Genome-wide identification of MATE and ALMT genes and their expression profiling in mungbean (Vigna radiata L.) under aluminium stress.

The Multidrug and toxic compound extrusion (MATE) and aluminium activated malate transporter (ALMT) gene families are involved in response to aluminium (Al) stress. In this study, we identified 48 MATE and 14 ALMT gene families in Vigna radiata genome and classified into 5 (MATE) and 3 (ALMT) clades by phylogenetic analysis. All the VrMATE and VrALMT genes were distributed across mungbean chromosomes. Tandem duplication was the main driving force for evolution and expansion of MATE gene family. Collinearity of mungbean with soybean indicated that MATE gene family is closely linked to Glycine max. Eight MATE transporters in clade 2 were found to be associated with previously characterized Al tolerance related MATEs in various plant species. Citrate exuding motif (CEM) was present in seven VrMATEs of clade 2. Promoter analysis revealed abundant plant hormone and stress responsive cis-elements. Results from quantitative real time-polymerase chain reaction (qRT-PCR) revealed that VrMATE19, VrMATE30 and VrALMT13 genes were markedly up-regulated at different time points under Al stress. Overall, this study offers a new direction for further molecular characterization of the MATE and ALMT genes in mungbean for Al tolerance.

Food density drives diet shift of the invasive mysid shrimp, Limnomysis benedeni.

Understanding the diet preferences and food selection of invasive species is crucial to better predict their impact on community structure and ecosystem functioning. Limnomysis benedeni, a Ponto-Caspian invasive mysid shrimp, is one of the most successful invaders in numerous European river and lake ecosystems. While existing studies suggest potentially strong trophic impact due to high predation pressure on native plankton communities, little is known of its food selectivity between phyto- and zooplankton, under different food concentrations. Here, we therefore investigated the feeding selectivity of L. benedeni on two commonly occurring prey organisms in freshwaters, the small rotifer zooplankton Brachionus calyciflorus together with the microphytoplankton Cryptomonas sp. present in increasing densities. Our results demonstrated a clear shift in food selection, with L. benedeni switching from B. calyciflorus to Cryptomonas sp. already when the two prey species were provided in equal biomasses. Different functional responses were observed for the two food types, indicating somewhat different foraging mechanisms for each food type. These findings provide experimental evidence on the feeding flexibility of invasive mysid shrimps and potential implications for trophic interactions in invaded ecosystems.

Expression profiling of Nuclear Factor-Y (NF-Y) transcription factors during dehydration and salt stress in finger millet reveals potential candidate genes for multiple stress tolerance.

MAIN CONCLUSION: Expression profiling of NF-Y transcription factors during dehydration and salt stress in finger millet genotypes contrastingly differing in tolerance levels identifies candidate genes for further characterization and functional studies. The Nuclear Factor-Y (NF-Y) transcription factors are known for imparting abiotic stress tolerance in different plant species. However, there is no information on the role of this transcription factor family in naturally drought-tolerant crop finger millet (Eleusine coracana L.). Therefore, interpretation of expression profiles against drought and salinity stress may provide valuable insights into specific and/or overlapping expression patterns of Eleusine coracana Nuclear Factor-Y (EcNF-Y) genes. Given this, we identified 59 NF-Y (18 NF-YA, 23 NF-YB, and 18 NF-YC) encoding genes and designated them EcNF-Y genes. Expression profiling of these genes was performed in two finger millet genotypes, PES400 (dehydration and salt stress tolerant) and VR708 (dehydration and salt stress sensitive), subjected to PEG-induced dehydration and salt (NaCl) stresses at different time intervals (0, 6, and 12 h). The qRT-PCR expression analysis reveals that the six EcNF-Y genes namely EcNF-YA1, EcNF-YA5, EcNF-YA16, EcNF-YB6, EcNF-YB10, and EcNF-YC2 might be associated with tolerance to both dehydration and salinity stress in early stress condition (6 h), suggesting the involvement of these genes in multiple stress responses in tolerant genotype. In contrast, the transcript abundance of finger millet EcNF-YA5 genes was also observed in the sensitive genotype VR708 under late stress conditions (12 h) of both dehydration and salinity stress. Therefore, the EcNF-YA5 gene might be important for adaptation to salinity and dehydration stress in sensitive finger millet genotypes. Therefore, this gene could be considered as a susceptibility determinant, which can be edited to impart tolerance. The phylogenetic analyses revealed that finger millet NF-Y genes share strong evolutionary and functional relationship to NF-Ys governing response to abiotic stresses in rice, sorghum, maize, and wheat. This is the first report of expression profiling of EcNF-Ys genes identified from the finger millet genome and reveals potential candidate for enhancing dehydration and salt tolerance.

Assessment of physio-biochemical assessment and gene expression analysis of sugarcane genotypes under water stress.

BACKGROUND: Sugarcane, an economically important crop cultivated for its unique character of accumulating sucrose into its stalk and the world's major crop according to production quantity. Sugarcane production is negatively influenced by abiotic stresses because it faces all types of environments due to its long-life cycle period. Among the various abiotic stresses, drought is one of the major limiting factors creates obstacle in sugarcane production. Thus, an attempt was made to assess the molecular insights into sugarcane genotypes under water stress. A preliminary screening was done in ten sugarcane genotypes grown under semi-arid region of India through physiological, biochemical and antioxidant responses of these genotypes under two water deficit levels. METHODS: In the current study, drought was imposed on ten sugarcane genotypes during their formative stage (110 DAP) by depriving them of irrigation. A pot experiment was carried out to see how several commercial sugarcane genotypes responded to water scarcity. Sugarcane received two treatments, the first after 125 days and the second after 140 days. The physio-biochemical and antioxidant responses recorded were RWC, MSI, SCMR, Proline accumulation, SOD, Catalase, Peroxidase and Lipid peroxidation. The significant variations were recorded in responses of all genotypes. On the basis of physio-biochemical, three genotypes Cos 98,014, Cos 13,235 and Colk 14,201 were selected for differential gene expression pattern analysis. The total RNA was isolated and reverse transcribe to cDNA and real time PCR was performed for expression analysis under 10 genes. RESULTS: Under drought conditions, all sugarcane genotypes showed significantly decreased RWC, chlorophyll content, and MSI. However, when water was scarce, proline buildup, malondialdehyde (MDA) contents, enzymatic antioxidant activity (CAT, POD, and SOD), and contents all increased dramatically. Finally, in all physiological and biochemical parameters, Co 98,014 genotype displayed superior adaptation responses to drought stress, followed by Co 018, Cos 13,235, and Colk 14,201. For gene expression analysis out of 21 genes, 10 genes were expressed in sugarcane genotypes, in which 7 genes (Shbbx2, Shbbx3, Shbbx4, Shbbx5, Shbbx8, Shbbx15 and Shbbx20) were upregulated and 3 genes (Shbbx1, Shbbx16 and Shbbx17) were downregulated. CONCLUSION: The statistical analysis conducted in this study demonstrated that drought stress had a negative impact on physiological responses, including RWC, SPAD, and MSI, in sugarcane crops. However, it was found that the crops were able to survive in these stress conditions by increasing their biochemical parameters, all while maintaining their growth and function.

In Vivo Cancer Microenvironment Responsive Glycan Receptor-Targeted Nanoparticles for Gemcitabine Delivery to Benzo[a]pyrene-Induced Lung Cancer Model.

Targeted gemcitabine (GEB) loaded 5-N-acetyl-neuraminic acid (Neu5Ac) assembled chitosan nanoparticles (CA-NPs) were formulated by ionotropic gelation process and evaluated for physicochemical and morphological characterization, in vitro and in vivo studies in A-549 cells and lung cancer mice model, respectively. The mean diameter of GEB-CA-Neu5Ac-NPs determined by dynamic light scattering was 161.16 ± 7.70 nm with a polydispersity index (PDI) value of 0.303 ± 0.011 and its zeta potential and entrapment efficiency (%EE) were 40.3 ± 3.45 mv and 66.11 ± 1.94%, respectively. The in vitro cellular uptake studies showed that glycan receptor-targeted nanoparticles deliver significantly more amount (p < 0.001) of GEB into the A-549 lung cancerous cells than non-targeted nanoparticles. The cytotoxicity study using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay clearly demonstrated that GEB-CA-Neu5Ac-NPs have lower IC50 value (6.39 ± 3.78 µg/ml) than others groups that showed that the greater lung cancerous cells inhibition potential of targeted nanoparticles. The in vivo biodistribution of the GEB-loaded 5-N-acetyl-neuraminic acid conjugated chitosan nanoparticles was revealed that targeted nanoparticles showed higher accumulation and retention for an extended period of time due to the active targeting ability of Neu5Ac to glycan receptors. Histopathological examination showed significant recovery in the physiological architecture upon administration of targeted nanoparticles. The glycan receptor-targeted nanoparticles treated groups showed a significant decline in the number of metastatic lung epithelial cells, as compared to the untreated positive control group (p < 0.001) confirming higher anticancer efficacy of the GEB-CA-Neu5Ac-NPs.

Comparison of Mechanical Properties, Physical Properties, and Biocompatibility of Four Different Denture Base Resins: An In vitro Study.

Four new dental replacement base tars were evaluated in vitro to determine their mechanical qualities, authentic properties, and biocompatibility. Materials and Methods: In this experiment, we employed SR Triplet HOT (a fiber-developed heat fix tar), Sunflex (a multipurpose force fix sap), Trevalon-Hello (a high-impact heat fix tar), DPI (a digital pigment imaging system), and a variety of other pigments and inks (normal power fix tar). For these models, the ISO specification 1567 for dental substitute base gums called for testing of flexural strength, hardness, impact strength, water sorption and dissolvability, and cytotoxicity. Results: All the strength and mechanical properties tested had a statistically significant difference when intergroup analysis was performed. Conclusion: The exceptional physical and mechanical capabilities of the Sunflex denture base resin, together with its biocompatibility with oral tissues, make it a good candidate for use as a denture base material in routine clinical practice.

pH-influenced self-assembled stealth nanoscaffolds encapsulating memantine for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurological disorder characterized by the accumulation of ß-amyloid peptides. The only medication used to treat moderate-to-severe AD progression is memantine. In this study, polyethylene glycol (PEG)-coated poly D, L-lactic-co-glycolic acid (PLGA) nanostructures were prepared, as their self-assembling ability helps to penetrate the drug at disease sites with altered pH range (5.7-6.8) due to AD. Drug and polymer interaction studies by FTIR showed no interaction among them, and the thermal properties of drugs, polymers, and nanostructures tell us about their melting behaviour, thermal degradation, and glass transition temperatures. Characterization of prepared self-assembled nanoscaffolds signifies that the acquired properties such as size, structure, surface charges, zeta-potential, stability, thermal properties, biodegradability, biocompatibility, swelling ability, encapsulation, and drug loading provide an efficient therapeutic activity to the nanostructures for the treatment of AD. In addition, parallel artificial membrane permeability assay (PAMPA) has revealed the paracellular transport mechanism of nanoscaffolds across the blood-brain barrier. In vitro release kinetics showed a sustained release pattern exhibiting the Korsmeyer-Peppes drug release kinetic model with a correlation coefficient (R2) value of 0.9905, which describes the drug release pattern from a polymeric system. In vitro enzymatic studies demonstrated the inhibition activity of nanostructures on acetylcholinesterase (AChE), butyrylcholinestrase (BUChE), and ß-secretase enzyme which prevents the breakdown of acetylcholine, butyrylcholine, and amyloid precursor protein, and retention of these neurotransmitters constituted the primary therapeutic strategy for AD. Also, behavioural studies have shown a significant (p<0.05) improvement in cognition behaviour among nanostructures- administered animal groups in a scopolamine-induced amnesia model. The designed nanocarrier can also accelerate the treatment strategies for AD by incorporating stem cells and self-assembled nanoscaffolds that could provide a 3D extracellular matrix to facilitate neuron regeneration, hence improving cognition behaviour effectively.

"Millet Models" for harnessing nuclear factor-Y transcription factors to engineer stress tolerance in plants: current knowledge and emerging paradigms.

MAIN CONCLUSION: The main purpose of this review is to shed light on the role of millet models in imparting climate resilience and nutritional security and to give a concrete perspective on how NF-Y transcription factors can be harnessed for making cereals more stress tolerant. Agriculture faces significant challenges from climate change, bargaining, population, elevated food prices, and compromises with nutritional value. These factors have globally compelled scientists, breeders, and nutritionists to think of some options that can combat the food security crisis and malnutrition. To address these challenges, mainstreaming the climate-resilient and nutritionally unparalleled alternative crops like millet is a key strategy. The C4 photosynthetic pathway and adaptation to low-input marginal agricultural systems make millets a powerhouse of important gene and transcription factor families imparting tolerance to various kinds of biotic and abiotic stresses. Among these, the nuclear factor-Y (NF-Y) is one of the prominent transcription factor families that regulate diverse genes imparting stress tolerance. The primary purpose of this article is to shed light on the role of millet models in imparting climate resilience and nutritional security and to give a concrete perspective on how NF-Y transcription factors can be harnessed for making cereals more stress tolerant. Future cropping systems could be more resilient to climate change and nutritional quality if these practices were implemented.

Regulation of ethylene metabolism in tomato under salinity stress involving linkages with important physiological signaling pathways.

The tomato is well-known for its anti-oxidative and anti-cancer properties, and with a wide range of health benefits is an important cash crop for human well-being. However, environmental stresses (especially abiotic) are having a deleterious effect on plant growth and productivity, including tomato. In this review, authors describe how salinity stress imposes risk consequences on growth and developmental processes of tomato through toxicity by ethylene (ET) and cyanide (HCN), and ionic, oxidative, and osmotic stresses. Recent research has clarified how salinity stress induced-ACS and - ß-CAS expressions stimulate the accumulation of ET and HCN, wherein the action of salicylic acid (SA),compatible solutes (CSs), polyamines (PAs) and ET inhibitors (ETIs) regulate ET and HCN metabolism. Here we emphasize how ET, SA and PA cooperates with mitochondrial alternating oxidase (AOX), salt overly sensitive (SOS) pathways and the antioxidants (ANTOX) system to better understand the salinity stress resistance mechanism. The current literature evaluated in this paper provides an overview of salinity stress resistance mechanism involving synchronized routes of ET metabolism by SA and PAs, connecting regulated network of central physiological processes governing through the action of AOX, ß-CAS, SOS and ANTOX pathways, which might be crucial for the development of tomato.

In-vivo anticancer efficacy of self-targeted methotrexate-loaded polymeric nanoparticles in solid tumor-bearing rat.

Here, cytotoxicity and antitumor efficacy against a chemically (N-methyl-N-nitrosourea) generated mammary tumor in rats were assessed using methotrexate-loaded chitosan nanoparticles (Meth-Cs-NPs). Meth-Cs-NPs intravenous administrated resulted in noticeably decreased tumor incidence, multiplicity, and weight. Further, kidney function tests for the treated groups resulted in noticeably decreased ALP (Meth-Cs-NPs; 244 ± 15, diseases control; 403 ± 14 U/L), Creatinine (Meth-Cs-NPs; 0.81 ± 0.05, diseases control; 2 ± 0.05 mg/dl), and Urea (Meth-Cs-NPs; 56.62 ± 5, diseases control; 113 ± 6 mg/dl) levels, close to a normal control group. Similarly, liver function tests showed significantly decreased serum biomarkers, SGPT (Meth-Cs-NPs; 40 ± 1.8, diseases control; 84 ± 1.9 U/L) and SGOT (Meth-Cs-NPs; 15 ± 2, diseases control; 55 ± 4 U/L) levels in treated groups as compared to the untreated group (diseases control). From the results, pro-inflammatory cytokines were also markedly reduced in the treated group such as, TNF-α (Meth-Cs-NPs; 17.31 ± 1.15, diseases control; 36.9 ± 5 pg/mL), IL-1ß (Meth-Cs-NPs; 433.3 ± 66.5, diseases control; 1540 ± 131.1 pg/mL), and IL-6 (Meth-Cs-NPs; 1515 ± 53, diseases control; 2200.6 ± 69 pg/mL) levels. Whereas Meth-Cs-NPs not only helped in lowering tumor multiplicity rates but also decrease inflammation. The studies could be successfully performed in chemically induced mammary tumors due to their easy, quick tumor growth and low mortality rates in rat models. According to the current study, Meth-Cs-NPs have high treatment potency and represent a possible therapeutic alternative for breast cancer treatment.

Role of pro-inflammatory cytokines in Alzheimer's disease and neuroprotective effects of pegylated self-assembled nanoscaffolds.

Neurodegeneration and synaptic loss in Alzheimer's disease (AD) lead to impairment in memory functions. Neuroinflammation causes activation of microglia and astrocytes cells that locally and systemically produces inflammatory cytokines which can serve as early diagnostic markers or therapeutic targets in AD. Pro-inflammatory cytokines (Interleukins (IL-1ß, IL-6 and IL-10) and tumor necrosis factor (TNF α)) levels were estimated in serum, cerebral tissue, hepatic tissue, and renal tissue in treatment groups of scopolamine-induced amnesia mice model using ELISA protocol. The results showed that cerebral tissue of AD mice exhibited elevated levels of IL1ß, IL6, IL10 and TNFα which indicate contribution of pro-inflammatory cytokines in the progression of AD. A significant reduction in the concentration of IL1ß, IL-10 and TNF-α were noticed in serum, cerebral tissue and hepatic tissue of animal group treated with marketed memantine tablet (Admenta), pure memantine drug (MEMp), memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds (MEM-PLGA) SANs, Polyethylene Glycol coated memantine-poly (lactic-co-glycolic acid) self-assembled nanoscaffolds [(PEG-MEM-PLGA) SANs] and Polyethylene Glycol coated memantine-poly [(lactic-co-glycolic acid)] self-assembled nanoscaffolds grafted with Bone Marrow Derived Stem Cell ((PEG-MEM-PLGA) SANs-BMSc), whereas a high level of IL-6 was observed in hepatic tissue, cerebral tissue and renal tissues of normal and AD induced mice which showed the emerging potential of IL-6 cytokines that can trigger either neurons survival after injury or causing neurodegeneration and cell apoptosis. The Neuroregenerative potential of stem cells helps in the proliferation of neuronal cell and thus improves cognition in AD animal model.

Changing paradigms in the treatment of tuberculosis.

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease long dealt with, but still remains the second leading cause of death world-wide. The current anti-tubercular chemotherapy primarily targets the microbial pathogenesis, which however, is failing due to the development of drug resistance. Moreover, with fewer new drugs reaching the market, there is a need to focus on alternate treatment approaches that could be used as stand-alone or adjunct therapy and the existing drugs, referred to as Track II chemotherapy. This article is an attempt to review the changing global patterns of tuberculosis and its treatment. Further, newer drug delivery approaches like multi-particulate drug carriers which increase the therapeutic efficacy and bring down the systemic toxicity associated with drugs have also been discussed. There is also a need to use interventions which can be used as Track II therapy. Host-directed therapeutics (HDT) is an emerging area concept in which host cell functions and hence the response to pathogens can be modulated, which can help manage TB. HDT decreases damage induced due to inflammation and necrosis in the lungs and other parts of the body due to the disease. Various immuno-modulatory pathways have been discussed in this review which could be explored further to treat TB. An in-depth understanding of multi-particulate drug carriers and HDT could help in dealing with tuberculosis; however, there is still a long way to go.

Design, fabrication, optimization and characterization of memantine-loaded biodegradable PLGA nanoscaffolds for treatment of Alzheimer's disease.

This study aimed to design and develop nanoscaffolds for the controlled release of memantine by non-solvent-induced phase separation (N-TIPS) method. The development and optimization of nanoscaffolds was performed by Box-Behnken Design in which two independent formulation variables and one independent process variable: poly(lactic-co-glycolic acid) (PLGA) (X1), Pluronics F-127 (X2), and rotation speed (X3) were used. The design provided 15 formulation designs which were prepared to determine the response: percentage porosity (Y1) and drug loading (Y2). Polynomial equations were generated and analyzed statistically to establish a relationship between independent and dependent variables and develop an optimal formulation with maximized porosity (%) and drug loading (%). The optimized formulation batch was prepared using 19.18% w/v PLGA, 4.98% w/v Pluronics at 500 rpm rotation speed and exhibited drug loading of 11.66% and porosity of 82.62%. Further, correlation between the independent and dependent variables were established and statistically analyzed by using model generated mathematical regression equations, ANOVA, residual plots, interaction plot, main effect plot, contour plot and response surface designs. The analysis of model showed the significant individual effect of PLGA and significant interactive effect of Pluronics F-127 and rotation speed on drug loading and porosity. Further, its physicochemical characterization, andin-vitro(drug release kinetics, and PAMPA study),ex-vivo(enzyme inhibition assay and pro-inflammatory cytokines study) andin-vivo(neurobehavioral and histological study) studies were performed to evaluate the potential of memantine-loaded nanoscaffolds in the treatment of Alzheimer's disease (AD).

Evolutionary change in metabolic rate of Daphnia pulicaria following invasion by the predator Bythotrephes longimanus.

Metabolic rate is a trait that may evolve in response to the direct and indirect effects of predator-induced mortality. Predators may indirectly alter selection by lowering prey densities and increasing resource availability or by intensifying resource limitation through changes in prey behavior (e.g., use of less productive areas). In the current study, we quantify the evolution of metabolic rate in the zooplankton Daphnia pulicaria following an invasive event by the predator Bythotrephes longimanus in Lake Mendota, Wisconsin, US. This invasion has been shown to dramatically impact D. pulicaria, causing a ~60% decline in their biomass. Using a resurrection ecology approach, we compared the metabolic rate of D. pulicaria clones originating prior to the Bythotrephes invasion with that of clones having evolved in the presence of Bythotrephes. We observed a 7.4% reduction in metabolic rate among post-invasive clones compared to pre-invasive clones and discuss the potential roles of direct and indirect selection in driving this change.

Rationally designed far-red emitting styryl chromones and a magnetic nanoconjugate for strip-based 'on-site' detection of metabolic markers.

The global burden of liver damage and renal failure necessitates technology-aided evolution towards point-of-care (POC) testing of metabolic markers. Hence in the prevalence of current health conditions, achieving on-site detection and quantifying serum albumin (SA) can contribute significantly to halting the increased mortality and morbidity rate. Herein, we have rationally designed and synthesized far-red emitting, solvatofluorochromic styryl chromone (SC) derivatives SC1 and SC2, and SC2-conjugated fluorescent magnetic nanoparticles (SCNPs) for sensing SA with a fluorogenic response via interacting at an atypical drug binding site. In solution, the highly sensitive and selective fluorogenic response was evaluated by the prominent amplification and blue-shift in the emission maxima of the probes from deep red to dark yellow through an intermediate orange emission. The transformation of the fluorogen into a fluorophore was manifested through spectroscopic measurements. The stabilization of the probes at protein pockets was ascribed to the non-covalent interactions, such as H-bonding, cation-π, and hydrophobic interactions, as unveiled by docking studies. The practical applications revealed the novelty of SC derivatives through (a) the capability to detect SA isolated from real blood samples via a turn-on fluorescence response; (b) the design of a simple, cheap, and portable test-strip using a glass-slide loaded with solid-state emissive SC2, which provided differential emission color of the SC2-HSA complex in solution and the solid-state with increasing concentration of HSA. Moreover, a smartphone-based color analysis application was employed to obtain the ratio of green and red (G/R) channels, which was utilized for quantitative detection of HSA; (c) the biocompatibility of the SC1 was ascertained through confocal laser scanning microscopic imaging (CLSM). Detailed investigation showed that SC1 could entirely localize in the mitochondria and evolve as a promising biomarker for distinguishing cancer cells from normal cells. Additionally, the validation of uncommon binding of SC1 and SC2 between domains I and III was determined using competition experiments with a known site-specific binder and molecular docking studies. This unique property of the probes can be further exploited to understand the cellular intake of HSA-drug complexes in the multifaceted biological system. These results find the utility of SC derivatives as small molecule-based chemosensors for at-home SA detection and as a biomarker for cancer.

New paradigm in combination therapy of siRNA with chemotherapeutic drugs for effective cancer therapy.

Chemotherapeutics drugs play a pivotal role in the treatment of cancer. However, many issues generate by chemotherapy drugs, including unfavorable harm to healthy cells and multidrug resistance (MDR), persist and have a negative impact on therapeutic outcomes. When compared to monotherapy, combination cancer therapy has many advantages, like improving efficacy through synergistic effects and overcoming drug resistance. Combination treatment may comprise several chemotherapeutics drugs and combinations of chemotherapeutic drugs with some other therapeutic options such as surgery or radiation. Cancer treatment that utilizes co-delivery strategies with siRNA and chemotherapeutic drugs has been shown to have highly effective antitumor effects in the treatment of many cancers. However, the highly complex mechanisms of chemotherapeutic drugs-siRNA pairs during the co-delivery process have received little attention. The ideal combination of chemotherapeutic drugs with siRNA is very crucial for producing the desirable anticancer effects that would greatly enhance therapeutic efficiency. This review puts an emphasis on the logic for choosing suitable chemotherapeutic drug-siRNA combinations, which may open the way for the co-delivery of chemotherapeutic drugs and siRNA for treating cancer in the clinic. This review summarizes recent breakthrough in the area of diverse mechanism-based chemotherapeutic drugs-siRNA combinations in cancer treatment.

Pyrazole Containing Anti-HIV Agents: An Update.

BACKGROUND: Pyrazole scaffolds have gained importance in drug discovery and development for various pharmacological activities like antiviral, antifungal, anticancer, antidepressant, antiinflammatory, antibacterial, etc. Additionally, the pyrazole moiety has shown potent anti-HIV activity as a core heterocycle or substituted heterocycles derivatives (mono, di, tri, tetra, and fused pyrazole derivatives). To assist the development of further potential anti-HIV agents containing pyrazole nucleus, here we have summarized pyrazole containing anti-HIV compounds that have been reported by researchers all over the world for the last two decades. OBJECTIVE: The present review concentrates on an assortment of pyrazole containing compounds, particularly for potential therapeutic activity against HIV. METHODS: Google Scholar, Pubmed, and SciFinder were searched databases with ''pyrazol'' keywords. Further, the year of publication and keywords ''Anti-HIV'' filter was applied to obtain relevant reported literature for anti-HIV agents containing pyrazole as a core or substituted derivatives. RESULTS: This review article has shown the comprehensive compilation of 220 compounds containing pyrazole nucleus and possessing anti-HIV activity by sorting approximately 40 research articles from 2001 to date. 1-(4-Benzoylpiperazin-1-yl)-2-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin- 3-yl)ethane-1,2-dione (13), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-fluoro-1H-pyrrolo[2,3- c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (31), 3-(3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4- fluoro-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxamide (88), 3-cyanophenoxypyrazole derivative (130), and 4-(4-chlorophenyl)-5-(4-methyl-5-((4-nitrophenyl)diazenyl)thiazol-2-yl)-3- phenyl-5,6-dihydro-4H-pyrazolo[4,3-d]isoxazole (178) were the most potent mono-, di-, tri-, tetrasubstituted, and fused pyrazole derivatives, respectively, which have shown potent anti-HIV activity among all the described derivatives as compared with standard anti-HIV drugs. CONCLUSION: This review article provides an overview of the potential therapeutic activity of pyrazole derivatives against HIV that will be helpful for designing pyrazole containing compounds for anti-HIV activity.

Biogenesis and mechanisms of microRNA-mediated gene regulation.

Endogenous RNAs that control posttranscriptional gene expression are microRNAs (miRNAs). These small regulatory molecules play a crucial role in certain biological processes and their expression is often strictly regulated. They are small 21-24 nucleotide molecules that act as major regulators of gene expression at the posttranscriptional level. One of the mechanisms by which miRNAs control the gene expression is to interact the interaction of the seeds with the 3'-end and and more seldom the 5'-end of mRNA transcribed by the target genes. miRNAs have been identified as important cytoplasmic regulators of gene expression. miRNAs function as posttranscriptional regulators of their messenger RNA (mRNA) targets by mRNA degradation and/or translational repression. It is becoming evident, however, that miRNAs have nuclear functions as well. About the cell type, the physiological state of the body, and various external factors, the following explanation will summarize the complex multilevel regulation of miRNA expression. A better understanding of the molecular mechanisms controlling miRNA expression will provide clarification of the variations in the expression of protein-coding genes.

Zinc Oxide Nanoparticles Ameliorate Dimethylnitrosamine-Induced Renal Toxicity in Rat.

Dimethylnitrosamine (DMN) is an established carcinogen. It is toxic to several organs, viz., the liver, kidney, and lungs, and immune system. Several drugs have been used in the past to modulate its toxicity using experimental animal models. The present study was designed to investigate the effect of zinc oxide nanoparticles (ZnONPs) on renal toxicity caused by DMN in laboratory rat. Since oxidative mechanisms are mainly involved in its toxicity, the proposed study focuses on the amelioration of oxidative stress response by ZnONPs, if any. The present results show that administration of ZnONPs (50 mg/kg body weight/rat) to DMN (2 µl/100 g body weight/rat)-treated rats diminuted the concentration of malonaldehyde, H2O2, and NO in the kidney. However, reduced glutathione (GSH) concentration increased after ZnONP treatment. Results on glutathione S-transferase and glutathione peroxidase favored its antioxidative effects. These results are supported by the recovery of oxidative DNA damage and less pronounced histopathological changes in the kidney. It is hypothesized that ZnONPs might be toxic to renal tissue; however, its strong therapeutic/antioxidative potential helps in ameliorating DMN-induced renal toxicity in rat.