Chemical synthetic approaches to mimic the TRAIL: promising cancer therapeutics.

Apoptosis is programmed cell death that eliminates undesired cells to maintain homeostasis in metazoan. Aberration of this process may lead to cancer genesis. The tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in cancer cells after ligation with death receptors (DR4/DR5) while sparing most normal cells. Therefore, strategies to induce apoptosis in cancer cells by mimicking the TRAIL emerge as a promising therapeutic tool. Hence, approaches are taken to develop TRAIL/DR-based cancer therapeutics. The recombinant soluble TRAIL (rhTRAIL) and death receptor agonistic antibodies were produced and tested pre-clinically and clinically. Pre-clinical and clinical trial data demonstrate that these therapeutics are safe and relatively well tolerated. But some of these therapeutics failed to exert adequate efficacy in clinical settings. Besides these biotechnologically derived therapeutics, a few chemically synthesized therapeutics are reported. Some of these therapeutics exert considerable efficacy in vitro and in vivo. In this review, we will discuss chemically synthesized TRAIL/DR-based therapeutics, their chemical and biological behaviour, design concepts and strategies that may contribute to further improvement of TRAIL/DR-based therapeutics.

Biodegradation of hydroxylated boron nitride nanoplatelets, their toxic effect and drug delivery application.

Boron nitride is extensively used in various biomedical applications and often interacting with the blood circulatory system. However, the effect of its biotransformation in blood plasma, drug delivery applications, and antitumor effects remains unclear. Herein, we synthesized hydroxylated BN nanoplatelets (-OH/BNNPs) that are used to load doxorubicin (DOX) for cancer therapy. The stability of the -OH/BNNPs was tested in a lab-made, artificially developed, in vivo system for up to sixty days at two different pH values (pH 5.5 & 7.4). The results were compared thoroughly with pristine BN, and it is observed that -OH/BNNPs was very stable for up to two months compared to pristine BN that degraded during the next day. The -OH functionalization on the BNNP surface improves the DOX loading compared to the bulk BN since the -OH functional group facilitates drug absorption through hydrogen bonding. This causes the sustained release of the drug, which is an ideal requirement in drug delivery systems. The DOX-loaded -OH/BNNPs showed excellent therapeutic abilities on different cancer cell lines and organoids derived from colorectal cancer patients.

Irisin alleviates CFA-induced inflammatory pain by modulating macrophage polarization and spinal glial cell activation.

Although the potent anti-inflammatory effects of irisin have been documented in various inflammatory disorders, its efficacy against inflammatory pain remains unexplored. Herein, we examined the therapeutic effects of irisin in a mouse model of inflammatory pain induced by complete Freund's adjuvant (CFA). Mice were divided into three groups: normal control, CFA-injected (CFA), and CFA plus irisin-treated (CFA+Irisin). The irisin-treated group exhibited a gradual reduction in mechanical allodynia and thermal hyperalgesia when compared with the CFA group. Moreover, treatment with irisin significantly upregulated the expression of M2 macrophage markers (interleukin [IL]-4 and IL-10) and downregulated M1 macrophage markers (IL-1ß, IL-6, and tumor necrosis factor-α) in the local paw tissue, dorsal root ganglion, and spinal cord tissue. However, there was no significant difference in the total number of F4/80+ macrophages in the paw tissue and dorsal root ganglion, indicating phenotypic exchange. Treatment with irisin also downregulated the expression of the glial cell activation-related markers Iba-1 and GFAP in the spinal cord tissue. To elucidate the underlying mechanisms, we detected the expression of Toll-like receptor 4 (TLR4), MyD88, and interferon regulatory factor 5 (IRF5) in paw tissues, dorsal root ganglion, and spinal tissues, revealing that irisin could downregulate the expression of these proteins. Irisin alleviated inflammatory pain by modulating local tissue inflammation and peripheral and central neuroinflammation and reducing glial cell activation and M2 macrophage polarization by modulating the TLR4-MyD88-IRF5 signaling pathway. Accordingly, irisin is a promising candidate for treating inflammatory pain in various diseases.

Specific transcription factors Ascl1 and Lhx6 attenuate diabetic neuropathic pain by modulating spinal neuroinflammation and microglial activation in mice.

Gamma-aminobutyric acid (GABA) neuronal system-related transcription factors (TFs) play a critical role in GABA production, and GABA modulates diabetic neuropathic pain (DNP). The present study investigated the therapeutic effects of intrathecal delivery of two TFs achaete-scute homolog 1 (Ascl1) and LIM homeobox protein 6 (Lhx6) in a mouse model of DNP and elucidated their underlying mechanisms. GABA-related specific TFs, including Ascl1, Lhx6, distal-less homeobox 1, distal-less homeobox 5, the Nkx2.1 homeobox gene, and the Nkx2.2 homeobox gene, were investigated under normal and diabetic conditions. Among these, the expression of Ascl1 and Lhx6 was significantly downregulated in mice with diabetes. Therefore, a single intrathecal injection of combined lenti-Ascl1/Lhx6 was performed. Intrathecal delivery of lenti-Ascl1/Lhx6 significantly relieved mechanical allodynia and heat hyperalgesia in mice with DNP. Ascl1/Lhx6 delivery also reduced microglial activation, decreased the levels of pro-inflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-1ß, increased the levels of anti-inflammatory cytokines including IL-4, IL-10, and IL-13, and reduced the activation of p38, c-Jun N-terminal kinase, and NF-κB in the spinal cord of mice with DNP, thereby reducing DNP. The results of this study suggest that intrathecal Ascl1/Lhx6 delivery attenuates DNP via upregulating spinal GABA neuronal function and inducing anti-inflammatory effects.

Entelon150® (Vitis vinifera Seed Extract) Attenuates Degenerative Changes in Intravascular Valve Prostheses in Rabbits.

BACKGROUND AND OBJECTIVES: The therapeutic strategy for inflammation and degenerative calcification is of utmost importance for bioprosthetic heart valve (BHV) implanted patients. The purpose of this study was to compare the anti-inflammatory and anti-calcification effects of Entelon150® (grape seed extract), losartan, and rosuvastatin, in a rabbit model of intravascular BHV leaflet implantation in bovine pericardium. METHODS: A total of 28 rabbits were implanted with BHV leaflet in the external jugular veins. The Entelon150® group was administered 7.7 mg/kg Entelon150® twice daily for 6 weeks after surgery. The losartan and rosuvastatin groups received 5.14 mg/kg and 1 mg/kg, respectively, once per day. The control group received 1 ml of saline once daily. And then, calcium concentration was measured in the implanted BHV, and histological and molecular analyses were performed on the surrounding tissues. RESULTS: The calcium content of the implanted tissue in the Entelon150® group (0.013±0.004 mg/g) was lower than that in the control group (0.066±0.039 mg/g) (p=0.008). The losartan (0.024±0.016 mg/g, p=0.032) and rosuvastatin (0.022±0.011 mg/g, p=0.032) groups had lower calcium content than the control group, and higher tendency than the Entelon150® group. Immunohistochemistry revealed that the expressions of bone morphogenic protein 2 (BMP2), S-100, and angiotensin II type 1 receptor in the Entelon150® group showed lower tendency than those in the control group. The protein expression levels of BMP2 were reduced in the Entelon150® group compared with those in the control group. CONCLUSIONS: Entelon150® exhibited a significant effect, similar to other drugs, in reducing calcification and inflammation in the intravascular bovine pericardium.

Silver nitroprusside as an efficient chemodynamic therapeutic agent and a peroxynitrite nanogenerator for targeted cancer therapies.

INTRODUCTION: Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H2O2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome. OBJECTIVES: To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli. METHODS: A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism. RESULTS: AgNP have an effective ability to decompose endogenous H2O2 in cells. The decomposed endogenous H2O2 generates several different types of reactive species (•OH, O2•-) including peroxynitrite (ONOO-) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO). CONCLUSION: This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis.

Proposing a hybrid technique of feature fusion and convolutional neural network for melanoma skin cancer detection.

Skin cancer is among the most common cancer types worldwide. Automatic identification of skin cancer is complicated because of the poor contrast and apparent resemblance between skin and lesions. The rate of human death can be significantly reduced if melanoma skin cancer could be detected quickly using dermoscopy images. This research uses an anisotropic diffusion filtering method on dermoscopy images to remove multiplicative speckle noise. To do this, the fast-bounding box (FBB) method is applied here to segment the skin cancer region. We also employ 2 feature extractors to represent images. The first one is the Hybrid Feature Extractor (HFE), and second one is the convolutional neural network VGG19-based CNN. The HFE combines 3 feature extraction approaches namely, Histogram-Oriented Gradient (HOG), Local Binary Pattern (LBP), and Speed Up Robust Feature (SURF) into a single fused feature vector. The CNN method is also used to extract additional features from test and training datasets. This 2-feature vector is then fused to design the classification model. The proposed method is then employed on 2 datasets namely, ISIC 2017 and the academic torrents dataset. Our proposed method achieves 99.85%, 91.65%, and 95.70% in terms of accuracy, sensitivity, and specificity, respectively, making it more successful than previously proposed machine learning algorithms.

Establishing a surveillance system on sexual and reproductive health and rights (SRHR) of key populations (KPs) at risk of compromised outcome of SRHR- A protocol for a mixed-method study.

BACKGROUND: Key populations (KPs) who are at risk of compromised situation of sexual and reproductive health and rights in Bangladesh constitute including males having sex with males, male sex workers, transgender women (locally known as hijra) and female sex workers. Globally, these key populations experience various sexual and reproductive health and rights burdens and unmet needs for ailments such as sexually transmitted infections including Neisseria Gonorrhoea, Chlamydia Trachomatis and human papillomavirus. Most key population focused interventions around the world, including Bangladesh, primarily address human immune deficiency virus and sexually transmitted infections-related concerns and provide syndromic management of sexually transmitted infections, other sexual and reproductive health and rights issues are remained overlooked that creates a lack of information in the related areas. There is currently no systematic research in Bangladesh that can produce representative data on sexual and reproductive health and rights among key populations, investigates their sexual and reproductive health and rights needs, how their needs evolve, and investigate underlying factors of sexual and reproductive health and rights issues that is crucial for informing more sexual and reproductive health and rights-friendly interventions for key populations. Keeping all these issues in mind, we are proposing to establish a sexual and reproductive health and rights surveillance system for key populations in Bangladesh. METHOD: The sexual and reproductive health and rights surveillance system will be established in Dhaka for males having sex with males, male sex workers and transgender women, and the other in Jashore for female sex workers. The duration will be for 3 years and data will be collected twice, in year one and year two adopting a mixed method repeated cross-sectional design. All key populations 15 years and above will be sampled. Behavioural data will be collected adopting a face-to-face technique and then biological samples will be collected. Those who will be found positive for human papillomavirus, will be referred to a government hospital for treatment. Free treatment will be provided to those who will be found positive for other sexually transmitted infections. In total, 2,240 key populations will be sampled. Written assent/consent will be taken from everyone. Data will be entered by Epi-Info and analysed by Stata. Report will be produced in every year. DISCUSSION: This surveillance system will be the first of its kind to systematically assess the situation of sexual and reproductive health and rights among selected key populations in Bangladesh. It is expected that this study will provide insights needed for improving the existing sexual and reproductive health and rights intervention modalities for these vulnerable and marginalized key populations.

Iron nitroprusside as a chemodynamic agent and inducer of ferroptosis for ovarian cancer therapy.

ChemoDynamic Therapy (CDT) is a powerful therapeutic modality using Fenton/Fenton-like reactions to produce oxidative stress for cancer treatment. However, the insufficient amount of catalyst ions and ROS scavenging activity of glutathione peroxidase (GPX4) limit the application of this approach. Therefore, a tailored strategy to regulate the Fenton reaction more efficiently (utilizing dual metal cations) and inhibit the GPX4 activity, is in great demand. Herein, a CDT system is based on dual (Fe2+ metals) iron pentacyanonitrosylferrate or iron nitroprusside (FeNP) having efficient ability to catalyze the reaction of endogenous H2O2 to form highly toxic ˙OH species in cells. Additionally, FeNP is involved in ferroptosis via GPX4 inhibition. In particular, FeNP was structurally characterized, and it is noted that a minimum dose of FeNP is required to kill cancer cells while a comparable dose shows negligible toxicity on normal cells. Detailed in vitro studies confirmed that FeNP participates in sustaining apoptosis, as determined using the annexin V marker. Cellular uptake results showed that in a short time period, FeNP enters lysosomes and, due to the acidic lysosomal pH, releases Fe2+ ions, which are involved in ROS generation (˙OH species). Western blot analyses confirmed the suppression of GPX4 activity over time. Importantly, FeNP has a therapeutic effect on ovarian cancer organoids derived from High-Grade Serous Ovarian Cancer (HGSOC). Furthermore, FeNP showed biocompatible nature towards normal mouse liver organoids and in vivo. This work presents the effective therapeutic application of FeNP as an efficient Fenton agent along with ferroptosis inducer activity to improve CDT, through disturbing redox homeostasis.

Melatonin Supplement Plus Exercise Effectively Counteracts the Challenges of Isoproterenol-Induced Cardiac Injury in Rats.

To explore the combined effects of exercise and melatonin supplement against the challenges of isoproterenol-induced cardiac oxidative stress and injury in rats., the expression of peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α), mitochondrial biogenesis, and adenosine triphosphate (ATP) was up-regulated in cardiac muscle in normal rats and in a melatonin and exercise regimented group. Cardiac injury was induced by two subcutaneous injections of isoproterenol in the rats. The combination of exercise and melatonin supplement successfully counteracted the isoproterenol-induced cardiac injury, which is reflected by the improved hemodynamic parameters, reduction in oxidative stress markers, and cardiac injury serum markers (cardiac troponin-I and creatine kinase-MB). The cardiac tissue level of ATP, expression of PGC-1α and mitochondrial biogenesis-related genes, mitochondrial membrane potential, and the activities of typical antioxidants (glutathione, superoxide dismutase) were preserved, whereas the levels of reactive oxygen species, lipid peroxidation, and inflammatory cytokines were suppressed in the melatonin and exercise regimented (MEI) group compared to the group treated with isoproterenol alone. Furthermore, the expression of endoplasmic reticular stress- and apoptosis-related proteins (Bax, Bcl2, and caspase-3) was also effectively suppressed in the MEI group. Therefore, the present study suggests that melatonin supplement in combination with exercise prevents cardiac injury, possibly through the preservation of mitochondrial function and inhibition of oxidative stress in rats.

Investigating the Anti-Inflammatory Effects of RCI001 for Treating Ocular Surface Diseases: Insight Into the Mechanism of Action.

The ocular surface is continuously exposed to various environmental factors, and innate and adaptive immunity play crucial roles in ocular surface diseases (OSDs). Previously, we have reported that the topical application of RCI001 affords excellent anti-inflammatory and antioxidant effects in dry eye disease and ocular chemical burn models. In this study, we examined the inhibitory effects of RCI001 on the Rac1 and NLRP3 inflammasomes in vitro and in vivo. Following RCI001 application to RAW264.7 and Swiss 3T3 cells, we measured Rac1 activity using a glutathione-S-transferase (GST) pull-down assay and G-protein activation assay kit. In addition, we quantified the expression of inflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor [TNF]-α) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells using ELISA and real-time PCR. In the mouse ocular alkali burn model, RCI001 was administered via eye drops (10 mg/mL, twice daily) for 5 days, and 1% prednisolone acetate (PDE) ophthalmic suspension was used as a positive control. Corneal epithelial integrity (on days 0-5) and histological examinations were performed, and transcript and protein levels of Rac1, NLRP3, caspase-1, and IL-1ß were quantified using real-time PCR and western blotting in corneal tissues collected on days 3 and 5. We observed that RCI001 dose-dependently inhibited Rac1 activity and various inflammatory cytokines in LPS-stimulated murine macrophages. Furthermore, RCI001 restored corneal epithelial integrity more rapidly than corticosteroid treatment in chemically injured corneas. Compared to the saline group, activation of Rac1 and the NLRP3 inflammasome/IL-1ß axis was suppressed in the RCI001 group, especially during the early phase of the ocular alkali burn model. Topical RCI001 suppressed the expression of activated Rac1 and inflammatory cytokines in vitro and rapidly restored the injured cornea by inhibiting activation of Rac1 and the NLRP inflammasome/IL-1ß axis in vivo. Accordingly, RCI001 could be a promising therapeutic agent for treating OSDs.

Insights into the leaves of Ceriscoides campanulata: Natural proanthocyanidins alleviate diabetes, inflammation, and esophageal squamous cell cancer via in vitro and in silico models.

Fourteen flavones (1-14) including twelve polymethoxylated flavones, two A-type proanthocyanidins (oligomeric flavonoids) (15, 16), one benzoyl glucoside (17), one triterpenoid (18), and one phenylpropanoid (19) were isolated from the leaves of the South Asian medicinal plant Ceriscoides campanulata (Roxb.) Tirveng (Rubiaceae). The structures of the compounds were identified based on their spectroscopic and spectrometric data and in comparison with literature data. Isolated compounds were tested in vitro against inflammatory enzymes (COX-2, iNOS), pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α), esophageal squamous carcinoma cell line (TE13), and carbohydrate digestion enzymes (α-amylase, α-glucosidase). Proanthocyanidins 15 and 16 significantly attenuated the LPS-induced inflammatory response of COX-2, iNOS, IL-1ß, IL-6, TNF-α in RAW 264.7 cells. Proanthocyanidins also satisfactorily inhibited the regrowth (64%), migration (51%), and formation of tumor-spheres (48%) in ESCC cell line TE13 at 50% toxic concentration. Compounds 15 and 16 showed the most potent effect against mammalian α-amylase (IC50 8.4 ± 0.3 µM and 3.5 ± 0.0 µM, respectively) compared to reference standard acarbose (IC50 5.9 ± 0.1 µM). As yeast α-glucosidase inhibitors, compounds 15 and 16 also displayed significant activities (IC50 6.2 ± 0.3 and 4.7 ± 0.1 µM, respectively), while compounds 1-6 displayed weaker α-glucosidase inhibitory activities, ranging from 49 to 142 µM, compared to acarbose (IC50 665 ± 42 µM). In an anticholinesterase assay, compounds 1, 2, 6 (IC50 51 ± 2, 53 ± 7, 64 ± 5 µM, respectively), and 4 (IC50 44 ± 1 µM) showed moderate inhibitory activities against acetylcholinesterase and butyrylcholinesterase, respectively. Furthermore, molecular docking and molecular dynamic simulation analyses of compounds 15 and 16 were performed against human pancreatic α-amylase and human lysosomal acid α-glucosidase to elucidate the interactions of these compounds in the respective enzymes' active sites.

Acyl-CoA-dependent and acyl-CoA-independent avocado acyltransferases positively influence oleic acid content in nonseed triacylglycerols.

In higher plants, acyl-CoA:diacylglycerol acyltransferase (DGAT) and phospholipid:diacylglycerol acyltransferase (PDAT) catalyze the terminal step of triacylglycerol (TAG) synthesis in acyl-CoA-dependent and -independent pathways, respectively. Avocado (Persea americana) mesocarp, a nonseed tissue, accumulates significant amounts of TAG (~70% by dry weight) that is rich in heart-healthy oleic acid (18:1). The oil accumulation stages of avocado mesocarp development coincide with high expression levels for type-1 DGAT (DGAT1) and PDAT1, although type-2 DGAT (DGAT2) expression remains low. The strong preference for oleic acid demonstrated by the avocado mesocarp TAG biosynthetic machinery represents lucrative biotechnological opportunities, yet functional characterization of these three acyltransferases has not been explored to date. We expressed avocado PaDGAT1, PaDGAT2, and PaPDAT1 in bakers' yeast and leaves of Nicotiana benthamiana. PaDGAT1 complemented the TAG biosynthesis deficiency in the quadruple mutant yeast strain H1246, and substantially elevated total cellular lipid content. In vitro enzyme assays showed that PaDGAT1 prefers oleic acid compared to palmitic acid (16:0). Both PaDGAT1 and PaPDAT1 increased the lipid content and elevated oleic acid levels when expressed independently or together, transiently in N. benthamiana leaves. These results indicate that PaDGAT1 and PaPDAT1 prefer oleate-containing substrates, and their coordinated expression likely contributes to sustained TAG synthesis that is enriched in oleic acid. This study establishes a knowledge base for future metabolic engineering studies focused on exploitation of the biochemical properties of PaDGAT1 and PaPDAT1.

[Ni(Np#)(η5-Cp)Cl]: Flexible, Sterically Bulky, Well-Defined, Highly Reactive Complex for Nickel-Catalyzed Cross-Coupling.

Ni-NHCs (NHC = N-heterocyclic carbene) have become an increasingly important class of complexes in catalysis and organometallic chemistry owing to the beneficial features of nickel as an abundant 3d metal. However, the development of well-defined and air-stable Ni-NHC complexes for cross-coupling has been more challenging than with Pd-NHC catalysis because of less defined reactivity trends of NHC ancillary ligands coordinated to Ni. Herein, we report the synthesis and catalytic activity of well-defined [Ni(NHC)(η5-Cp)Cl] complexes bearing recently commercialized IPr# family of ligands (Sigma Aldrich) and versatile cyclopentadienyl throw-away ligand. The NHC ligands, IPr#, Np# and BIAN-IPr#, are prepared by robust and modular peralkylation of anilines. Most crucially, we identified [Ni(Np#)(η5-Cp)Cl] as a highly reactive [Ni(NHC)(η5-Cp)Cl] complex, with the reactivity outperforming the classical [Ni(IPr)(η5-Cp)Cl] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene). These [Ni(NHC)(η5-Cp)Cl] precatalysts were employed in the Suzuki and Kumada cross-coupling of aryl chlorides and aryl bromides. Computational studies were conducted to determine steric effect and bond order analysis. Considering the attractive features of well-defined Ni-NHCs, we anticipate that this class of bulky and flexible Ni-NHC catalysts will find broad application in organic synthesis and catalysis.

Self-Therapeutic Cobalt Hydroxide Nanosheets (Co(OH)2 NS) for Ovarian Cancer Therapy.

High-grade serous ovarian cancer (HGSOC) is one of the major life-threatening cancers in women, with a survival rate of less than 50%. So far, chemotherapy is the main therapeutic tool to cure this lethal disease; however, in many cases, it fails to cure HGSOC even with severe side effects. Self-therapeutic nanomaterials could be an effective alternative to chemotherapy, facilitated by their diverse physicochemical properties and the ability to generate reactive species for killing cancer cells. Herein, inorganic cobalt hydroxide nanosheets (Co(OH)2 NS) were synthesized by a simple solution process at room temperature, and morphological, spectroscopic, and crystallographic analyses revealed the formation of Co(OH)2 NS with good crystallinity and purity. The as-prepared Co(OH)2 NS showed excellent potency, comparable to the FDA-approved cisplatin drug to kill ovarian cancer cells. Flow cytometric analysis (nnexin V) revealed increased cellular apoptosis for Co(OH)2 NS than cobalt acetate (the precursor). Tracking experiments demonstrated that Co(OH)2 NS are internalized through the lysosome pathway, although relocalization in the cytoplasm has been observed. Hence, Co(OH)2 NS could be an effective self-therapeutic drug and open up an area for the optimization of self-therapeutic properties of cobalt nanomaterials for cancer treatment.

Low-Cost and Efficient Nickel Nitroprusside/Graphene Nanohybrid Electrocatalysts as Counter Electrodes for Dye-Sensitized Solar Cells.

Novel nickel nitroprusside (NNP) nanoparticles with incorporated graphene nanoplatelets (NNP/GnP) were used for the first time as a low-cost and effective counter electrode (CE) for dye-sensitized solar cells (DSSCs). NNP was synthesized at a low-temperature (25 °C) solution process with suitable purity and crystallinity with a size range from 5 to 10 nm, as confirmed by different spectroscopic and microscopic analyses. The incorporation of an optimized amount of GnP (0.2 wt%) into the NNP significantly improved the electrocatalytic behavior for the redox reaction of iodide (I-)/tri-iodide (I3-) by decreasing the charge-transfer resistance at the CE/electrolyte interface, lower than the NNP- and GnP-CEs, and comparable to the Pt-CE. The NNP/GnP nanohybrid CE when applied in DSSC exhibited a PCE of 6.13% (under one sun illumination conditions) with the Jsc, Voc, and FF of 14.22 mA/cm2, 0.628 V, and 68.68%, respectively, while the PCE of the reference Pt-CE-based DSSC was 6.37% (Jsc = 14.47 mA/cm2, Voc = 0.635 V, and FF = 69.20%). The low cost of the NNP/GnP hybrid CE with comparable photovoltaic performance to Pt-CE can be potentially exploited as a suitable replacement of Pt-CE in DSSCs.

Antiproliferative and antioxidant potentials of bioactive edible vegetable fraction of Achyranthes ferruginea Roxb. in cancer cell line.

In the present study, the aerial parts of Achyranthes ferruginea underwent investigation of their in vitro antioxidant and free radical-scavenging activities in cell-free conditions, their phytoconstituents using gas chromatography-mass spectrometry (GC-MS), and their cytotoxic activity in HeLa cells. A. ferruginea was extracted with 80% methanol and successively fractionated with solvents to yield petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF), and aqueous (AQF) fractions. GC-MS analysis revealed that CHF contained ten phytoconstituents, including different forms of octadecanoic acid methyl esters. The total antioxidant and ferric-reducing antioxidant capacities of the extracts and the standard catechin (CA) were as follows: CA >CHF >PEF >CME (crude methanolic extract) >EAF >AQF, and CA >CHF >EAF >PEF >AQF >CME, respectively. CHF showed the highest DPPH-free radical-scavenging activity, with a median inhibitory concentration of 10.5 ± 0.28 µg/ml, which was slightly higher than that of the standard butylated hydroxytoluene (12.0 ± 0.09 µg/ml). In the hydroxyl radical-scavenging assay, CHF showed identical scavenging activity (9.25 ± 0.73 µg/ml) when compared to CA (10.50 ± 1.06 µg/ml). Moreover, CHF showed strong cytotoxic activity (19.95 ± 1.18 µg/ml) in HeLa cells, which was alike to that of the standards vincristine sulfate and 5-fluorouracil (15.84 ± 1.64 µg/ml and 12.59 ± 1.75 µg/ml, respectively). The in silico study revealed that identified compounds were significantly linked to the targets of various cancer cells and oxidative enzymes. However, online prediction by SwissADME, admetSAR, and PASS showed that it has drug-like, nontoxic, and potential pharmacological actions.

Functional and Predictive Structural Characterization of WRINKLED2, A Unique Oil Biosynthesis Regulator in Avocado.

WRINKLED1 (WRI1), a member of the APETALA2 (AP2) class of transcription factors regulates fatty acid biosynthesis and triacylglycerol (TAG) accumulation in plants. Among the four known Arabidopsis WRI1 paralogs, only WRI2 was unable to complement and restore fatty acid content in wri1-1 mutant seeds. Avocado (Persea americana) mesocarp, which accumulates 60-70% dry weight oil content, showed high expression levels for orthologs of WRI2, along with WRI1 and WRI3, during fruit development. While the role of WRI1 as a master regulator of oil biosynthesis is well-established, the function of WRI1 paralogs is poorly understood. Comprehensive and comparative in silico analyses of WRI1 paralogs from avocado (a basal angiosperm) with higher angiosperms Arabidopsis (dicot), maize (monocot) revealed distinct features. Predictive structural analyses of the WRI orthologs from these three species revealed the presence of AP2 domains and other highly conserved features, such as intrinsically disordered regions associated with predicted PEST motifs and phosphorylation sites. Additionally, avocado WRI proteins also contained distinct features that were absent in the nonfunctional Arabidopsis ortholog AtWRI2. Through transient expression assays, we demonstrated that both avocado WRI1 and WRI2 are functional and drive TAG accumulation in Nicotiana benthamiana leaves. We predict that the unique features and activities of ancestral PaWRI2 were likely lost in orthologous genes such as AtWRI2 during evolution and speciation, leading to at least partial loss of function in some higher eudicots. This study provides us with new targets to enhance oil biosynthesis in plants.

Unfolding the apoptotic mechanism of antioxidant enriched-leaves of Tabebuia pallida (lindl.) miers in EAC cells and mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: Tabebuia pallida (Lindl.) Miers (T. pallida) is a well-known native Caribbean medicinal plant. The leaves and barks of T. pallida are used as traditional medicine in the form of herbal or medicinal tea to manage cancer, fever, and pain. Moreover, extracts from the leaves of T. pallida showed anticancer activity. However, the chemical profile and mechanism of anticancer activity of T. pallida leaves (TPL), stem bark (TPSB), root bark (TPRB) and flowers (TPF) remain unexplored. AIM OF THE STUDY: The present study was designed to explore the regulation of apoptosis by T. pallida using Ehrlich Ascites Carcinoma (EAC) cultured cells and an EAC mouse model. LC-ESI-MS/MS was used for compositional analysis of T. pallida extracts. MATERIALS AND METHODS: Dried and powdered TPL, TPSB, TPRB and TPF were extracted with 80% methanol. Using cultured EAC cells and EAC-bearing mice with and without these extracts, anticancer activities were studied by assessing cytotoxicity and tumor cell growth inhibition, changes in life span of mice, and hematological and biochemical parameters. Apoptosis was analyzed by microscopy and expression of selected apoptosis-related genes (Bcl-2, Bcl-xL, NFκ-B, PARP-1, p53, Bax, caspase-3 and -8) using RT-PCR. LC-ESI-MS analysis was performed to identify the major compounds from active extracts. Computer aided analyses was undertaken to sort out the best-fit phytoconstituent of total ten isolated compounds of this plant for antioxidant and anticancer activity. RESULTS: In EAC mice compared with untreated controls, the TPL extract exhibited the highest cancer cell toxicity with significant tumor cell growth inhibition (p < 0.001), reduced ascites by body weight (p < 0.01), increased the life span (p < 0.001), normalized blood parameters (RBC/WBC counts), and increased the levels of superoxide dismutase and catalase. TPL-treated EAC cells showed increased apoptotic characteristics of membrane blebbing, chromatin condensation and nuclear fragmentation, and caspase-3 activation, compared with untreated EAC cells. Moreover, annexin V-FITC and propidium iodide signals were greatly enhanced in response to TPL treatment, indicating apoptosis induction. Pro- and anti-apoptotic signaling after TPL treatment demonstrated up-regulated p53, Bax and PARP-1, and down-regulated NFκ-B, Bcl-2 and Bcl-xL expression, suggesting that TPL shifts the balance of pro- and anti-apoptotic genes towards cell death. LC-ESI-MS data of TPL showed a mixture of glycosides, lapachol, and quercetin antioxidant and its derivatives that were significantly linked to cancer cell targets. The compound, pelargonidin-3-O-glucoside was found to be most effective in computer aided models. CONCLUSIONS: In conclusion, the TPL extract of T. pallida possesses significant anticancer activity. The tumor suppressive mechanism is due to apoptosis induced by activation of antioxidant enzymes and caspases and mediated by a change in the balance of pro- and anti-apoptotic genes that promotes cell death.

Myocardial tuberculosis and beyond: A rare form of extra pulmonary TB in a young boy.

Myocardial tuberculosis is an exceptionally rare form of extra-pulmonary TB. Few cases were reported world-wide. Here a young snake charmer who had skin tuberculosis 5 yrs back admitted into National institute of diseases of Chest and hospital (NIDCH), Dhaka with the complaints of cough, palpitation and breathlessness for 2 months. He had right axillary firm matted lymphadenopathy, left sided large pleural effusion, left ventricular and septal hypertrophy with band and mass inside the ventricle (evident on CT scan of heart and echocardiography). His ESR was 95 mm in1st hr, Mantaux test was 15mm, Pleural fluid was exudative lymphocyte predominant with adenosin deaminase (ADA) 68.6 U/L. Fine needle aspirates from right axillary LNs showed Mycobacterium tuberculosis on GeneXpert for MTB/RIF testing and caseous granuloma on cytopathological study. Whole Body F18 FDG PET-CT revealed numerous low FDG avid size significant lymph nodes in right side of neck, mediastinum and right axilla with cardiomegaly with focal FDG avid within the left ventricular cavity likely to be prominent papillary muscle. MRI of heart or Myocardial biopsy for histology was not done due to their cost and invasiveness and also for that there was sufficient evidence of having tuberculosis in lymph node, pleura nas myocardium. This patient was treated with anti tubercular medications (3HRZE2S/5HRE) with prednisolone for six months. After treatment, myocardial lesions, pleural effusion and lymphadenopathy were found resolved. Thus a case of fatal and serious tuberculosis was explored and managed successfully.