Imperative connotation of SODs in cancer: Emerging targets and multifactorial role of action.

Superoxide dismutase (SOD) is a crucial enzyme responsible for the redox homeostasis inside the cell. As a part of the antioxidant defense system, it plays a pivotal role in the dismutation of the superoxide radicals ( O 2 - $$ {{\mathrm{O}}_2}^{-} $$ ) generated mainly by the oxidative phosphorylation, which would otherwise bring out the redox dysregulation, leading to higher reactive oxygen species (ROS) generation and, ultimately, cell transformation, and malignancy. Several studies have shown the involvement of ROS in a wide range of human cancers. As SOD is the key enzyme in regulating ROS, any change, such as a transcriptional change, epigenetic remodeling, functional alteration, and so forth, either activates the proto-oncogenes or aberrant signaling cascades, which results in cancer. Interestingly, in some cases, SODs act as tumor promoters instead of suppressors. Furthermore, SODs have also been known to switch their role during tumor progression. In this review, we have tried to give a comprehensive account of SODs multifactorial role in various human cancers so that SODs-based therapeutic strategies could be made to thwart cancers.

The Potential Pharmacological Effects of Natural Product Withaferin A in Cancer: Opportunities and Challenges for Clinical Translation.

Cancer is one of the biggest health concerns with a complex pathophysiology. Currently, available chemotherapeutic drugs are showing deleterious side effects, and tumors often show resistance to treatment. Hence, extensive research is required to develop new treatment strategies to fight against cancer. Natural resources from plants are at the forefront of hunting novel drugs to treat various types of cancers. Withaferin A (WA) is a naturally occurring withanolide, a biologically active component obtained from the plant Ashwagandha. Various in vitro and in vivo oncological studies have reported that Withaferin A (WA) has shown protection from cancer. WA shows its activity by inhibiting the growth and proliferation of malignant cells, apoptosis, and inhibiting angiogenesis, metastasis, and cancer stem cells (CSCs). In addition, WA also showed chemo- and radio-sensitizing properties. Besides the beneficiary pharmacological activities of WA, a few aspects like pharmacokinetic properties, safety, and toxicity studies are still lacking, hindering this potent natural product from entering clinical development. In this review, we have summarized the various pharmacological mechanisms shown by WA in in vitro and in vivo cancer studies and the challenges that must be overcome for this potential natural product's clinical translation to be effective.

Oxygen-Isotope Exchange between CO2 and NO2 with Implications for Atmospheric Chemistry.

Elucidating isotope exchange between atmospheric trace molecular species is important for environment monitoring, climate control studies, and a fundamental understanding of atmospheric chemistry. Here, we provide direct experimental evidence of oxygen-isotopic exchange between carbon dioxide (CO2) and nitrogen dioxide (NO2), which are simultaneously emitted into the atmosphere from common sources. A combined near-infrared and UV-vis optical cavity-enhanced experimental investigation along with quantum-chemical calculations followed by a reaction modeling study revealed that CO2 and NO2 can communicate isotopically by near-ultraviolet-driven NO2 photolysis. Our results found evidence for a near-barrierless (1.67 kcal/mol) nitrate-containing complex having a very short lifetime (∼13 ns) which facilitates the transfer of 18O-isotopes from 18O12C16O to N16O16O, leading to isotopic depletion of 18O in 18O12C16O, thus opening a new gas-phase isotope-selective chemical transformation mechanism in the lower atmosphere. This isotope exchange study may serve as a new window into the fundamental understanding of isotopic photochemistry, oxygen isotopic fractionations, and climate modeling.

Anti-melanoma and antioxidant properties of the methanol extract from the leaves of Phragmenthera capitata (Spreng.) Balle and Globimetula braunii (Engl.) Van Tiegh.

OBJECTIVES: Phragmenthera capitata (Spreng.) Balle and Globimetula braunii (Engler.) Van Tiegh are African mistletoe traditionally used in cancers treatment. Thus, the aim of the study was to assess the anti-melanoma potential of the methanol extract of Phragmenthera capitata (Spreng.) Balle (PCMe-OH) and Globimetula braunii (Engler.) (GBMe-OH) Van Tiegh. METHODS: Antioxidant potential was evaluated using DPPH, FRAP and hydroxyl assays. Total flavonoid and phenolic contents was also determined. MTT assay was used to estimate the effects on cell viability using SK-MLE28 and B16-F10 cell lines. Colony formation and wound healing were also assessed. Fluorometry methods were used for qualitative analysis of apoptosis and estimate ROS production. Western blot analysis was used for protein expression. RESULTS: Phragmenthera capitata (PCMe-OH) showed the highest antioxidant activity and possess the highest phenolic contents (1,490.80 ± 55 mgGAE/g extract) in comparison with G. braunii (GBMe-OH) and (1,071.40 ± 45 mgGAE/g extract). Flavonoid content was similar in both extracts (11.63 ± 5.51 mg CATE/g of extract and 12.46 ± 2.58 mg CATE/g of extract respectively). PC-MeOH showed the highest cytotoxicity effect (IC50 of 55.35 ± 1.17 µg/mL) and exhibited anti-migrative potential on B16-F10 cells. Furthermore, PC-MeOH at 55.35 and 110.7 µg/mL; promoted apoptosis-induced cell death in B16-F10 cells by increasing intracellular ROS levels and reducing Bcl-2 expression level at 110.7 µg/mL. Significant upregulation of P-PTEN expression was recorded with PC-MeOH at 110.7 µg/mL; inhibiting therefore PI3K/AKT/m-Tor signaling pathway. Moreover, at 55.37 µg/mL significant reduction of c-myc and cyclin D1 was observed; dysregulating the MAPK kinase signaling pathway and cell cycle progression. CONCLUSIONS: Phragmenthera capitata may be developed into selective chemotherapy to fight against melanoma.

Development of an all-solid-state air-cooled high-power blue diode laser for metal processing.

We present the design and development of an all-solid-state (fluid/refrigerant-free) 100 W scale blue-laser system and show its applications in precision copper works. We combine powerful laser-diode arrays with Peltier chips on a compact laser head to achieve stable thermal and optical performance. Good agreement between the thermal simulation of the 3D laser head and experiments validates stable thermal performance. The laser system emits 40-100 W continuous wave at λ = 452.2 ± 2.5 nm with 98% power stability and ∼24% wall-plug efficiency inside a portable enclosure. This is the first, to the best of our knowledge, all-solid-state air-cooled laser with a 100 W class output. We achieved kW/cm2 intensity level on an mm-size focus with this source and demonstrated cutting, bending, and soldering copper on a battery pack. Furthermore, the copper-solder joints have nanoscale adhesion without cracks. Additionally, we unveil that 0.5-4 kW/cm2 intensity laser annealing scan makes copper strips mechanically resilient to withstand extreme loading cycles without nanoscale cracks.

Regioselective synthesis and in vitro cytotoxicity evaluation of 3-thiooxindole derivatives: Tubulin polymerization inhibition and apoptosis inducing studies.

Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3-substituted-thiooxindole derivatives as anticancer agents. Among the new series, compounds 7d and 9c exhibited promising cytotoxic activity toward HCT-116 cells with IC50 values of 6.73 ± 0.36 and 6.64 ± 0.95 µM, respectively. Further, AO/EB, DCFDA, and DAPI staining studies were executed to establish the underlying apoptosis mechanism which displayed significant nuclear and morphological alterations. JC-1 staining and annexin V binding assay inferred the loss of mitochondrial membrane potential in HCT-116 cancer cells. Cell cycle analysis showed the treatment of 9c against HCT-116 cells, arrested the cell cycle in G2-M phase. In addition, tubulin binding assay revealed that compound 9c exhibited tubulin polymerase inhibition with IC50 value of 9.73 ± 0.18 µM. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.

Nanodiamonds enable femtosecond-processed ultrathin glass as a hybrid quantum sensor.

The quantum properties of fluorescent nanodiamonds offer great promise for fabricating quantum-enabled devices for physical applications. However, the nanodiamonds need to be suitably combined with a substrate to exploit their properties. Here, we show that ultrathin and flexible glass (thickness 30 microns) can be functionalized by nanodiamonds and nano-shaped using intense femtosecond pulses to design cantilever-based nanomechanical hybrid quantum sensors. Thus fabricated ultrathin glass cantilevers show stable optical, electronic, and magnetic properties of nitrogen-vacancy centers, including well-defined fluorescence with zero-phonon lines and optically detected magnetic resonance (ODMR) near 2.87 GHz. We demonstrate several sensing applications of the fluorescent ultrathin glass cantilever by measuring acoustic pulses, external magnetic field using Zeeman splitting of the NV centers, or CW laser-induced heating by measuring thermal shifting of ODMR lines. This work demonstrates the suitability of the femtosecond-processed fluorescent ultrathin glass as a new versatile substrate for multifunctional quantum devices.

Amelioration of experimentally induced inflammatory arthritis by intra-articular injection of visnagin.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by synovial hyperplasia, cartilage destruction and bone erosion. Visnagin (VIS) is a proven anti-inflammatory agent and in this study, we aimed to evaluate the anti-arthritic activity of VIS when administered via intra-articular (I.A.) route of administration. Materials and methods: RAW 264.7 â€‹cells were stimulated with lipopolysaccharide (LPS) (1 â€‹µg/mL) and treated with VIS at concentrations of 12.5 and 25 â€‹µM. Arthritis was induced in Sprague Dawley rats by administering Complete Freund's Adjuvant (CFA) (1 â€‹mg/mL) through (I.A.) route and treated with VIS via (I.A.) route at doses of 3 and 10 â€‹mg/kg twice a week for 3 weeks. Protective effects were assessed by arthritic score, behavioral studies for pain evaluation, radiological assessment, histopathological examination and molecular studies. Results: Our results indicated that VIS significantly reduced LPS induced inflammation in RAW 264.7 â€‹cells. While in arthritic rats, VIS reduced the disease scorings with improvement towards pain. Pathological examination demonstrated that VIS reduced knee joint inflammation and cartilage destruction. Radiographic analysis and molecular studies also supported the protective effects of VIS. Conclusion: The results of the study imply that VIS exerted potential anti-inflammatory and anti-arthritic activity in in vitro and in vivo models of RA.

Synthesis of indolo/pyrroloazepinone-oxindoles as potential cytotoxic, DNA-intercalating and Topo I inhibitors.

A series of 17 indolo/pyrroloazepinone-oxindole conjugates was synthesized and evaluated for their antiproliferative activity against a panel of selected human cancer cell lines including A549 (lung cancer), HCT116 (colon cancer), MCF7 (breast cancer), and SK-MEL-28 (melanoma). Among the synthesized molecules (14a-m and 15a-d), compound 14d displayed remarkable activity against A549, HCT116 and SK-MEL-28 cells with IC50 values < 4 µM with the best cytotoxicity and a 13-fold selectivity towards lung cancer cells (IC50 value of 2.33 µM) over the normal rat kidney cells (NRK). Further, 14d-mediated apoptosis affected the cellular and nuclear morphology of the cancer cells in a dose-dependent manner. Wound healing and clonogenic assays inferred the inhibition of cell growth and migration. Target-based studies of compound 14d corroborated its DNA-intercalative capability and Topo I inhibitory activity which have been fortified by molecular modeling studies. Finally, the drug-likeness of the potent compound was determined by performing in silico ADME/T prediction studies.

Co-treatment of Nimbolide augmented the anti-arthritic effects of methotrexate while protecting against organ toxicities.

Prolonged exposure to the pharmacological doses of disease-modifying anti-rheumatic drugs (DMARDs) often results in major organ toxicities resulting in poor patient compliance. Methotrexate (MTX) is one of the commonly prescribed DMARDs for the treatment of arthritis, which results in vital organ dysfunction. To retain the anti-arthritic activity of MTX with the reduction in toxicities, combination therapies are warranted. Nimbolide (NMB) is a potent anticancer, anti-inflammatory and anti-fibrotic agent whose potential has been demonstrated in various pre-clinical models. Monoarthritis was developed with Complete Freund's Adjuvant in the knees of Wistar rats and treatment was given with either NMB (3 mg/kg/day) or MTX (2 mg/kg/week) alone or combination therapy (NMB + MTX). The anti-arthritic effects were evaluated by arthritic scoring, radiological imaging, synovial tissue proteins analysis, and histopathological staining. While hepato-renal toxicity was assessed in serum by evaluating the kidney and liver functional parameters, in tissues by oxidative-nitrosative stress markers, and pro-inflammatory cytokines levels. Histopathological analysis was performed to study the extent of tissue damage. Molecular studies like immunoblotting and immunohistochemistry were performed to understand the effect of combination therapy. We thereby report that monotherapy with either NMB or MTX exhibited significant anti-arthritic effects, while combination therapy resulted in augmented anti-arthritic effects with significant reduction in hepato-renal toxicity produced by MTX probably through anti-inflammatory and anti-oxidant effects. Therefore, our proposed combination of NMB and MTX may serve as a potential strategy for the effective management of arthritis.

Dithiocarbamation of spiro-aziridine oxindoles: a facile access to C3-functionalised 3-thiooxindoles as apoptosis inducing agents.

Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecific ring-opening by using in situ generated nucleophilic dithiocarbamates as an instant source of sulfur. This approach afforded C3-functionalised-3-thiooxindoles in good to excellent yields with a wide substrate scope under catalyst-free and mild reaction conditions. These compounds were screened for their anticancer activity against a panel of human cancer cell lines, wherein compound 3u exhibited significant cytotoxic activity against human lung cancer cells with an IC50 value of 4.31 ± 1.88 µM. Phase contrast microscopy as well as different staining assays such as acridine orange/ethidium bromide (AO/EB), DAPI and DCFDA demonstrated the induction of apoptosis in A549 lung cancer cells after treatment with compound 3u. In addition, the clonogenic assay and migration assay demonstrated the ability of compound 3u to inhibit colony formation and cell migration, respectively, in A549 cells in a dose-dependent manner.

Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine.

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity for humans, there is considerable interest in the development of synthetic analogues; in particular, conformationally restricted analogues of nicotine have emerged as promising drug molecules for selective nAChR-targeting ligands. In the present mini-review, we will describe the synthesis of the conformationally restricted analogues of nicotine involving one or more catalytic processes. In particular, we will follow a systematic approach as a function of the heteroarene structure, considering: (a) 2,3-annulated tricyclic derivatives; (b) 3,4-annulated tricyclic derivatives; (c) tetracyclic derivatives; and (d) other polycyclic derivatives. For each of them we will also consider, when carried out, biological studies on their activity for specific nAChR subunits.

Mesenchymal Stem Cell-Derived Exosomes as an Emerging Paradigm for Regenerative Therapy and Nano-Medicine: A Comprehensive Review.

Mesenchymal Stem Cells are potent therapeutic candidates in the field of regenerative medicine, owing to their immunomodulatory and differentiation potential. However, several complications come with their translational application like viability, duration, and degree of expansion, long-term storage, and high maintenance cost. Therefore, drawbacks of cell-based therapy can be overcome by a novel therapeutic modality emerging in translational research and application, i.e., exosomes. These small vesicles derived from mesenchymal stem cells are emerging as new avenues in the field of nano-medicine. These nano-vesicles have caught the attention of researchers with their potency as regenerative medicine both in nanotherapeutics and drug delivery systems. In this review, we discuss the current knowledge in the biology and handling of exosomes, with their limitations and future applications. Additionally, we highlight current perspectives that primarily focus on their effect on various diseases and their potential as a drug delivery vehicle.

Optimal Protein Sequence Design Mitigates Mechanical Failure in Silk ß-Sheet Nanocrystals.

The excellent mechanical strength and toughness of spider silk are well characterized experimentally and understood atomistically using computational simulations. However, little attention has been focused on understanding whether the amino acid sequence of ß-sheet nanocrystals, which is the key to rendering strength to silk fiber, is optimally chosen to mitigate molecular-scale failure mechanisms. To investigate this, we modeled ß-sheet nanocrystals of various representative small/polar/hydrophobic amino acid repeats for determining the sequence motif having superior nanomechanical tensile strength and toughness. The constant velocity pulling of the central ß-strand in the nanocrystal, using steered molecular dynamics, showed that homopolymers of small amino acid (alanine/alanine-glycine) sequence motifs, occurring in natural silk fibroin, have better nanomechanical properties than other modeled structures. Further, we analyzed the hydrogen bond (HB) and ß-strand pull dynamics of modeled nanocrystals to understand the variation in their rupture mechanisms and explore sequence-dependent mitigating factors contributing to their superior mechanical properties. Surprisingly, the enhanced side-chain interactions in homopoly-polar/hydrophobic amino acid models are unable to augment backbone HB cooperativity to increase mechanical strength. Our analyses suggest that nanocrystals of pristine silk sequences most likely achieve superior mechanical strength by optimizing side-chain interaction, packing, and main-chain HB interactions. Thus, this study suggests that the nanocrystal ß-sheet sequence plays a crucial role in determining the nanomechanical properties of silk, and the evolutionary process has optimized it in natural silk. This study provides insight into the molecular design principle of silk with implications in the genetically modified artificial synthesis of silk-like biomaterials.

Spectroscopic investigation of hydrogen and triple-oxygen isotopes in atmospheric water vapor and precipitation during Indian monsoon season.

Water vapor, the most important greenhouse gas in the atmosphere, has four natural stable isotopologues (H216O, H217O, H218O and HD16O), and their isotopic compositions can be used as hydrological tracers. But the underlying processes and pattern-dynamics of the isotopic compositions of atmospheric water vapor and precipitation in response to various meteorological conditions during monsoon season in a tropical hot and humid region is poorly understood. Here, we present results of H and triple-O-isotopes of water in precipitation and atmospheric water vapor during monsoon season exploiting high-resolution integrated cavity output spectroscopy technique. We observed a distinct temporal variation of the isotopic compositions of water at different phases of the monsoon. The diurnal patterns of the isotopic variations were influenced by the local meteorological factors such as temperature, relative humidity and amount of precipitation. We also investigated the monsoonal dynamics of the second-order isotopic parameters, so-called d-excess and 17O-excess along with the influence of local meteorological factors on isotopic variations to improve our understanding of the underlying isotopic fractionation processes. Consequently, our results provide a unique isotopic-fingerprint dataset of rainwater and atmospheric water vapor for a tropical region and thus shed a new light on hydrological and meteorological processes in the atmosphere.

Bioactive compounds from marine invertebrates as potent anticancer drugs: the possible pharmacophores modulating cell death pathways.

Marine invertebrates are extremely diverse, largely productive, untapped oceanic resources with chemically unique bioactive lead compound contributing a wide range of screening for the discovery of anticancer compounds. The lead compounds have unfurled an extensive array of pharmacological properties owing to the presence of polyphenols, alkaloids, terpenoids and other secondary metabolites. The antioxidant, immunomodulatory and anti-tumor activities exhibited, are possibly regulated by the apoptosis induction, scavenging of ROS and modulation of cellular signaling pathways to defy the cellular deafness during carcinogenesis. Despite the enriched bioactive compounds, the marine invertebrates are largely unexplored as identification, screening, pre-clinical and clinical assessment of lead compounds and their synthetic analogs remain a major task to be solved. In the current review, we focus on the principle strategy and underlying mechanisms deployed by the bioactive anticancer compounds derived from marine invertebrates to combat cancer with special insight into the cell death mechanism.

Gas-Phase Isotopic Fractionation Study of Singly and Doubly Deuterated Isotopologues of Water in the H-D Exchange Reaction by Cavity Ring-Down Spectroscopy.

The underlying mechanisms of the triple-oxygen (16O, 17O, and 18O) isotopic content of deuterated (D) isotopologues of water in H-D exchange reactions in the gas phase remain elusive. Herein, we have demonstrated a high-resolution gas-phase spectral analysis of doubly (D2O) and singly (HDO) deuterated isotopologues of water in the region around 7.8 µm using quantum cascade laser-based cavity ring-down spectroscopy. Isotopic fractionations among doubly and singly deuterated species of water, D216O, HD16O, HD17O, and HD18O, in the gas phase were carried out by probing the fundamental and hot band transitions in the ν2 (bending) mode of D2O and the fundamental ν2 transitions for the other water isotopes. We subsequently investigated the fractionations of different D-enriched water isotopologues for the H-D exchange reaction using various mixtures of D2O in H2O. We explored the potential role of triple-oxygen isotopic contents through enrichments and depletions of HD16O, HD17O, and HD18O, involved in the H-D reaction. Our first clear, direct, and quantitative experimental evidence reveals a new picture of gas-phase isotopic fractionation chemistry in a mixture of light and heavy water (H2O-D2O).

Time-resolved nano-Newton force spectroscopy in air and vacuum using a load cell of ultra micro-balance.

We demonstrate a simple and versatile nanomechanical force measuring setup with 1 nN precision in air and vacuum using a load cell of an ultra-microbalance. We validate stability, precision, and linearity of the load cell with simple tests. The setup is customized to measure stress-strain response of biomaterials (silk, leaf, and flower) and capillary force in fluids. We isolated an optical pull force induced by a Watt-level laser reflected from a mirror/solid surface in air, in addition to optical push force. Furthermore, we add an interferometric probe to directly measure nanoscale deflection of cantilever of the load cell in real-time, thus bypassing its conventional electromagnetic readout, to improve speed and precision of the instrument. We demonstrate nanomechanical force measurement in high vacuum with the same precision and employ radiation pressure to calibrate the load cell for various precision measurements.

Ecotoxic impact assessment of graphene oxide on lipid peroxidation at mitochondrial level and redox modulation in fresh water fish Anabas testudineus.

Rapidly expanding nanoparticle industries are predicted to have turnover of ∼$173.95 billion by 2025, indicating an urgency to study their comprehensive toxicological impact(s). Toxic effects of Graphene Oxide (GO) on oxidative stress physiology especially at mitochondrial level and redox modulation in fish in general and in climbing perch Anabas testudineus is absent. Therefore, we have investigated the toxic impacts of sub lethal doses of GO on selected oxidative stress physiology markers, protein and nucleic acid content along with haematological parameters in A. testudineus. Discriminant function and correlation analyses suggest that GO had toxic effects on the fish, as revealed from the studied parameters. Liver and gill tissues had shown strong response to GO than muscle. Augmented gradual accumulation of cellular lipid peroxides, specifically in mitochondria, was noticed. Activity of superoxide dismutase, catalase, and glutathione-S-transferase was augmented in contrast to the lowered level of the reduced glutathione titre. Alleviated total red blood corpuscle count and haemoglobin titre was parallel with an augmentation of white blood corpuscle count under GO administration. The protein level was also alleviated gradually in liver with clear changes in tissue specific nucleic acid levels, which was reduced under GO treatment. Results of the present study indicate that GO induces oxidative stress in cell and mitochondria in fish. Therefore, very careful future practices of use of GO directly, or as cargo in environmental monitoring processes in aquatic models in vitro in general and Pisces model in particular are suggested.

Gold catalysis: regio- and stereoselective total synthesis of xyloketals D and G and the related natural product alboatrin.

A new and efficient one-pot desilylation-gold-catalyzed cycloisomerization of alkynes containing a silyl-protected phenolic -OH and a free alcoholic -OH unit leads selectively to the formation of tetrahydrofuranobenzopyran ring system. This approach has been used for the regio- and stereoselective synthesis of xyloketal D, xyloketal G, and the related natural product alboatrin.