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Alteration of gut microflora results in a metabolic imbalance in the liver. In the present study, we investigate the reversal potential of alteration of the colonic microflora via improving metabolism balance and regulating the altered tight junction of the intestinal tract. Animals were fed with high sugar diet to mimic the onset of the pathophysiological conditions of diabetes. Following induction, animals were divided into two reversal groups i.e., crude cefdinir and colon-specific formulated cefdinir, to alter the gut microflora. In the present study, we have tried to quantify the microbial content via metagenome analysis to provide an actual picture of the alteration and subsequent reversal. Expression of mRNA of junctional protein and parameters involved in liver metabolism was determined using qPCR. Results indicated direct effect of altered composition of gut microflora on the gut permeability and metabolic alteration. Metagenomic analysis showed least evenness and richness in the HSD group whereas antibiotic-treated groups showed reversal of microflora towards control group with increased richness, evenness and decreased distance on PCoA plot. This changes in gut microflora composition changes expression of metabolic markers and thus insulin sensitivity. Targeting colonic microflora to have a reversal effect on T2D pathogenesis, found to have a positive impact on liver metabolic state with improved permeability markers of gut with SCFA alteration.The online version contains supplementary material available at 10.1007/s12088-022-01032-x.

The world is moving towards E-mobility solutions and Battery Electric Vehicles (BEVs) are the main enabler towards it. Li-ion cells are the fundamental building block of any BEVs. There are three common types of Li-ion cell design i.e., cylindrical cells, Prismatic Cells and Pouch cells. Ensuring safety of BEVs are critical to gain customer trust and acceptance over Internal Combustion Engine (ICE) vehicles. EV fire is found to be one of the major concerns related to using higher energy batteries. During a crash event, Post-Crash Electrical Integrity of the BEV is to be ensured and hence primary focus is on mitigation of Li-ion cell internal short circuit. It has been seen in prior published articles that cell internal short circuit can be triggered by physical intrusion of cell. This paper primarily focusses on simulating the mechanical behavior of cylindrical cell under various crush conditions. In this paper, we will discuss about the trade-off between Computer Aided Engineering (CAE) model fidelity of cylindrical Li-ion cell & usage of such models in full vehicle crash simulations in LS-DYNA®. Proposed method for Cell CAE model is validated against 3 different crush tests conducted. This approach has shown acceptable accuracy for crushability in all 3 test conditions with reduced modeling complexity when compared with prior published work. Proposed Cell CAE model is found to be compatible in use with full vehicle level crash simulations, thus helps in predicting Li-ion cell intrusion accurately during crash simulations of BEVs.

Battery Electric Vehicles (BEVs) are becoming more competitive day by day to achieve maximum peak power and energy requirement. This poses challenges to the design of Thermal Interface Material (TIM) which maintains the cell temperature and ensure retention of cell and prevent electrolyte leak under different crash loads. TIM can be in the form of adhesives, gels, gap fillers. In this paper, TIM is considered as structural, and requires design balance with respect to thermal and mechanical requirements. Improving structural strength of TIM will have negative impact on its thermal conductivity; hence due care needs to be taken to determine optimal strength that meets both structural and thermal performance. During various crash conditions, due to large inertial force of cell and module assembly, TIM is undertaking significant loads on tensile and shear directions. LS-DYNA® is used as simulation solver for performing crash loading conditions and evaluate structural integrity of TIM. Prior literature discuss usage of MAT138 (Cohesive mixed mode), MAT169 (Arup adhesive) for modeling TIM adhesive failure. To generate such material models, there is extensive coupon level testing needs to be performed. In early development of battery module design, such sophisticated failure models are not feasible to implement. To overcome this challenge, TIE BREAK contacts in LS-DYNA® are leveraged to define interface failure for quick turnaround. TIE BREAK is penalty-based contact definition which allows to model both tensile and compressive forces until failure on adhesive/glue. Variation studies could be performed in short time for designing the required TIM strength before generating detailed material models. Various techniques available in TIE BREAK contacts such as failure initiation (force based/stress based), shell offset and critical parameters are iterated to arrive at more appropriate modeling considerations. In this paper, contact-based failure is compared with various material-based failure models to gain confidence and simplify design iterations for selection of appropriate TIM.

An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150-200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV-vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The

With a rapid increase in the global human population in recent years, the Earth is in dire need of alternative energy sources. The objective of this paper is to assess the feasibility of implementing piezoelectricity as a primary source of renewable energy. Specifically, this paper looks at its consequent impact if introduced in 3 fundamental areas of implementation: bus tires, train tracks and railway stations. Each of these areas provide input elements at scale to generate electricity and are simple to implement, maintain and measure through government support. This paper limits the data to the city of Cairo, Egypt. Being low cost as well, the three areas come close to an ideal situation from an economic standpoint. Predictive algorithms and existing data are used to evaluate the consequent change in global green-house emissions and other environmental parameters, had piezoelectricity been previously implemented. The results of the equations show that there would be improved environmental conditions - thus, a net positive impact - that switching to piezoelectricity would have had on the atmosphere and environment. The predictions stay true, provided that the efficiency of the piezoelectric crystal remains constant- an outcome which serves to boost output and lower greenhouse emissions

Glioblastoma Multiforme is one of the most aggressive brain tumours with very poor prognosis, low progression free survival rates and overall survival rates. This is predominantly due to the difficulty in transporting drugs across the blood brain barrier. Therefore, the need for more efficacious treatments is increasing. This paper explains the pathophysiology behind how signal transduction pathways leading from faults in the EGFRvIII and the IDH gene lead to gliomagenesis. It moves on to highlight and contrast conventional therapies such as Surgical Resection, Chemotherapy, Bevacizumab and Radiotherapy with novel, alternative therapies such as oncolytic virotherapy, photodynamic therapy and tumour treatment fields. A literature review was also conducted, wherein methods and results - specifically, the phase of trial, number of patients, treatment modality, median progression free survival, median overall survival and general comments- of five past research studies were explicated and interpreted for each GBM alternative treatment modalities - Photodynamic therapy, oncolytic virotherapy and tumour treatment fields. Each of the 5 clinical trial studies for each alternative treatment yielded varied results: The mean mOS (median Overall Survival) and mPFS (median Progression Free Survival) of patients were 15.3 months and 7.5 months for OV, 18.4 months and 16 months for PDT, and 19.9 months and 6 months for TTF respectively. This paper intends to provide an insight into the future of Glioblastoma Multiforme treatment to further improve its diagnosis, prognosis and treatment.

Decontaminating water bodies has always been a problem in terms of developing and maintaining solutions. Our eutrophication solution is an organic island made of coconut husk(Cocos nucifera) and Indian Mustard(Brassica juncea) plants. It uses remediation techniques, such as phytoremediation and adsorption. Eutrophication primarily stems from human-induced causes such as poor sewage treatment and fertilizer overuse, which results in excess phosphate and nitrate ions accumulating in water bodies. This can have severe consequences, including algal bloom, and a reduction in aquaculture. Our investigation was done over a 21-day period, during which the concentration of phosphate ions was reduced, alleviating one factor that causes eutrophication. There were 3 tanks (A, B, and C): A contained the island and the plants, B contained only the island, and C was a control that contained neither. A Phosphate ion water testing kit was used to measure phosphate ion concentration in the sample contaminated water over a 21 day period. Each phosphate ion test produced a color of a different wavelength. Using a Vernier colorimeter, the percentage of transmittance was measured for each trial. Using the Beer-Lambert Law, the concentration values were obtained, which supported our hypothesis: A and B experienced a substantial increase in transmittance levels, whereas C experienced no change. The Pearson correlation test showed a positive correlation, hence phosphate ions were absorbed at a constant rate. Our solution also uses AI (Bellman equation) to analyze regions with the greatest phosphate ion concentration, where sensors and motors are present for maneuverability.

Plastic is handy as an industrial packaging material because it is mouldable, rigid yet flexible, durable, reusable, and cheaper than most alternatives, making it profitable to use. Although it has many advantages, its fair share of drawbacks, the most concerning being the amount of pollution it causes. Although plastics have been in use only since 1907, they have accumulated over time in astronomical quantities, destroying our environment. There are already some excellent sustainable packaging materials out on the market, but it still isn’t as mainstream as it needs to be to put a real dent into plastic pollution. Unless we can find ways to modify plastic to lessen its environmental impact, we must find sustainable packaging alternatives. Our project presents a novel solution to the pervasive plastic problem and sustainably looks into the issue. Our review showcases how materials such as seed extracts and natural binder extracts can be used to develop material that can serve as a potential replacement for the thermoplastic used presently.

Dietary patterns with excess caloric have shaped a complex metabolic disorders like type 2 diabetes (T2D). T2D involves complications in the metabolism of glucose, lipid, cholesterol and their storage. Along with the metabolic dysregulation, systemic inflammation is also the reason for Insulin Resistance and T2D. The importance of gut microbiota has recently been highlighted. It establishes a link between dietary patterns and the types of bacteria that overgrow and modify fermentation bi-products such as SCFA, secondary bile acids, and mucosal immune cells. These changes have a direct impact on the liver's metabolism and immune system. As a result, using Pre-Pro-biotics to manage microbiota can assist overcome or lessening disease symptoms. Antibiotics are currently employed to produce a germ-free environment or to eradicate specific types of bacteria in order to better understand the role of microflora. This chapter covers the basics of good bacteria, as well as the mechanisms that they work on.

Asafoetida resin has been reported for various biological activities but its use has been widely restricted owing to its pungent smell and pool water solubility. AIM In vitro study of the anticancer potential of microwave-extracted essential oil (EO) of Ferula asafoetida. MATERIALS AND METHODS The phytochemical investigation and in vitro cytotoxicity assessment was carried out in two human liver cancer cell lines. The expression of NFKB1, TGFB1, TNF, CASP3 was analyzed by reverse transcription polymerase chain reaction. RESULTS Ferula asafoetida EO contains high concentrations of dithiolane, which possess antiproliferative activity in human liver carcinoma cell lines (HepG2 and SK-Hep1) in a dose-dependent manner. The bioactive compounds in F. asafoetida are capable of induction of apoptosis and altered NF-kB and TGF-β signalling with increase in caspase-3 and TNF-α expression. CONCLUSION Further elucidation of bioactive molecules and underlying mechanisms could lead to potential intervention in liver cancer in animal models. The safety and efficacy as well as the mode of EO action in animal models would be highly crucial.

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma. Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model. Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity. Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity.

Background: Novel bioactive plant secondary metabolites, including flavonoids, offer a spectrum of chemo-protective responses against a range of human tumor models. However, the clinical translation of these promising anti-cancer agents has been hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Objective: To circumvent the challenges associated with herbal drug development and for effective integration into clinical setting, nano-engineering is one of the emerging pragmatic strategies which has promise to deliver therapeutic concentrations of bio-actives upon oral administration. Method: We assessed the nano-encapsulated flavonoid-rich fraction isolated from a traditional Indian herb Selaginella bryopteris (Sanjeevani) (NP.SB). Both in vitro and in vivo studies were performed to evidence the epigenetic protection mechanisms of NP.SB through a mitochondrial-targeted pre-clinical validation strategy. Results: The mito-protective activity of NP.SB revealed a dose-dependent effect when tested in GC-1 spg (mouse spermatogonial epithelial) and B/CMBA.Ov (mouse ovarian epithelial) following exposure to Nsuccinimidyl N-methylcarbamate, a potential human carcinogen. Smaller size, rapid internalization, faster mobility and site specific delivery conferred significant cancer protection in cultured cells. Notably, this encapsulated flavonoid supplementation; prevented emergence of neoplastic daughter clones from senescent mother phenotypes in pro-oxidant treated GC-1 spg and B/CMBA.Ov cells by selective abrogation of mitochondrial oxidative stress-induced aberrant epigenetic modifications. In vivo studies using a diethylnitrosamine and 2- acetylaminofluorene mouse model demonstrated that NP.SB has a significant inhibitory effect on tumor growth which clearly substantiated our in vitro findings. Conclusion: Anti-carcinogenic property in conjunction with low toxicity of NP.SB, underscores the translational significance of dietary flavonoids as cancer-protective agents for preferential application in clinical settings.

High-fat diet (HFD) alters the gut microbiota and its fermentation products mainly acetate, propionate, and butyrate. Butyrate is well studied as a regulator of host metabolism and inflammation while acetate and propionate still need to be studied. Therefore, we aim to decipher the role of acetate and propionate alone and in combination in HFD-induced diabetic mice. HFD was given to mice for 4 months followed by treatment of butyrate, acetate, and propionate as well as acetate + propionate in combination for 1 month. Diabetic outcome was confirmed by evaluating fasting glucose, lipid profile, oral glucose tolerance test, % HbA1c, fasting insulin, and glucagon. To check the immune response, spleen and mesenteric lymph node-specific T cell polarization and serum cytokine profile were studied. HFD-fed mice showed increased body weight and diabetic characteristics while treatment with acetate and propionate regulated their levels in a healthy manner similar to butyrate. In HFD-fed mice, Th1 and Th17 cells were increased while Treg cells were decreased along with increased pro-inflammatory cytokines and decreased IL-10 in serum. The T cell polarization and cytokine profile was reversed by the treatment of acetate and propionate alone and in combination. Acetate reduced the levels of IL-1β and IL-6 and acetate + propionate reduced IL-6 more significantly than butyrate. Although, we did not find any synergistic effect in combination group, the results were better compared with acetate, propionate, and butyrate. In conclusion, acetate + propionate effectively reduced inflammation and improved insulin sensitivity in HFD-induced diabetic mice.

One of the characteristic features of obesity is increased body weight and accumulation of adipose tissue. It is associated with low grade inflammation and gut dysbiosis. Probiotics and its products could be an ideal strategy to prevent or treat diabetes. In the present study, animals were induced obesity by providing them with high fat diet. Three purified bacteriocins i.e., DT24, PJ4 and TSU4, previously isolated and purified from various probiotic strains, were given as treatment strategies, following the induction of obesity. Upon the completion of the study, animals were sacrificed and were checked for their tissue expression of inflammatory mediators and adipokines. Serum hormone and cytokines analysis were performed to check their inflammatory state. Treatment with purified bacteriocin DT24 did not show any therapeutic effect in any of the parameter studied. Bacteriocin TSU4 on the other hand showed better reversal compared to DT24. Bacteriocin PJ4 showed the most promising results by reversing all the altered parameters significantly. It significantly reversed all the biochemical, immunological in terms of serum cytokines as well as altered morphological characteristics. PJ4 can be further explored to determine its mode of action. The anti-microbial proteins or to be more specific, bacteriocins, which shows broad spectrum efficacy, could be a better alternative in modulating gut microflora for the treatment of obesity and diabetes characteristics. The efficacy of bacteriocin PJ4 may also be due to the source of the host of Lactobacillus.

Despite several setbacks in the fight against malaria such as insecticide and drug resistance as well as low efficacy of available vaccines, considerable success in reducing malaria burden has been achieved in the past decade. Artemisinins (ARTs and their combination therapies, ACTs), the current frontline drugs against uncomplicated malaria, rapidly kill plasmodial parasites and are non-toxic at short exposures. Though the exact mode of action remains unclear, the endoperoxide bridge, indispensable for ART activity, is thought to react with heme released from hemoglobin hydrolysis and generate free radicals that alkylate multiple protein targets, thereby disrupting proteostasis pathways. However, rapid development of ART resistance in recent years with no potential alternatives on the horizon threaten the elimination efforts. The Greater Mekong Subregion in South-East Asia continues to churn out mutants resistant to multiple ACTs and detected in increasingly expanding geographies. Extensive research on ART-resistant strains have identified a potential candidate Kelch13, crucial for mediating ART resistance. Parasites with mutations in the propeller domains of Plasmodium falciparum Kelch13 protein were shown to have enhanced phosphatidylinositol 3-kinase levels that were concomitant with delayed parasite clearance. Current research focused on understanding the mechanism of Kelch13-mediated ART resistance could provide better insights into Plasmodium resistome. This review covers the current proposed mechanisms of ART activity, resistance strategies adopted by the parasite in response to ACTs and possible future approaches to mitigate the spread of resistance from South-East Asia.

Nutritional abundance associated with chronic inflammation and dyslipidemia impairs the functioning of endoplasmic reticulum (ER) thereby hampering cellular responses to insulin. PHLPP1 was identified as a phosphatase which inactivates Akt, the master regulator of insulin mediated glucose homeostasis. Given the suggestive role of PHLPP1 phosphatase in terminating insulin signalling pathways, deeper insights into its functional role in inducing insulin resistance are warranted. Here, we show that PHLPP1 expression is enhanced in skeletal muscle of insulin resistant rodents which also displayed ER stress, an important mediator of insulin resistance. Using cultured cells and PHLPP1 knockdown mice, we demonstrate that PHLPP1 facilitates the development of ER stress. Importantly, shRNA mediated ablation of PHLPP1 significantly improved glucose clearance from systemic circulation with enhanced expression of glucose transporter 4 (GLUT-4) in skeletal muscle. Mechanistically, we show that endogenous PHLPP1 but not PP2Cα interacts with and directly dephosphorylates AMPK Thr172 in myoblasts without influencing its upstream kinase, LKB1. While the association between endogenous PHLPP1 and AMPK was enhanced in ER stressed cultured cells and soleus muscle of high fat diet fed mice, the basal interaction between PP2Ac and AMPK was minimally altered. Further, we show that PHLPP1α is phosphorylated by ERK1/2 at Ser932 under ER stress which is required for its ability to interact with and dephosphorylate AMPK and thereby induce ER stress. Taken together, our data position PHLPP1 as a key regulator of ER stress.

Bacteriocin TSU4 is a novel antimicrobial peptide isolated from Catla catla gut isolate Lactobacillus animalis TSU4. It has been reported for its potential antimicrobial activity against fish pathogens and food spoilage bacteria. In vivo safety evaluation is necessary to determine its immunogenicity, toxicity, and importance in real-life applications. The present study was designed to evaluate the immunogenicity, acute and sub-chronic toxicity of bacteriocin TSU4 in BALB/c mice to ensure its safety in industrial application. Male BALB/c mice were administered intraperitoneally for immunogenicity assessment, by oral gavage with 50, 100, and 200 mg/kg/body weight for acute test and 0.5 mg/kg/day dose of bacteriocin TSU4 for sub-chronic toxicity test. Neither mortality nor any infections were observed during experimental period. There was no major increase in antibody titer during the immunogenicity test, and no mortality was observed during acute or sub-chronic toxicity tests. The LD50 value of bacteriocin TSU4 was found to be higher than 200 ± 0.45 mg/kg. No significant change in the serum biochemical markers, histopathological analysis and visual observation in spleen sizes was observed. These findings revealed that bacteriocin TSU4 is a non-immunogenic, safe, non-toxic, and could be a potential candidate for industrial applications in food preservation and aquaculture industries.

Background: Gut microbiota has a significant role in the pathogenesis of diabetes. Colonic microflora modulation using an antibiotic might have an emerging role to treat the metabolic disorders. The present study was aimed to optimize the Moxifloxacin loaded chitosan microspheres (MCMs) by emulsion cross linking method for colon targeted delivery to alter the microflora. Methods: Preliminary optimization of MCMs was carried out using Placket-Burman design (PBD) following by final optimization with Box-Behnken design (BBD). Optimized MCMs were evaluated for yield, particle size, entrapment efficiency and in vitro/ in vivo antimicrobial activities. Results: FTIR spectroscopy of MCMs confirms the absence of chemical interactions during the formulation. MCMs were found to be smooth, spherical with particle size around 20μm. An enteric coating of MCMs prevented the drug release in the acidic environment of the stomach and ileum with complete release at the colon. MCMs had followed the korsmeyer - peppas model of drug release, indicating the drug release by non-fickian diffusion pattern. MCMs showed significant in vitro antimicrobial activity against Lactobacillus casei and Escherichia coli. In vivo results of MCMs exhibited prolonged antimicrobial effect of drug in the cecal content of rats. Significant protective activity observed in the ileum and colon histology in rats treated with MCMs compared to the pure drug. Conclusion: MCMs were formulated by emulsion cross linking method using QBD approach. An enteric coating around the microspheres prevented the premature drug release at upper gastrointestinal tract, while chitosan cross linking has provided the sustain release of the drug in the colonic region over the time.

A combination of cocktail chemotherapy (CCT), photothermal therapy (PTT) and inhibition of angiogenesis was investigated as an effective approach to combat major challenges of multidrug resistance and non-targeted drug delivery encountered in conventional cancer therapy. An injectable nanocarrier was developed through functionalization of carbon nanotubes (CNTs) with rationally modified carbohydrate (β-Cyclodextrin-CD) derived pH and thermo responsive polymer. Embedding CNT to CD polymer offers a nanocarrier which effectively demonstrated CCT, high NIR triggered photothermal efficiency, anti-angiogenic potential for selective tumor homing as well as enhanced multi-drug resistance (MDR) reversal with minimal toxic effects on normal cells. The simultaneously loading with curcumin and doxorubicin hydrochloride exhibited synergistic effect for triggering antitumor effect in vitro and demonstrated down regulation of growth factors associated with angiogenesis ex-ovo. In-vivo studies ascertained that the nanocarrier synthesized with the rational for MDR reversal can lead to enhanced cancer cell death via multiple approaches.

The microbiota living in gut influences the immune response, metabolism, mood and behavior. The diet plays a pivotal role in maintaining healthy gut microbiota composition and its fermentation leads to production of Short Chain Fatty Acids (SCFAs) mainly acetate, propionate and butyrate. During pancreatic dysfunction, insulin mediated suppression of glucagon is impaired leading to uncontrolled glucose production by liver and state of hyperglycemia. Insulin and glucagon balance is as important as insulin sensitivity which is reduced during Type 2 Diabetes (T2D). Glucagon like peptide-1 (GLP1) produced by Intestinal epithelial cells regulates insulin and glucagon secretion directly via GLP1 receptor on pancreatic cells or via nervous system. But half-life period of GLP1 is very short i.e. about 2 minutes, after which it is cleaved and inactivated. SCFAs are well documented to induce GLP1 but its direct effect on pancreatic dysfunction has not been reported. This review opens a new avenue to study the role of SCFAs as a treatment to pancreatic dysfunction and T2D.

Statins are first-line therapy drugs for cholesterol lowering. While they are highly effective at lowering cholesterol, they have propensity to induce hyperglycemia in patients. Only limited studies have been reported which studied the impact of statins on (a) whether they can worsen glucose tolerance in a high sucrose fed animal model and (b) if so, what could be the molecular mechanism. We designed studies using high sucrose fed animals to explore the above questions. The high sucrose fed animals were treated with atorvastatin and simvastatin, the two most prescribed statins. We examined the effects of statins on hyperglycemia, glucose tolerance, fatty acid accumulation and insulin signaling. We found that chronic treatment with atorvastatin made the animals hyperglycemic and glucose intolerant in comparison with diet alone. Treatment with both statins lead to fatty acid accumulation and inhibition of insulin signaling in the muscle tissue at multiple points in the pathway.

Multifunctional nanoconjugates possessing an assortment of key functionalities such as magnetism, florescence, cell-targeting, pH and thermo-responsive features were developed for dual drug delivery. The novelty lies in careful conjugation of each of the functionality with magnetic Fe3O4 nanoparticles by virtue of urethane linkages instead of silica in a simple one pot synthesis. Further β-cyclodextrin (CD) was utilized to carry hydrophobic as well as hydrophilic drug. Superlative release of DOX could be obtained under acidic pH conditions and elevated temperature, which coincides with the tumor microenvironment. Mathematical modelling studies revealed that the drug release kinetics followed diffusion mechanism for both hydrophobic drug and hydrophilic drug. A number of fluorophores onto a single nanoparticle produced a strong fluorescence signal to optically track the nanoconjugates. Enhanced internalization due to folate specificity could be observed by fluorescence imaging. Further their accumulation driven by magnet near tumor site led to magnetic hyperthermia. in vitro studies confirmed the nontoxicity and hemocompatibility of the nanoconjugates. Remarkable cell death was observed with drug-loaded nanoconjugates at very low concentrations in cancer cells. The internalization and cellular uptake of poor bioavailable anticancer agent curcumin were found to be remarkably enhanced on dosing the drug loaded nanoconjugates as compared to free curcumin. Site specific drug delivery due to folate conjugation and subsequent significant suppression in tumor growth was demonstrated by in vivo studies.

Falcipain-2 (FP2) and falcipain-3 (FP3) constitute the major hemoglobinases of Plasmodium falciparum. Previous biochemical and structural studies have explained the mechanism of inhibition of these enzymes by small molecules. However, a residue-level protein-protein interaction (PPI) with its natural macromolecular substrate, hemoglobin is not fully characterized. Earlier studies have identified a short motif in the C-terminal of FP2, an exosite protruding away from the active site, essential for hemoglobin degradation. Our structural and mutagenesis studies suggest that hemoglobin interacts with FP2 via specific interactions mediated by Glu185 and Val187 within the C-terminal motif, which are essential for hemoglobin binding. Since FP3 is also a major hemoglobinase and essential for parasite survival, we further demonstrate its interactions with hemoglobin. Our results suggest that Asp194 of FP3 is required for hemoglobin hydrolysis and residue-swap experiments confirmed that this position is functionally conserved between the two hemoglobinases. Residues involved in protein-protein interactions constitute important targets for drug-mediated inhibition. Targeting protein-protein interactions at exosites may likely be less susceptible to emergence of drug resistance and thus is a new field to explore in malaria.

Background: A sugar rich diet induces inflammation and insulin resistance (IR) mainly through gut microbiota alteration. Gut dysbiosis increases lipopolysaccharide (LPS) and reduces propionate and butyrate levels to impair the insulin signalling cascades by different molecular pathways, which progresses into IR. The present study was designed to investigate the effect of spectrum specific antibiotics on the modulation of gut microbiota and its signalling pathways to prevent diet-induced diabetes. Methods: Healthy male Wistar rats were divided into a non-diabetic group with a control diet (CD), a diabetic group with a high sucrose diet (HSD) and two antibiotic fed groups (linezolid and cefdinir; administered by oral gavage) along HSD. Physiological, biochemical, inflammatory and microbiome parameters were examined. Results: Cefdinir administration in HSD rats reduced fasting glucose, serum triglyceride, and cholesterol levels compared to HSD alone. In addition, cefdinir reduced serum LPS by decreasing the population of Gram-negative phyla, that is, Bacteroidetes and Proteobacteria in the fecal content. Furthermore, cefdinir treatment decreased hepatic/ileal/colonic Tlr4, Nlr1, and Nf-κB at the mRNA level. Moreover, cefdinir-treated rats had shown increased fecal butyrate and propionate and reduced acetate levels compared to HSD alone. Cefdinir treatment also induced ileal/colonic Gpr43 and Glut4 at the mRNA level after 12 weeks of administration. Conclusions: Taken together, these data suggest that administration of a Gram-negative spectrum antibiotic, that is, cefdinir, has modulated the gut microbiota, and reduced serum LPS and triglycerides, which prevented the progression of IR and inflammation in HSD rats.

The human microbiome is increasingly being showed to have a direct and intimate relationship to human health and various disease conditions. Most of this microbiome is resident in the human gut, of which the colon is an important part. Microbial members of this gut community actively communicate among themselves through the process of quorum sensing (QS), and also with their human host. The level and nature of these communication processes play a crucial role in determining the overall health status, and susceptibility to various diseases, of the human system. Controlled modulation of QS-based and other communication processes within the human gut can prove to be a very effective tool in safeguarding human health. However, to achieve the full potential of any such approach, targeted delivery of QS-modulators specifically to the parts of human body, like the colon, which are characterized by high microbial density, is desired. Nanotechnological approaches can be of considerable use in such colon-specific delivery of potent QS-modulators, with lesser scope for degradation of any such therapeutic agents in their pre-colon journey.

Lifestyle and dietary habits directly influence the health of an individual constraining to understand the role of different types of diet components. Recently, dietary fibers are being studied comprehensively to understand its role in prevention of heart diseases, obesity, diabetes, cancer, etc. Dietary fibers provide nutrition to the gut microbiota directly and to intestinal epithelial cells indirectly via its fermentation products mainly short-chain fatty acids (SCFAs). Dietary fiber consumption alters gut microbiota, and its fermentation product mainly short-chain fatty acids modulates disease condition by maintaining energy homeostasis and immune response. Dietary fibers reduce serum LDL cholesterol and blood pressure preventing heart diseases. Dietary fiber consumption also helps in reducing BMI via inducing satiety signals and provides bulking effect. SCFAs act on different tissues via GPCR receptors and modulate disease condition. In case of obesity and diabetes, SCFA improves insulin secretion and glucose homeostasis via gut-brain axis.

Bacterial infections causing fish diseases and spoilage during fish food processing and storage are major concerns in aquaculture. Use of bacteriocins has recently been considered as an effective strategy for prevention of bacterial infections. A novel bacteriocin produced by Catla catla gut isolates, Lactobacillus animalis TSU4, designated as bacteriocin TSU4 was purified to homogeneity by a three-step protocol. The molecular mass of bacteriocin TSU4 was 4117 Da determined by Q-TOF LC/MS analysis. Its isoelectric point was ~9. Secondary conformation obtained by circular dichroism spectroscopy showed molecular conformation with significant proportions of the structure in α-helix (23.7 %) and β-sheets (17.1 %). N-terminal sequencing was carried out by the Edman degradation method; partial sequence identified was NH2-SMSGFSKPHD. Bacteriocin TSU4 exhibited a wide range of antimicrobial activity, pH and thermal stability. It showed a bacteriocidal mode of action against the indicator strain Aeromonas hydrophila MTCC 646. Bacteriocin TSU4 is the first reported bacteriocin produced by fish isolate Lactobacillus animalis. The characterization of bacteriocin TSU4 suggested that it is a novel bacteriocin with potential value against infections of bacteria such as A. hydrophila MTCC 646 and Pseudomonas aeruginosa MTCC 1688 and application to prevent spoilage during food preservation.

Introduction: Mosquito borne diseases continue to propagate and cause millions of deaths annually. They are caused either by protozoan parasites such as Plasmodium, Toxoplasma or by flaviviruses including Dengue and Zika. Among the proteome of such parasitic organisms, proteases play essential roles in events such as host invasion, hemoglobin hydrolysis, replication and immune evasion. Plasmepsin V (PMV), an endoplasmic reticulum resident aspartic protease of Plasmodium spp., is involved in the export of ~400 proteins containing the conserved Plasmodium Export Element motif (PEXEL). Interactions and cleavage of PEXEL proteins by PM V is necessary for export to and across the parasitophorous vacuole membrane. Protease System: Similarly in flaviviruses, a two-component protease system consisting of nonstructural proteins, NS2B and NS3, interacts with other non-structural proteins and plays a major role in viral replication, polyprotein cleavage and virion particle assembly. Thus, proteases involved in indispensable roles in pathogen machinery can be considered as attractive drug targets. Inhibitors against proteases are being used in clinical trials for other communicable and non-communicable diseases. Currently, hydroxyethylamine based inhibitors targeting the catalytic site of PM V with picomolar inhibitory concentrations have been tested in vitro. Conclusion: For recently characterized disease such as Zika, no known treatments exist while compound such as Policresulen has high affinity for Dengue NS2B/NS3 complex. Understanding proteases structure-function relationship and protease-inhibitor interactions can provide new insights for novel chemotherapeutic strategies.

Aquaculture is one of the fastest growing food producing sectors in the world. The increase in the world population requires faster growth in aquaculture for better food availability and to overcome malnutrition. But this worldwide growth of aquaculture is overwhelmed by catastrophic fish diseases and spoilage during cultivation and preservation problems caused by pathogenic bacteria. Various remedies are available for food preservation and also from the bacterial diseases in the fish production. Due to the emergence of antibiotic resistance and adverse effects, an alternative to antibiotic is the need of the hour. The proteins such as bacteriocins, i.e. ribosomally synthesized antimicrobial peptides (AMPs) and possess antagonistic against closely related and other bacteria. These proteins are produced by most lineages of bacteria which are playing key roles in recognition and possess a cognate immunity system for self-protection as well as host protection from infections. These proteins are potent immunomodulators with broad spectrum inhibition properties which are further used as novel therapeutic agents. In this review, we have tried to summarize the bacteriocins on the basis of their classifications, structural and functional attributes, mode of actions, bacteriocins isolated from fish and gut microbiota and presence of beneficiary bacteria in the fish gut. Further, this study highlighted where further research is a prerequisite to increase our basic understanding and search for novel bacteriocins to elucidate the proteins/peptides having antimicrobial properties for disease control in aquaculture as an alternative to antibiotics.

The present study investigates the anticancer and multidrug resistance (MDR) reversal potential of hydro-alcoholic Eclipta alba extract (EAE) through in vivo experiments. Diethylnitrosamine (DEN) and 2-acetylaminofluorene (AAF) were used for liver cancer induction in animal model, whereas for MDR induction, AAF was used. The level of antioxidant enzymes was studied in serum along with biochemical parameters. Cancer and MDR-induced liver cells have higher levels of reactive oxygen species (ROS) and, in turn, are responsible for the maintenance of the cancer phenotype. Treatment with EAE declines the ROS level and revealed the ROS scavenging properties. Alfa feto protein levels were found to increase significantly in cancer-induced animals confirming induction and progression of liver cancer, EAE treatment was found to bring back the altered levels within normal range indicating the therapeutic effect of plant extract over liver cancer. Zymogram showed the inhibition of MMPs and RT-PCR analysis revealed that the mRNA expression of nuclear factor-kB was markedly decreased upon EAE treatment. Further, our results showed that EAE could significantly inhibit mdr1 gene encode P-glycoprotein expression. Our data suggest that EAE is a novel anticancer and potent MDR reversal agent and may be a potential adjunctive agent for tumor chemotherapy.

Objective To determine the functional and biochemical variations in sperm and the neutrophil with the progression of age. Methods Ninety healthy male subjects were selected in the age group 26–40 for the collection of semen and blood samples were collected. Basic semen analysis, hematogram, differential count serum analysis, seminal plasma and serum biochemistry was performed. Mitochondrial isolation from sperm and neutrophil was done to ascertain mitochondrial markers. Results Our data shows a significant age–dependent reduction in the levels of mitochondrial Superoxide Dismutase (SOD) and Catalase (CAT) in sperm and the neutrophil. The functional attributes of sperm and neutrophil did not show any specific trend. Conclusion The decreasing trend of the mitochondrial antioxidants enzymes in the sperm and the neutrophil is an indicative of the reduction in the functioning of sperm and the neutrophil. The antioxidants enzymes of sperm and neutrophil shows similar declining trend with the progression of age suggesting its possible role as a prognostic marker for age related deformities and even in male fertility.

The development of multidrug resistance (MDR) causes problems in the chemotherapy of human cancer. The present study was designed to evaluate and establish the role of Eclipta alba as MDR reversal agent using multidrug resistant hepatocellular carcinoma cell line (DR-HepG2). To develop DR-HepG2, hepatocellular carcinoma cell line (HepG2) was transfected with 2-Acetylaminofluorene (AAF) and Aflatoxin B1 (AFB). Cytotoxic effects of the Eclipta alba hydroalcoholic extract (EAE) and standard anti-ancer drug Doxorubicin (DOX) were determined in DR-HepG2 and the parental cells HepG2 using MTT assay. The expression level of MDR1 gene and P-glycoprotein (P-gp) level was analyzed by RT-PCR and western blotting. From the present investigation, it was found that EAE (10 and 20 μg/ml) could significantly inhibit cell proliferation in DR-HepG2 whereas DOX (0.5 μg/ml) could not because of enhancement effect of MDR1/P-gp. This study demonstrated for the first time the antiproliferative activities of EAE in multidrug resistant DR-HepG2 cells. The findings revealed that Eclipta alba components are effective inhibitors of MDR1/P-gp.

The emergence of antibiotic resistance has increased the interest for finding new antimicrobials in the past decade. Probiotic Lactic acid bacteria producing antimicrobial proteins like bacteriocin can be excellent agents for development as novel therapeutic agents and complement to conventional antibiotic therapy. Uropathogenic Escherichia coli, most causative agent of Urinary tract infection, has developed resistance to various antibiotics. In the present investigation, antibacterial substance like bacteriocin (Bacteriocin DT24) produced by probiotic Lactobacillus brevis DT24 from vaginal sample of healthy Indian woman was partially purified and characterized. It was efficiently working against various pathogens, that is, Uropathogenic E. coli, Enterococcus faecium, Enterococcus faecalis and Staphylococcus aureus. The antimicrobial peptide was relatively heat resistant and also active over a broad range of pH 2-10. It has been partially purified by ammonium sulfate precipitation and gel filtration chromatography and checked on reverse-phase high-performance liquid chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of bacteriocin DT24 was approximately 7-kDa protein. The peptide is inactivated by proteolytic enzymes, trypsin and lipase but not when treated with catalase, α-amylase and pepsin. It showed bacteriostatic mode of action against uropathogenic E. coli. Such characteristics indicate that this bacteriocin-producing probiotic may be a potential candidate for alternative agents to control urinary tract infections and other pathogens.