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Visceral leishmaniasis is a vector-borne protozoan infection that is fatal if untreated. There is no vaccination against the disease, and the current chemotherapeutic agents are ineffective due to increased resistance and severe side effects. Buparvaquone is a potential drug against the leishmaniases, but it is highly hydrophobic resulting in poor bioavailability and low therapeutic efficacy. Herein, we loaded the drug into silicon nanoparticles produced from barley husk, which is an agricultural residue and widely available. The buparvaquone-loaded nanoparticles were several times more selective to kill the intracellular parasites being non-toxic to macrophages compared to the pure buparvaquone and other conventionally used anti-leishmanial agents. Furthermore, the in vivo results revealed that the intraperitoneally injected buparvaquone-loaded nanoparticles suppressed the parasite burden close to 100%. By contrast, pure buparvaquone suppressed the burden only by 50% with corresponding doses. As the conclusion, the biogenic silicon nanoparticles are promising carriers to significantly improve the therapeutic efficacy and selectivity of buparvaquone against resistant visceral leishmaniasis opening a new avenue for low-cost treatment against this neglected tropical disease threatening especially the poor people in developing nations.

Visceral leishmaniasis (VL) is a chronic protozoan infection in humans associated with significant global morbidity and mortality. There is an urgent need to develop drugs and strategy that will improve therapeutic response for effective clinical treatment of drug resistant VL. To address this need, andrographolide (AG) nanoparticles were designed with P-gp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethyleneglycol 1000 succinate) for sensitivity against drug resistant Leishmania strains. AG loaded PLGA (50∶50) nanoparticles (AGnps) stabilized by vitamin E TPGS were prepared for delivery into macrophage cells infested with sensitive and drug resistant amastigotes of Leishmania parasites. Physico-chemical characterization of AGnps by photon correlation spectroscopy exhibited an average particle size of 179.6 nm, polydispersity index of 0.245 and zeta potential of -37.6 mV. Atomic force microscopy and transmission electron microscopy visualization revealed spherical nanoparticles with smooth surfaces. AGnps displayed sustained AG release up to 288 hours as well as minimal particle aggregation and drug loss even after three months study period. Antileishmanial activity as revealed from selectivity index in wild-type strain was found to be significant for AGnp with TPGS in about one-tenth of the dosage of the free AG and one-third of the dosage of the AGnp without TPGS. Similar observations were also found in case of in vitro generated drug resistant and field isolated resistant strains of Leishmania. Cytotoxicity of AGnp with and without TPGS was significantly less than standard antileishmanial chemotherapeutics like amphotericin B, paromomycin or sodium stibogluconate. Macrophage uptake of AGnps was almost complete within one hour as evident from fluorescent microscopy studies. Thus, based on these observations, it can be concluded that the low-selectivity of AG in in vitro generated drug resistant and field isolated resistant strains was improved in case of AG nanomedicines designed with vitamin E TPGS.

Four formulations of Tamoxifen citrate loaded polylactide-co-glycolide (PLGA) based nanoparticles (TNPs) were developed and characterized. Their internalization by Michigan Cancer Foundation-7 (MCF-7) breast cancer cells was also investigated. Nanoparticles were prepared by a multiple emulsion solvent evaporation method. Then the following studies were carried out: drug-excipients interaction using Fourier transform infrared spectroscopy (FTIR), surface morphology by field emission scanning electron microscopy (FESEM), zeta potential and size distribution using a Zetasizer Nano ZS90 and particle size analyzer, and in vitro drug release. In vitro cellular uptake of nanoparticles was assessed by confocal microscopy and their cell viability (%) was studied. No chemical interaction was observed between the drug and the selected excipients. TNPs had a smooth surface, and a nanosize range (250-380 nm) with a negative surface charge. Drug loadings of the prepared particles were 1.5%±0.02% weight/weight (w/w), 2.68%±0.5% w/w, 4.09%±0.2% w/w, 27.16%±2.08% w/w for NP1-NP4, respectively. A sustained drug release pattern from the nanoparticles was observed for the entire period of study, ie, up to 60 days. Further, nanoparticles were internalized well by the MCF-7 breast cancer cells on a concentration dependent manner and were present in the cytoplasm. The nucleus was free from nanoparticle entry. Drug loaded nanoparticles were found to be more cytotoxic than the free drug. TNPs (NP4) showed the highest drug loading, released the drug in a sustained manner for a prolonged period of time and were taken up well by the MCF-7 breast cancer cell line in vitro. Thus the formulation may be suitable for breast cancer treatment due to the good permeation of the formulation into the breast cancer cells.

Leishmaniasis is a growing health problem in many parts of the world partly due to drug resistance of the parasite. This study reports on the fisibility of studying mitochondrial properties of two forms of wild-type L. donovani through the use of selective inhibitors. Amastigote forms of L. donovani exhibited a wide range of sensitivities to these inhibitors. Mitochondrial complex II inhibitor thenoyltrifluoroacetone and F o F 1 -ATP synthase inhibitors oligomycin and dicyclohexylcarbodiimide were refractory to growth inhibition of amastigote forms, whereas they strongly inhibited the growth of promastigote forms. This result indicated that complex II and F o F 1 -ATP synthase were not functional in amastigote forms suggesting the presence of attenuated oxidative phosphorylation in the mitochondria of amastigote forms. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited cellular multiplication and substrate level phosphorylation in amastigote forms, suggesting the role of complex I and complex III for the survival of amastigote forms. Further we studied the mitochondrial activities of both forms by measuring oxygen consumption and ATP production. In amastigote form, substantial ATP formation by substrate level phosphorylation was observed in NADPH-fumarate, NADH-fumarate, NADPH-pyruvate and NADH-pyruvate redox couples. None of the redox couple generated ATP formation was inhibited by F o F 1 -ATP synthase inhibitor oligomycin. Therefore, we may conclude that there are significant differences between these two forms of L. donovani in respect of mitochondrial bioenergetics. Our results demonstrated bioenergetic disfunction of amastigote mitochondria. Therefore, these alterations of metabolic functions might be a potential chemotherapeutic target.

Brain tumor causes of millions of life every year due to poor treatment options. The blood-brain barrier prevents most of the treatment molecules to reach the tumor region. Tight junctions within adjacent brain endothelial cell lines including other components make the brain highly impermeable to all the unwanted and foreign materials. The antineoplastic drug molecules which has a molecular weight of less than 400 daltons and have less than 8 hydrogen bonds are only able to access the brain without any hindrance. Hence, most of the small and large anti-cancer drug molecules hardly can cross the barrier. To overcome these problems formulation scientists have adopted various strategies and techniques so that the intended drug molecule can reach the target region of the brain tumor. Among them nanosponges drug delivery is highly appreciated as emerging brain tumor targeted drug delivery. Nanosponges are tiny sponge in the size of nano range with a vesicle filled with various types of drugs. These kinds of the formulation can circulate throughout the blood and reach the target region where drugs are released in a controlled manner. This review article highlights the unique features of blood-brain barrier and novel strategies based on drug formulation to access the core of the brain tumor by overcoming the resistance rendered by blood brain barrier. In addition, it also demonstrates how nanosponges is emerging as one of the best options to prevail over various challenges associated with penetration of the blood-brain barrier.

Leishmania , the causative agent of various forms of leishmaniasis, is the significant cause of morbidity and mortality. Regarding energy metabolism, which is an essential factor for the survival, parasites adapt to the environment under low oxygen tension in the host using metabolic systems which are very different from that of the host mammals. We carried out the study of susceptibilities to different inhibitors of mitochondrial electron transport chain and studies on substrate level phosphorylation in wild-type L. donovani . The amastigote forms of L. donovani are independent on oxidative phosphorylation for ATP production. Indeed, its cell growth was not inhibited by excess oligomycin and dicyclohexylcarbodiimide, which are the most specific inhibitors of the mitochondrial Fo/F1-ATP synthase. In contrast, mitochondrial complex I inhibitor rotenone and complex III inhibitor antimycin A inhibited amastigote cell growth, suggesting the role of complex I and complex III in cell survival. Complex II appeared to have no role in cell survival. To further investigate the site of ATP production, we studied the substrate level phosphorylation, which was involved in the synthesis of ATP. Succinate-pyruvate couple showed the highest substrate level phosphorylation in amastigotes whereas NADH-fumarate and NADH-pyruvate couples failed to produce ATP. In contrast, NADPH-fumarate showed the highest rate of ATP formation in promastigotes. Therefore, we can conclude that substrate level phosphorylation is essential for the survival of amastigote forms of Leishmania donovani .

Visceral leishmaniasis (VL) is a chronic protozoan infection in humans associated with significant global morbidity and mortality. There is an urgent need to develop drugs and strategy that will improve therapeutic response for effective clinical treatment of drug resistant VL. To address this need, andrographolide (AG) nanoparticles were designed with P-gp efflux inhibitor vitamin E TPGS (D- alpha -tocopheryl polyethyleneglycol 1000 succinate) for sensitivity against drug resistant Leishmania strains. AG loaded PLGA (50:50) nanoparticles (AGnps) stabilized by vitamin E TPGS were prepared for delivery into macrophage cells infested with sensitive and drug resistant amastigotes of Leishmania parasites. Physico-chemical characterization of AGnps by photon correlation spectroscopy exhibited an average particle size of 179.6 nm, polydispersity index of 0.245 and zeta potential of -37.6 mV. Atomic force microscopy and transmission electron microscopy visualization revealed spherical nanoparticles with smooth surfaces. AGnps displayed sustained AG release up to 288 hours as well as minimal particle aggregation and drug loss even after three months study period. Antileishmanial activity as revealed from selectivity index in wild-type strain was found to be significant for AGnp with TPGS in about one-tenth of the dosage of the free AG and one-third of the dosage of the AGnp without TPGS. Similar observations were also found in case of in vitro generated drug resistant and field isolated resistant strains of Leishmania. Cytotoxicity of AGnp with and without TPGS was significantly less than standard antileishmanial chemotherapeutics like amphotericin B, paromomycin or sodium stibogluconate. Macrophage uptake of AGnps was almost complete within one hour as evident from fluorescent microscopy studies. Thus, based on these observations, it can be concluded that the low-selectivity of AG in in vitro generated drug resistant and field isolated resistant strains was improved in case of AG nanomedicines designed with vitamin E TPGS.

Rice grain size and weight are major determinant of grain quality and yield and so have been under rigorous selection since domestication. However, genetic basis for contrasting grain size/weight trait among indian germplasm, and their association with domestication shaped evolutionary region is not studied before. To identify genetic basis of grain size/weight two long (LGG) and two short grain genotypes (SGG) were resequenced. LGG (LGR and Pusa Basmati 1121) differentiated from SGG (Sonasal and Bindli) by 504439 SNPs and 78166 InDels. The LRK gene cluster was significantly affected and a truncation mutation in the LRK8 kinase domain was uniquely associated with LGG. Phylogeny with 3000 diverse rice accessions revealed four sequenced genotypes belonged to japonica group and were at the edge of clades indicating source of genetic diversity available in Asian rice population. Five SNPs significantly were associated with grain size/weight and top three SNPs were validated in RIL mapping populations, suggesting this study as a valuable resource for high-throughput genotyping. A contiguous ~6 Mb polymorphism desert region carrying a major grain weight QTL was identified on chromosome 5 in four sequenced genotypes. Further, among 3000, this region was identified as evolutionary important site with significant positive selection, elevated LD, and multiple selection sweeps, stabilising many domestication-related traits including grain size/weight. The aus group genotype retained more allelic variations in the desert region than japonica and indica, and likely to be one of the differentiation point for aus group. We suggest this desert region as an important evolutionary node that can be selected in breeding programs for improvement of grain yield and quality. All data and analysis can be accessed from RiceSzWtBase database.

Diabetic Macular Edema (DME) is a major complication of diabetic retinopathy characterized by fluid accumulation in the macula, leading to vision impairment. The standard treatment involves anti-VEGF (Vascular Endothelial Growth Factor) therapy, but approximately 36% of patients do not respond adequately, highlighting the need for more precise predictive models to guide treatment. This study aims to develop a Hybrid Deep Learning model to predict treatment responses in DME patients undergoing anti-VEGF therapy, thereby improving the accuracy of treatment planning and minimizing the unnecessary use of costly anti-VEGF agents. The model integrates both Optical Coherence Tomography (OCT) images and clinical data from 181 patients, including key parameters such as serum VEGFR-2 concentration and the duration of DME. The architecture combines convolutional neural networks (CNNs) for image data with multi-layer perceptron (MLP) for tabular clinical data, allowing for a comprehensive analysis of both data types. These pathways converge into a unified predictive framework designed to enhance the model’s accuracy. This study utilized a Hybrid Deep Learning model that achieved an 85% accuracy, with additional metrics including precision, recall, and the area under the receiver operating characteristic curve (AUC-ROC) confirming its robustness and reliability. The findings suggest that the model accurately predicts patient responses to anti-VEGF therapy, paving the way for more personalized and targeted treatment strategies. This approach has the potential to enhance patient outcomes and minimize unnecessary administration of anti-VEGF agents, thereby optimizing therapeutic interventions in ophthalmology.