Role of Macrophage PIST Protein in Regulating Leishmania major Infection.

PDZ protein interacting specifically with Tc10 or PIST is a mammalian trans-Golgi resident protein that regulates subcellular sorting of plasma membrane receptors. PIST has recently emerged as a key player in regulating viral pathogenesis. Nevertheless, the involvement of PIST in parasitic infections remains unexplored. Leishmania parasites infiltrate their host macrophage cells through phagocytosis, where they subsequently multiply within the parasitophorous vacuole (PV). Host cell autophagy has been found to be important in regulating this parasite infection. Since PIST plays a pivotal role in triggering autophagy through the Beclin 1-PI3KC3 pathway, it becomes interesting to identify the status of PIST during Leishmania infection. We found that while macrophage cells are infected with Leishmania major (L. major), the expression of PIST protein remains unaltered; however, it traffics from the Golgi compartment to PV. Further, we identified that in L. major-infected macrophage cells, PIST associates with the autophagy regulatory protein Beclin 1 within the PVs; however, PIST does not interact with LC3. Reduction in PIST protein through siRNA silencing significantly increased parasite burden, whereas overexpression of PIST in macrophages restricted L. major infectivity. Together, our study reports that the macrophage PIST protein is essential in regulating L. major infectivity.

Finding the Ajoene Sweet-Spot: Structure-Activity Relations that Govern its Blood Stability and Cancer Cytotoxicity.

Ajoene is an organosulfur compound found in crushed garlic that exerts its anti-cancer activity by S-thiolating cysteine residues on proteins. Its development is hampered due to limited bioavailability, so in this study, we synthesised analogues of ajoene to probe the significance of the ajoene vinyl disulfide/sulfoxide core with respect to cytotoxicity and blood stability. Polar side groups were also incorporated to improve aqueous solubility. It was found that derivatives containing a vinyl disulfide functional group (4-7, as in ajoene), were more cytotoxic compared to analogues in which the double bond was removed, although the latter showed superior blood stability. It was also found that the allyl-S sulfur of the disulfide was more electrophilic to S-thiolysis based on the global electrophilicity index (ω) and the condensed electrophilic Fukui function f k + ${{ f}_{\rm{k}}^{\rm{ + }} }$ . S-Thiolysis was found to be exergonic for the vinyl disulfides based on entropy and enthalpy computations with a deprotonated thiolate. Derivatisation to the dihydro (10, 12) and deoxydihydroajoenes (9, 11) produced analogues that were slightly less potent but with greatly improved blood stability. Taken together, the deoxydihydroajoenes present themselves as good candidates for further therapeutic development.

Main-Chain Cationic Polyelectrolytes: Design, Synthesis, and Applications.

Polyelectrolytes have attracted a lot of attention spanning across disciplines, including polymer chemistry, materials chemistry, chemical biology, chemical engineering, as well as device physics, as a result of their widespread applications in sensing, biomedicine, food industry, wastewater treatment, optoelectronic devices, and renewable energy. In this review, we focus on the crucial synthetic strategies of structurally different classes of main-chain cationic polyelectrolytes. As a result of the presence of charged moieties in the main polymeric backbone, their solubility and photophysical properties can be easily tuned. Main-chain cationic polyelectrolytes provide various unique characteristics, including solubility in aqueous and organic solvents, easy processability, ease of film formation, ionic interaction, main-chain-directed charge transport, high conductivity, and aggregation. These properties make the main-chain polyelectrolyte a potential candidate for numerous applications ranging from chemo- and biosensing, antibacterial activity, optoelectronics, electrocatalysis, water splitting, ion conduction, to dye-sensitized solar cells.

Kaempferol 3-O-rutinoside from Antidesma acidum Retz. Stimulates glucose uptake through SIRT1 induction followed by GLUT4 translocation in skeletal muscle L6 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Antidesma acidum Retz, a perennial herb is known for its anti-diabetic potential among the traditional health care providers of the tribal communities of Manipur, India. Scientific validation of the ancient knowledge on traditional use of this plant with the help of modern tools and techniques can promote further research and its use in health care. AIM OF THE STUDY: Type 2 Diabetes (T2D) is a complex metabolic disorder and linked with hyperglycemia occurring from insufficiency in insulin secretion, action, or both. The aim of this study was to scientifically validate the traditional myth behind the uses of this plant material against diabetes. More specifically, it was aimed to determine the effect of methanolic extract of A. acidum leaves and/or any of its bioactive phytochemical(s), in enhancing insulin sensitization and subsequently stimulating the insulin signaling cascade of glucose metabolism. MATERIALS AND METHODS: Methanol was used for extraction from the leaf powder of A. acidum followed by bioactivity guided fractionation and isolation of most active component. Biological evaluation was performed to determine the glucose uptake ability against insulin resistance in skeletal muscle (L6) cells. To understand the detailed mechanism of actions of the purified compound, several molecular biology and structural biology experiments such as Western blot, siRNA transfection assay and molecular docking study were performed. RESULTS AND DISCUSSION: Bioactivity guided isolation of pure compound and spectral data analysis led us to identify the active component as Kaempferol 3-O-rutinoside (KOR) for the first time from the leaf of A. acidum. Over expression of NAD-dependent histone deacetylase, Sirtuin 1 (SIRT1) was observed following KOR treatment. SIRT1 plays an important role in the metabolic pathway and over expression of SIRT implies that it involves in insulin signaling directly or indirectly. Molecular docking and simulation study showed the strong involvement between KOR and SIRT1.Treatment with KOR resulted in significant over expression of SIRT1followed by upregulation of insulin-dependent p-IRS, AKT and AMPK signaling molecules, and stimulation of the GLUT4 translocation, which ultimately enhanced the glucose uptake in sodium palmitate-treated insulin resistant L6 myotubes. Further, the effect of KOR on IRS1, AKT and AMPK phosphorylation, GLUT4 translocation, and glucose uptake was attenuated in SIRT1-knockdown myotubes. CONCLUSION: Overall, the results of this study suggest that Kaempferol 3-O-rutinoside is the active component presents in the leaf of A. acidum which increases glucose consumption by inducing SIRT1 activation and consequently improves insulin sensitization. These results may find future applications in drug discovery research against T2DM.

Triphenylamine-anthraquinone based donor-acceptor conjugated microporous polymers for photocatalytic hydroxylation of phenylboronic acids.

Triphenylamine-based donor-acceptor conjugated microporous polymers, namely PTPA-AQ and PTPA-AM, were synthesized for the first time via Suzuki-Miyaura coupling of tris(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-amine as a donor with 2,6-dibromoanthracene-9,10-dione and 2,2'-(2,6-dibromoanthracene-9,10-diylidene)dimalononitrile acceptors for efficient visible-light driven oxidative hydroxylation of various phenylboronic acids. The dimalononitrile derivative having greater acceptor ability showed tunable photophysical properties of PTPA-AM (lower band gap of 1.47 eV and better exciton separation efficiency) as well as porosity (lower Brunauer-Emmett-Teller (BET) surface area of 43 m2 g-1). PTPA-AQ having higher BET surface area (400 m2 g-1), suitable HOMO-LUMO positions and an optimal band gap (1.94 eV) showed better photocatalytic activity for the hydroxylation with yields up to 96%.

Chemical composite of indigenous whole grain scented joha rice varietal prevents type 2 diabetes in rats through ameliorating insulin sensitization by the IRS-1/AKT/PI3K signalling cascade.

Preventive measures to lower the prevalence of type-2 diabetes development using dietary phytochemicals are most realistic. A phytochemical composite derived from whole grain scented joha rice (PCKJ), which is indigenous to the North-eastern Region, India, was investigated to understand its preventive efficacy in rats in which type 2 diabetes was induced using a high-fat high-fructose (HFHF) diet and a low dose of streptozotocin, and the findings were correlated with those in L6-myotubes. Studies on cultured L6 myotubes revealed that treatment with PCKJ facilitated glucose uptake and GLUT-4 translocation to the plasma membrane, as evidenced by confocal microscopy and/or cell fractionation studies. Furthermore, the FFA-induced L6 myotubes were identified as having elevated levels of PI3K, p-AKT (Ser473) and GLUT-4, which returned to the basal level upon exposure to PCKJ. The administration of PCKJ (100 mg per kg body weight, oral gavage, 24 weeks) to rats significantly reduced their blood glucose levels along with common lipid and liver biomarkers (LDL, triglycerides, cholesterol, ALT, and AST) compared to the control group. Moreover, immunoblotting analysis showed that upon PCKJ treatment, PI3K, p-AKT and GLUT-4 levels are upregulated in the skeletal tissue of HFHF-fed rats, similar to the in vitro model. The alteration in the levels of inflammatory cytokines IL-6, IL-10 and IFN-γ in diabetic rats returned to normal levels upon exposure to PCKJ. Histological analysis of vital tissues further strengthens the findings of the preventive value of PCKJ against the development of insulin resistance. In conclusion, this study showed the prophylactic effect of PCKJ as a potent chemical composite, which can be used to develop functional foods (nutraceuticals) for ameliorating type-2 diabetes by improving insulin sensitization and thereby glucose metabolism.

Machine Learning approach to Predict net radiation over crop surfaces from global solar radiation and canopy temperature data.

As the ground-based instruments for measuring net radiation are costly and need to be handled skillfully, the net radiation data at spatial and temporal scales over Indian subcontinent are scanty. Sometimes, it is necessary to use other meteorological parameters to estimate the value of net radiation, although the prediction may vary based on season, ground cover and estimation method. In this context, artificial intelligence can be used as a powerful tool for predicting the data considering past observed data. This paper proposes a novel method to predict the net radiation for five crop surfaces using global solar radiation and canopy temperature. This contribution includes the generation of real-time data for five crops grown in West Bengal state of India. After manual analysis and data preprocessing, data normalization has been done before applying machine learning approaches for training a robust model. We have presented the comparison in various machine learning algorithm such as ridge and spline regression, random forest, ensemble and deep neural networks. The result shows that the gradient boosting regression and ridge regression are outperforming other ML approaches. The estimated predictors enable to reduce the number of resources in terms of time, cost and manpower for proper net radiation estimation. Thus, the problem of predicting net radiation over various crop surfaces can be sorted out through ML algorithm.

Phosphate based new organic polymer networks for efficient dye sorption and catalyst loading for chemo-selective reactivity.

Phosphate based organic polymer networks (OPNs) have been synthesized for the first time for dye sorption and heterogeneous catalysis. The OPNs were sythesized by the polycondensation of POCl3 with di- and tri-hydroxy organic linkers e.g., quinol, 4,4'-biphenol, phloroglucinol and 1,3,5-(4-hydroxyphenyl)benzene. These show remarkably selective adsorption of cationic dyes methylene blue and propidium iodide via the electrostatic interaction of the polymers with the dyes. These OPNs also allow the in situ synthesis and stabilization of gold nanoparticles within the polymer networks which demonstrate effective heterogeneous, catalytic reduction of the aromatic nitro to amino group.

Pharmacologically active chemical composite of Musa balbisiana ameliorates oxidative stress, mitochondrial cellular respiration, and thereby metabolic dysfunction.

The ripe fruit pulp of different Musa species is known for its excellent source of nutrient contents. Musa balbisiana (MB) is one such variety of Musa species, mainly found in the southern part of Asia, especially in the North-eastern part of India, remains unexplored despite its continuous use by the local traditional healers. The present study focuses on identifying and quantifying the active chemicals present in the ripe fruit pulp of Musa balbisiana (RFPMB) to understand its combined efficacy and nutritional benefit to control human metabolic complications specially related to diabetes and cardiovascular disorder. Characterization and confirmation through targeted LC-MS and HPLC-PDA based assays followed by quantitative analysis led us to identify the major bioactive compounds in RFPMB as shikimic acid, p-hydroxybenzoic acid, vanillic acid, ferulic acid, sinapic acid, caffeic acid, syringic acid, chlorogenic acid, trans-cinnamic acid, and two essential fatty acids; linolenic acid and linoleic acid. The ripe fruit pulp is further analyzed to understand the nutritional and mineral content and found a substantial presence of calcium and potassium (15.74 ± 0.43 and 395.20 ± 9.5 mg/100 g of raw pulp, respectively) compared to other reported varieties. The active portion of RFPMB reduces the production of ROS, the expression of inflammatory marker genes TNF-α and TGF-ß, and accelerates the mitochondrial oxygen consumption rate (OCR) by enhancing the basal respiration, maximal respiration, and ATP production capacity of the targeted cells. The present study concluded that, a particular phytopharmaceutical composition of RFPMB with 11-biomarker compounds might be an efficacious formulation for developing a value-added nutraceutical product in managing metabolic complications and its related oxidative stress. PRACTICAL APPLICATIONS: This study has provided the prior information regarding the potential nutraceutical and phytochemical advantages of Musa balbisiana (MB) fruit pulp over other reported banana varieties. The HPLC-based quantification will give a clear understanding of the food values in comparison of bioactive compounds present in the active fraction of RFPMB, which can be an effective phytopharmaceutical in combating metabolic disorders and oxidative stress. Overall this study will help to commercialize a value-added product from this variety of banana with proper scientific validation.

Dietary phytochemicals/nutrients as promising protector of breast cancer development: a comprehensive analysis.

Genetic change, particularly epigenetic alteration, is one of the imperative factors for sporadic breast cancer development in the worldwide population of women. The DNA methylation process is essential and natural for human cellular renewal and tissue homeostasis, but its dysregulation contributes to many pathological changes, including breast tumorigenesis. Chemopreventive agents mainly protect the abnormal DNA methylation either by hindering the division of pre-malignant cells or looming the DNA damage, which leads to malignancy. The present review article is about understanding the potential role of dietary phytochemicals in breast cancer prevention. Accordingly, a literature search of the published article until August 2021 has been performed. Further, we have investigated the binding affinity of different phytochemicals isolated from diverse dietary sources against the various oncogenic proteins related to breast cancer initiation to understand the common target(s) in breast cancer prevention mechanisms. Various small phytochemicals, especially dietary phytochemicals including sulforaphane, mahanine, resveratrol, linolenic acid, diallyl sulfide, benzyl/phenethyl isothiocyanate, etc. are being investigated as the chemopreventive agent to manage breast cancer development, and some of them have shown promising outcomes in the cited research. In this present review, we discuss the recent advancement in acceptance of such types of potential dietary phytochemicals as a chemopreventive agent against breast cancer development and their inner lining mechanism. The critical clinical trials and cohort studies have also been considered to understand the progress in contemporary perspectives.

Astragalin mediates the pharmacological effects of Lysimachia candida Lindl on adipogenesis via downregulating PPARG and FKBP51 signaling cascade.

Metabolic disturbances in different tissue cells and obesity are caused by excessive calorie intake, and medicinal plants are potential sources of phytochemicals for combating these health problems. This study investigated the role of methanolic extract of the folklore medicinal plant Lysimachia candida (LCM) and its phytochemical, astragalin, in managing obesity in vivo and in vitro. Administration of LCM (200 mg/kg/body weight) daily for 140 days significantly decreased both the body weight gain (15.66%) and blood triglyceride and free fatty acid levels in high-fat-diet-fed male Wistar rats but caused no substantial change in leptin and adiponectin levels. The protein expression of adipogenic transcription factors in visceral adipose tissue was significantly reduced. Further, the 3T3-L1 cell-based assay revealed that the butanol fraction of LCM and its isolated compound, astragalin, exhibited antiadipogenic activity through downregulating adipogenic transcription factors and regulatory proteins. Molecular docking studies were performed to depict the possible binding patterns of astragalin to adipogenesis proteins. Overall, we show the potential antiobesity effects of L. candida and its bioactive compound, astragalin, and suggest clinical studies with LCM and astragalin.

Evaluation of therapeutic effect of Premna herbacea in diabetic rat and isoverbascoside against insulin resistance in L6 muscle cells through bioenergetics and stimulation of JNK and AKT/mTOR signaling cascade.

BACKGROUND: Premna herbacea Roxb., a perennial herb is well documented for its therapeutic uses among the traditional health care-givers of Assam, India. Scientific validation on the traditional use of the medicinal plant using modern technology may promote further research in health care. PURPOSE: This study evaluates the therapeutic potential of methanolic extract of P. herbacea (MEPH) against type 2 diabetes mellitus (T2DM) and its phytochemical(s) in ameliorating insulin resistance (IR), thereby endorsing the plant bioactives as effective anti-hyperglycemic agents. METHODS: The anti-diabetic potential of the plant extract was explored both in L6 muscle cells and high fructose high fat diet (HF-HFD) fed male Sprague Dawley (SD) rats. Bioactivity guided fractionation and isolation procedure yielded Verbascoside and Isoverbascoside (ISOVER) as bioactive and major phytochemicals in P. herbacea. The bioenergetics profile of bioactive ISOVER and its anti-hyperglycemic potential was validated in vitro by XFe24 analyzer, glucose uptake assay and intracellular ROS generation by flourometer, FACS and confocal microscopy. The potential of ISOVER was also checked by screening various protein markers via immunoblotting. RESULTS: MEPH enhanced glucose uptake in FFA-induced insulin resistant (IR) L6 muscle cells and decreased elevated blood glucose levels in HF-HFD fed rats. Isoverbascoside (ISOVER) was identified as most bioactive phytochemical for the first time from the plant in the Premna genus. ISOVER activated the protein kinase B/AMP-activated protein kinase signaling cascades and enhanced glucose uptake in IR-L6 muscle cells. ISOVER decreased the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) and increased that of mammalian target of rapamycin (mTOR), thereby attenuating IR. However, molecular docking revealed that ISOVER increases insulin sensitivity by targeting the JNK1 kinase as a competitive inhibitor rather than mTOR. These findings were further supported by the bioenergetics profile of ISOVER. CONCLUSION: This study for the first time depicts the functional properties of ISOVER, derived from Premna herbacea, in ameliorating IR. The phytochemical significantly altered IR with enhanced glucose uptake and inhibition of ROS through JNK-AKT/mTOR signaling which may pave the way for further research in T2DM therapeutics.

Arsenic contamination, impact and mitigation strategies in rice agro-environment: An inclusive insight.

Arsenic (As) contamination and its adverse consequences on rice agroecosystem are well known. Rice has the credit to feed more than 50% of the world population but concurrently, rice accumulates a substantial amount of As, thereby compromising food security. The gravity of the situation lays in the fact that the population in theAs uncontaminated areas may be accidentally exposed to toxic levels of As from rice consumption. In this review, we are trying to summarize the documents on the impact of As contamination and phytotoxicity in past two decades. The unique feature of this attempt is wide spectrum coverages of topics, and that makes it truly an interdisciplinary review. Aprat from the behaviour of As in rice field soil, we have documented the cellular and molecular response of rice plant upon exposure to As. The potential of various mitigation strategies with particular emphasis on using biochar, seed priming technology, irrigation management, transgenic variety development and other agronomic methods have been critically explored. The review attempts to give a comprehensive and multidiciplinary insight into the behaviour of As in Paddy -Water - Soil - Plate prospective from molecular to post-harvest phase. From the comprehensive literature review, we may conclude that considerable emphasis on rice grain, nutritional and anti-nutritional components, and grain quality traits under arsenic stress condition is yet to be given. Besides these, some emerging mitigation options like seed priming technology, adoption of nanotechnological strategies, applications of biochar should be fortified in large scale without interfering with the proper use of biodiversity.

Effect of multiple doses of N-methyl-N-nitrosourea, an end product of methylguanidine (found in processed food), on the fertility of female Swiss albino mice.

Methylguanidine, an originator of carcinogenic methylnitrosourea, has been found in many animal meats and processed stored food often in high concentration. The present study was designed to understand the multiple dose effect of N-methyl-N-nitrosourea (MNU), an end product of methylguanidine, in Swiss albino mice fertility as well as cancer induction. Accordingly, a total of five experimental groups of animal (female Swiss albino mice) were taken, considering group-I as vehicle control and group-II-V as treatment groups (whereas group-II-Vwere treated with single to quadruple doses of 50 mg/kg of MNU respectively in a three weeks interval). After accomplishment of MNU injection, each female mice was mated with male mice to check the fertility efficiency. The results of the study indicated that, mice treated with highest number of MNU doses were 42.85% less efficient in getting pregnant than the control mice. There were noted changes in body weight, food and water intake upon MNU-exposure compared to control group. A significant increase in cumulative weight of vital female organs like uterus and ovary were also observed in mice injected with quadruple doses of MNU (50 mg/kg) compared to control mice. The findings of the study suggest the direct effect of MNU in pregnancy, without any cancer incidence in the vital female organs of Swiss albino mice.

Variation in biosynthesis of an effective anticancer secondary metabolite, mahanine in Murraya koenigii, conditional on soil physicochemistry and weather suitability.

Murraya koenigii (MK) leaf being a rich source of bioactive secondary metabolites has received inordinate attention in drug development research. Formation of secondary plant metabolite(s) in medicinal plants depends on several factors and in this study the cause of variation in bioavailability and content of a vital bioactive phytochemical, mahanine in the MK leaves from different geographical locations of varying soil properties and weather parameters was determined. Accordingly, MK leaves and soil samples around the plant base in quintuplicate from each site across five states of India at similar time point were collected. Mahanine content was determined and compared among samples from different regions. The quantitative analysis data comprised that MK-leaves of southern part of India contains highest amount of mahanine, which is 16.9 times higher than that of MK-leaves of north-eastern part of India (which measured as the lowest). The results suggested that pH, conductivity and bacterial populations of the soil samples were positively correlated with mahanine content in the MK-leaves. For examples, the average soil pH of the southern India sites was in basic range (8.8 ± 0.6); whereas that of the north-east India sites was in slightly acidic ranges (6.1 ± 0.5) and mean soil conductivity value for the north east India soils was 78.3 ± 16.3 µS/cm against mean value of 432.4 ± 204.5 µs/cm for south India soils. In conclusion, this study proclaims that higher level of bioactive phytochemical, mahanine in MK leaves depending upon geographical location, weather suitability and soil's physiochemical and microbial parameters of its cultivation sites.

Assessment of nutritional value and quantitative analysis of bioactive phytochemicals through targeted LC-MS/MS method in selected scented and pigmented rice varietals.

Scented (joha) and black rice indigenous to northeast region (NER) of India are the two among 40,000 varieties of species Oryza sativa, prevalent for its great aroma, medicinal property, and/or equally noteworthy taste. Biochemical and target-based liquid chromatography mass spectrometry (LCMS) analysis was performed to identify and quantify the different phytonutrients from the selected rice grains of those two varieties. Biochemical assay revealed that the selected black rice (Chakhao Amubi) contains ∼1.8-fold higher amount of total phenolic and ∼2.3-fold higher amount of total flavonoid than the scented rice grain (Kon joha). The total starch content was significantly lower in scented rice in comparison to black rice grain. The health beneficial ratio of ω-6/ω-3 essential unsaturated fatty acid is notably better in scented rice grain than black rice grain. The targeted LC-MS/MS analysis confirms the presence of oryzanol and ferulic acid in both the samples. The presence of 4-hydroxy benzoic acid, apigenin, tricin, avenasterol, coumarin, coumaric acid, phenyl alanine, caffeic acid, and α-tocophenol were confirmed in the scented rice, whereas the black rice confirms the presence of protocatechuic acid and dehydroxy myricetin. Further the quantitative analysis showed that the lipids lysophosphatidylinositol (LPI) 16:0, lysophosphatidyl ethanolamine (LPE) 14:0, lysophosphatidyl choline (LPC) 18:2, LPE 18:2, phosphatidyl etanolamine (PE), along with oryzanol, hydroxy docosanoic acid are at least threefold higher in scented rice varietal; whereas, in Chakhao Amubi, the content of petunidin galactoside, LMMPE18:2, PC14:0 are higher than the scented rice grain. In conclusion, different phytonutrients including phenol, polyphenol, and flavonoid have been identified as bioactive phytochemicals in selected rice varietals. PRACTICAL APPLICATION: This work will provide the information about the nutritional benefit of studied rice varietals. The used targeted LC-MS/MS analysis will provide the one-step information about the bioactive phytochemicals. Overall, this study will help to commercialize those varieties with proper scientific evidences.