Role of Bcl-2 family proteins and caspases in the regulation of apoptosis

Apoptosis, or programmed cell death, plays a pivotal role in the elimination of unwanted, damaged, or infected cells in multicellular organisms and also in diverse biological processes, including development, cell differentiation, and proliferation. Apoptosis is a highly regulated form of cell death, and dysregulation of apoptosis results in pathological conditions including cancer, autoimmune and neurodegenerative diseases. The Bcl-2 family proteins are key regulators of apoptosis, which include both anti- and pro-apoptotic proteins, and a slight change in the dynamic balance of these proteins may result either in inhibition or promotion of cell death. Execution of apoptosis by various stimuli is initiated by activating either intrinsic or extrinsic pathways which lead to a series of downstream cascade of events, releasing of various apoptotic mediators from mitochondria and activation of caspases, important for the cell fate. In view of recent research advances about underlying mechanism of apoptosis, this review highlights the basics concept of apoptosis and its regulation by Bcl-2 family of protein. Furthermore, this review discusses the interplay of various apoptotic mediators and caspases to decide the fate of the cell. We expect that this review will add to the pool of basic information necessary to understand the mechanism of apoptosis which may implicate in designing better strategy to develop biomedical therapy to control apoptosis.     

One size fits all in prostate cancer: a story tale whose time has come and gone

The touchstone to evaluate accurately the aggressiveness and invasiveness of prostate cancer is something of a holy grail in the facet of urologic oncology. Gene expression and sequencing studies have improved our interpretations of the genetic determinants of the disease but are unsuccessful in the establishment of any unified classification to improve the molecular stratification. These questions addressing failure in rational drug design are difficult to answer in the multifaceted and heterogeneous pathogenesis of prostate cancer. In this review, we have developed a roadmap of the "recalcitrant prostate cancer proteome" to recognize the aspects of prostate cancer that may be helpful in effectively translating these findings to the clinic.     

Cellular impact of combinations of endosulfan,atrazine, and chlorpyrifos on human primary hepatocytes and HepaRG cells after short and chronic exposures

Chronic exposure to low doses of pesticides present in the environment is increasingly suspected to cause major health issues to humans. Toxicological evaluations become more complex when the exposure concerns chemical combinations. Atrazine, chlorpyrifos, and endosulfan are pesticides used worldwide in agriculture and are therefore currently found at residual levels in food and the environment, even in countries in which they are now banned. Our study aimed to use Real-Time Cell Impedance Analyzer to investigate changes in phenotypical status of primary human hepatocytes and differentiated HepaRG cells induced by short and chronic exposures to these three chemicals. In contrast to the traditionally used endpoint cytotoxicity test, this technology allows kinetic measurements in real-time throughout the entire experiment. Our data show significantly higher cytotoxic effects of mixtures as compared to individual pesticides and a greater susceptibility of human hepatocytes as compared to HepaRG to short-term exposure (24 h). Repeated exposure over 2 weeks to endosulfan and endosulfan-containing mixture induced HepaRG cell death in a time- and dose-dependent manner. Of the typical genes involved in metabolism and cell-response to xenobiotics, we found an exposure time- and condition-dependent deregulation of the expression of CYP3A4 and UGT1A in HepaRG cells exposed to low doses of pesticides and mixtures. Our data demonstrate the usefulness of real-time cell monitoring in long-term toxicological evaluations of co-exposure to xenobiotics. In addition, they support but at the same time highlight certain limitations in the use of HepaRG cells as the gold standard liver cell model in toxicity studies.     

Genetic improvement of peanut (Arachis hypogea L.) genotypes by developing short duration hybrids

Peanut, the only cash crop of rainfed areas of Pakistan, is facing immense challenges due to global warming. Climatic factors particularly the temperature fluctuations and rain pattern shift significantly impact the production and yield of peanut and unavailability of resilient varieties exacerbate this impact. To deal with the cropping pattern change and yield losses, due to climate vagaries, a study was conducted to develop early maturing hybrids using line into tester mating design. The F₁ hybrids from the parental lines were produced in the year 2018 using Line × Tester mating design and then grown in the field in the year 2019 for further evaluation. The hybrids were evaluated based on the early maturity and yield-related attributes in comparison with the parental lines. Based on the general combining ability estimate, line V-3 (Golden), was found as best parent with highly significant values for plant height, days to peg formation, days to maturity, number of pegs per plant, number of pods per plants, number of seeds per plant, 100 pod weight 100 seed weight. Similarly, tester V-7 (PI 635006 01 SD) showed highly significant results of GCA for days to germination, day to 50% flowering, plant height, days to peg formation, days to maturity, number of pegs per plant, number of pods per plants, number of seeds per plant, 100 kernel weight, shelling percentage. All the combinations were evaluated for specific combining ability and significant results were observed for V-3 × V-4 (Golden × PI 619175 01 SD) and V-1 × V-6 (BARI-2000 × PI 564846 01 SD) by developing or maturity and yield-related attributes. The hybrid combinations V-3 × V-5 (Golden × PI 635006 01 SD) followed by V-3 × V-6 showed highly significant results for mid parent heterosis and better parent heterosis for days to 50% flowering, plant height, days to peg formation, number of pegs, days to maturity, number of mature seeds per plant, shelling ratio, 100 pod weight and 100 kernel weight. These parents and hybrid combinations with early maturity genes and high yield attributes can further be used for the development of short duration variety.     

Metabolism of benzonitrile and butyronitrile by Klebsiella pneumoniae.

A strain of Klebsiella pneumoniae that used aliphatic nitriles as the sole source of nitrogen was adapted to benzonitrile as the sole source of carbon and nitrogen. Gas chromatographic and mass spectral analyses of culture filtrates indicated that K. pneumoniae metabolized 8.4 mM benzonitrile to 4.0 mM benzoic acid and 2.7 mM ammonia. In addition, butyronitrile was metabolized to butyramide and ammonia. The isolate also degraded mixtures of benzonitrile and aliphatic nitriles. Cell extracts contained nitrile hydratase and amidase activities. The enzyme activities were higher with butyronitrile and butyramide than with benzonitrile and benzamide, and amidase activities were twofold higher than nitrile hydratase activities. K. pneumoniae appears promising for the bioremediation of sites contaminated with aliphatic and aromatic nitriles.     

Effects of nickel toxicity on morphological and physiological aspects of osmoregulation in <Emphasis Type="Italic">Typha domingensis</Emphasis> (<Emphasis Type="Italic">Typhaceae</Emphasis>) populations

The present work examined morphological and physiological aspects of osmoregulation in some differently adapted populations of Typha domingensis. Six populations of T. domingensis were grown in waterlogged conditions under four levels of nickel (0, 50, 100 and 1500 mg/kg of Ni). The Ni tolerance was explored on the basis of different characteristics of shoots. Along with the increasing level of Ni stress, all populations showed an increment of proline and glycinebetaine content, low photosynthetic and transpiration rates and decreased chlorophyll content. Analyzed morphological parameters revealed possible adaptations to deal with Ni stress. The less tolerant Sahianwala population produced more aerenchyma, less accumulation of osmolytes and reduced shoot fresh weight under Ni stress than the tolerant ones. Our results suggested that T. domingensis has the capacity to survive under Ni stress and could be used for the absorption of toxic metal ions from industrially polluted water.     

In vitro label‐free screening of chemotherapeutic drugs using Raman microspectroscopy: Towards a new paradigm of spectralomics

This overview groups some of the recent studies highlighting the potential application of Raman microspectroscopy as an analytical technique in preclinical development to predict drug mechanism of action and in clinical application as a companion diagnostic and in personalised therapy due to its capacity to predict cellular resistance and therefore to optimise chemotherapeutic treatment efficacy. Notably, the anthracyclines, doxorubicin and actinomycin D, elicit similar spectroscopic signatures of subcellular interaction characteristic of the mode of action of intercalation. Although cisplatin and vincristine show markedly different signatures, at low exposure doses, their signatures at higher doses show marked similarities to those elicited by the intercalating anthracyclines, confirming that anticancer agents can have different modes of action with different spectroscopic signatures, depending on the dose. The study demonstrates that Raman microspectroscopy can elucidate subcellular transport and accumulation pathways of chemotherapeutic agents, characterise and fingerprint their mode of action, and potentially identify cell‐resistant strains. The consistency of the spectroscopic signatures for drugs of similar modes of action, in different cell lines, suggests that this fingerprint can be considered a “spectralome” of the drug‐cell interaction suggesting a new paradigm of representing spectroscopic responses.