were evaluated in human colon cancer cell line SW480. The synthesized NPs had a size range of 50-150 nm diameter. The nano-formulation preserved the drug from degradation in wide ranges of pH environments. The nanoparticles treatment against SW480 cancer cell line triggered nuclear fragmentation, cell cycle blockade, inhibition of apoptosis and metastatic biomarkers. These drug-loaded nanoparticles may be potent nano-formulations against colon cancer because of its ability to tolerate extreme pH environments, thus having potential of oral drug-delivery.

Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of action.

Resveratrol is an important phenolic phytochemical from the therapeutic perspective. It has therapeutic impacts over wide range of diseases, especially the ones related to oxidative stress. Resveratrol, being primarily a potent anti-oxidant phytochemical, has significant impact against major diseases as inflammatory disorders, diabetes, and cancer. In the current review article, we intend to highlight the molecular aspects of the mechanism of action of resveratrol against major diabetic implications, namely, retinopathy and neuropathy. Both these diabetic implications are among the first fallouts of chronic hyperglycaemia. Resveratrol, via multiple molecular pathways, tend to attenuate and reverse these deformity and other disease-causing implications.

Current status of G-protein coupled receptors as potential targets against type 2 diabetes mellitus.

GPCRs are among the most abundant surface receptors that play diverse roles including cell signalling and molecular transportation. They are major therapeutic receptor targets against various diseases like cancer and diabetes. A number of new GPCRs are being consistently being identified and deorphanised. Among them, some GPCRs are constitutively expressed while others are down-regulated. New therapeutic agents in the form of small molecule, synthetic peptides, and recombinant nucleic acids and proteins act as antagonists and agonists against various GPCR targets that potentially regulate glucose homeostasis. In the current review, we intend to summarize the various categories of GPCRs. At the same time, we intend to highlight the major GPCRs that have been targeted by various pharmaceutical companies against diabetes mellitus. In addition, we intended to summarize the most recently identified orphan GPCRs and their therapeutic potential against diabetes.

Stabilizers influence drug-polymer interactions and physicochemical properties of disulfiram-loaded poly-lactide-co-glycolide nanoparticles.

AIM: Stabilizers are known to be an integral component of polymeric nanostructures. Ideally, they manipulate physicochemical properties of nanoparticles. Based on this hypothesis, we demonstrated that disulfiram (drug) and Poly-lactide-co-glycolide (polymer) interactions and physicochemical properties of their nanoparticles formulations are significantly influenced by the choice of stabilizers. METHODOLOGY: Electron microscopy, differential scanning calorimetry, x-ray diffraction, Raman spectrum analysis, isothermal titration calorimetry and in silico docking studies were performed. RESULTS & DISCUSSION: Polysorbate 80 imparted highest crystallinity while Triton-X 100 imparted highest rigidity, possibly influencing drug bioavailability, blood-retention time, cellular uptake and sustained drug release. All the molecular interactions were hydrophobic in nature and entropy driven. Therefore, polymeric nanoparticles may be critically manipulated to streamline the passive targeting of drug-loaded nanoparticles.

Inhibition of metastasis and angiogenesis in Hep-2 cells by wheatgrass extract - an in vitro and in silico approach.

Metastasis is the major hindrance in the treatment of all cancers, including laryngeal squamous cell carcinoma. Intensive researches are under way to identify the effective natural polyphenols with anti-metastatic ability for cancer treatment. Wheatgrass, an herbal plant has been reported to show anticancer effects. Hence, in this study, we aimed to analyze the anti-metastatic effect of methanol extract of wheatgrass (MEWG). The levels of metastatic marker proteins were determined by western blot. PI3K and AKT levels were determined by real time (RT)-PCR analysis. In silico molecular docking was done to check the interaction of the 14 components (identified by HPLC/GCMS) of MEWG with PI3K and AKT. MEWG effectively decreased the metastatic protein expressions, namely VEGF, MMP-9 and COX-2 and increased TIMP-2. RT-PCR results showed reduced m-RNA levels of both PI3K and AKT when compared to control. Molecular docking studies revealed interaction of most of the identified compounds of the extract with the important residues of PI3K and AKT. These findings indicate that MEWG inhibits metastasis and angiogenesis in Hep-2 cells possibly via PI3K/AKT due to the cumulative effect of polyphenols and other constituent present in extract. The compounds of the extract were also found to be directly involved in inhibition of AKT/PI3K, thus could help to restrain metastasis.

Anti-proliferative and apoptosis-triggering potential of disulfiram and disulfiram-loaded polysorbate 80-stabilized PLGA nanoparticles on hepatocellular carcinoma Hep3B cell line.

There is an emerging trend to restudy known drugs for their anti-cancer potential. One such anti-alcoholic drug, disulfiram, with significant anti-cancer potential was studied for its efficacy against Hep3B cell lines, an in vitro model of hepatocellular carcinoma. Simultaneously, we intended to study the effect of polysorbate 80-stabilized PLGA nanoparticles and its DSF-loaded counterpart. Cell and nuclear staining, comet assay, flow cytometry and Western blots were performed. Results suggest that cell proliferation was inhibited by DSF and its PLGA nanoparticles through cell cycle arrest, triggering activation of apoptotic pathways that culminates with cell death. DSF loaded nanoparticles when compared with free DSF, showed significantly lesser effect due to its sustained drug-releasing property, while empty nanoparticles showed negligible influence on Hep3B cells. Our results suggest that DSF alone contributes to cell death, while polysorbate 80-stabilized PLGA nanoparticles show sustained drug release patterns that would potentially lower dosage regimens.

Influence of stabilizers on the production of disulfiram-loaded poly(lactic-co-glycolic acid) nanoparticles and their anticancer potential.

AIM: Our hypothesis was to prove that surface modifiers themselves can be used as stabilizers and that their entrapment efficiency is directly influenced by the type of stabilizers used. MATERIALS & METHODS: Particle size and the polydispersity index of the nanoparticles (NPs) were measured by dynamic light scattering, whereas the morphology of the NPs was studied by scanning electron microscopy. Percentage nanoparticle yield, entrapment efficiency and drug loading capacity were measured by ultraviolet absorbance. The physical rigidity, robustness and drug releasing capability of these NPs were also assessed. CONCLUSION: Physiochemical characterization and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay suggest that polysorbate 80 has the dual capability of being a stabilizer and a surface modifier in addition to having better drug entrapment properties than Pluronic® 188. Disulfiram, the drug that was loaded on these NPs, is also observed for the first time to show significant anticancer potential against hepatocellular carcinoma (Hep3B) cell lines.

Phytochemical screening and analysis of antioxidant properties of aqueous extract of wheatgrass.

OBJECTIVE: To screen the phytochemical constituents and study antioxidant properties of the aqueous extract of the wheatgrass. METHODS: The current study was focused on broad parameters namely, phytochemical analysis, gas chromatography-mass spectrometry analysis and antioxidant properties in order to characterize the aqueous extract of wheatgrass as a potential free radical quencher. RESULTS: The phytochemical screening of the aqueous extract of wheatgrass showed the presence of various secondary metabolites but the absence of sterols and quinone in general. Wheatgrass was proved to be an effective radical scavenger in all antioxidant assays. The gas chromatography-mass spectrometry analysis confirmed the presence of diverse category of bioactive compounds such as squalene, caryophyllene and amyrins in varying percentage. CONCLUSIONS: From the results obtained, we conclude that wheatgrass aqueous extract contains various effective compounds. It is a potential source of natural antioxidants. Further analysis of this herb will help in finding new effective compounds which can be of potent use in pharmacological field.

Hepatoprotective role of kaempferol during alcohol- and ΔPUFA-induced oxidative stress.

BACKGROUND: The present study aimed to analyze the effect of kaempferol on oxidative stress induced by alcohol and thermally oxidized polyunsaturated fatty acid (ΔPUFA) in male albino Wistar rats. METHODS: The rats were divided into four groups. The animals in group 1 served as the normal group (standard diet), group 2 served as the hepatotoxic group (alcohol+ΔPUFA), group 3 served as the treated group (alcohol+ΔPUFA+kaempferol), and group 4 served as kaempferol control. The levels of marker enzyme γ-glutamyl transferase (GGT), lipid peroxidation markers [thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides (LH)], enzymatic antioxidants (catalase, superoxide dismutase, and glutathione peroxidase), and nonenzymatic antioxidants (reduced glutathione, vitamin E, and vitamin C) were analyzed in liver to evaluate the effects of kaempferol. RESULTS: The levels of GGT, TBARS, and LH were significantly increased in liver of the alcohol+ΔPUFA group and were found to be reduced on treatment with kaempferol. The levels of both enzymatic and nonenzymatic antioxidants were decreased in liver of the alcohol+ΔPUFA group and were found to be restored on treatment with kaempferol. CONCLUSIONS: From the results obtained, we conclude that kaempferol protects the liver against alcohol- and ΔPUFA- induced oxidative stress.