Metabolic oscillations on the circadian time scale in Drosophila cells lacking clock genes.

Circadian rhythms are cell-autonomous biological oscillations with a period of about 24 h. Current models propose that transcriptional feedback loops are the primary mechanism for the generation of circadian oscillations. Within this framework, Drosophila S2 cells are regarded as "non-rhythmic" cells, as they do not express several canonical circadian components. Using an unbiased multi-omics approach, we made the surprising discovery that Drosophila S2 cells do in fact display widespread daily rhythms. Transcriptomics and proteomics analyses revealed that hundreds of genes and their products, and in particular metabolic enzymes, are rhythmically expressed in a 24-h cycle. Metabolomics analyses extended these findings and demonstrate that central carbon metabolism and amino acid metabolism are core metabolic pathways driven by protein rhythms. We thus demonstrate that 24-h metabolic oscillations, coupled to gene and protein cycles, take place in nucleated cells without the contribution of any known circadian regulators. These results therefore suggest a reconsideration of existing models of the clockwork in Drosophila and other eukaryotic systems.

Cross-talk between circadian clocks, sleep-wake cycles, and metabolic networks: Dispelling the darkness.

Integration of knowledge concerning circadian rhythms, metabolic networks, and sleep-wake cycles is imperative for unraveling the mysteries of biological cycles and their underlying mechanisms. During the last decade, enormous progress in circadian biology research has provided a plethora of new insights into the molecular architecture of circadian clocks. However, the recent identification of autonomous redox oscillations in cells has expanded our view of the clockwork beyond conventional transcription/translation feedback loop models, which have been dominant since the first circadian period mutants were identified in fruit fly. Consequently, non-transcriptional timekeeping mechanisms have been proposed, and the antioxidant peroxiredoxin proteins have been identified as conserved markers for 24-hour rhythms. Here, we review recent advances in our understanding of interdependencies amongst circadian rhythms, sleep homeostasis, redox cycles, and other cellular metabolic networks. We speculate that systems-level investigations implementing integrated multi-omics approaches could provide novel mechanistic insights into the connectivity between daily cycles and metabolic systems.

Proteomics of Plasmodium vivax malaria: new insights, progress and potential.

INTRODUCTION: Plasmodium vivax has accounted for an enormous share of the global malaria burden in recent years, along with Plasmodium falciparum. The wide distribution of P. vivax and recent evidences of severe and complicated vivax malaria across several endemic regions of the world suggest that this disease may have been more overlooked than benign. While P. falciparum has been extensively studied, P. vivax has received limited research attention owing to its complex nature and absence of a continuous culture system. AREAS COVERED: This review briefly describes the epidemiology of vivax malaria, analyzes challenges towards effective control and summarizes major insights provided by genomics and transcriptomics research in the area. Subsequently, the review provides a detailed description of the applications of proteomics in vivax malaria research, focusing on both host responses and parasite proteomics studies to understand P. vivax biology. Expert commentary: In recent years, proteomics technologies are being used effectively to understand P. vivax biology and the underlying pathogenesis. Technological advances in mass spectrometry configurations, multiomics investigations and emerging strategies such as targeted proteomics may also immensely aid in studying disease severity, improving existing diagnosis and identifying new drug and vaccine targets.

Array-based proteomic approaches to study signal transduction pathways: prospects, merits and challenges.

Very often dysfunctional aspects of various signalling networks are found to be associated with human diseases and disorders. The major characteristics of signal transduction pathways are specificity, amplification of the signal, desensitisation and integration, which is accomplished not solely, but majorly by proteins. Array-based profiling of protein-protein and other biomolecular interactions is a versatile approach, which holds immense potential for multiplex interactome mapping and provides an inclusive representation of the signal transduction pathways and networks. Protein microarrays such as analytical protein microarrays (antigen-antibody interactions, autoantibody screening), RP microarrays (interaction of a particular ligand with all the possible targets in cell), functional protein microarrays (protein-protein or protein-ligand interactions) are implemented for various applications, including analysis of protein interactions and their significance in signalling cascades. Additionally, successful amalgamation of the array-based approaches with different label-free detection techniques allows real-time analysis of interaction kinetics of multiple interaction events simultaneously. This review discusses the prospects, merits and limitations of different variants of array-based techniques and their promising applications for studying the modifications and interactions of biomolecules, and highlights the studies associated with signal transduction pathways and their impact on disease pathobiology.

Multipronged quantitative proteomic analyses indicate modulation of various signal transduction pathways in human meningiomas.

Meningiomas (MGs) are frequent tumors of the CNS originating from the meningeal layers of the spinal cord and the brain. In this study, comparative tissue proteomic analysis of low and high grades of MGs was performed by using iTRAQ-based quantitative proteomics in combination with ESI-quadrupole-TOF and Q-Exactive MS, and results were validated by employing ELISA. Combining the results obtained from two MS platforms, we were able to identify overall 4308 proteins (1% false discover rate), among which 2367 exhibited differential expression (more than and equal to 2 peptide and ≥ 1.5-fold in at least one grade) in MGs. Several differentially expressed proteins were found to be associated with diverse signaling pathways, including integrin, Wnt, Ras, epidermal growth factor receptor, and FGR signaling. Proteins, such as vinculin or histones, which act as the signaling activators to initiate multiple signaling pathways, were found to be upregulated in MGs. Quite a few candidates, such as protein S-100A6, aldehyde dehydrogenase mitochondrial, AHNAK, cytoskeleton-associated protein 4, and caveolin, showed sequential increase in low- and high-grade MGs, whereas differential expressions of collagen alpha-1 (VI), protein S100-A9, 14 kDa phosphohistidine phosphatase, or transgelin-2 were found to be grade specific. Our findings provide new insights regarding the association of various signal transduction pathways in MG pathogenesis and may introduce new opportunities for the early detection and prognosis of MGs.

Challenges and prospects for biomarker research: a current perspective from the developing world.

Majority of deaths due to communicable and non-communicable diseases occur in the low and middle-income nations (LMNs), mainly due to the lack of early diagnoses and timely treatments. In such a scenario, biomarkers serve as an indispensible resource that can be used as indicators of biological processes, specific disease conditions or response to therapeutic interventions. Evaluation, diagnosis and management of diseases in developing world by following/extrapolating the findings obtained on the basis of the research work involving only the populations from the developed countries, could often be highly misleading due to existence of diverse patterns of diseases in developing countries compared to the developed world. Biomarker candidates identified from high-throughput integrated omics technologies have promising potential; however, their actual clinical applications are found to be limited, primarily due to the challenges of disease heterogeneity and pre-analytical variability associated with the biomarker discovery pipeline. Additionally, in the developing world, economic crunches, lack of awareness and education, paucity of biorepositories, enormous diversities in socio-epidemiological background, ethnicity, lifestyle, diet, exposure to various environmental risk factors and infectious agents, and ethical and social issues also cumulatively hinder biomarker discovery ventures. Establishment of standard operating procedures, comprehensive data repositories and exchange of scientific findings are crucial for reducing the variability and fragmentation of data. This review highlights the challenges associated with the discovery, validation and translational phases of biomarker research in LMNs with some of their amenable solutions and future prospects. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge.

Chemical characterization and assessment of antioxidant potentiality of Streptocaulon sylvestre Wight, an endangered plant of sub-Himalayan plains of West Bengal and Sikkim.

BACKGROUND: S. sylvestre Wright is an extremely rare plant, found only in the sub-Himalayan Terai region of West Bengal and neighboring Sikkim foot-hills. The plant has never been evaluated for any pharmaceutical properties. The phytochemical status of the plant is still unknown. Therefore, the aim of the study was to explore the antioxidant and free radical scavenging activities and analysis of bioactive compounds present in S. sylvestre. METHODS: S. sylvestre methanolic extract (SSME) was evaluated for different free radical scavenging activities such as hydroxyl radical, nitric oxide, singlet oxygen, hypochlorous acid, peroxynitrite, superoxide radical and hydrogen peroxide scavenging etc. Iron chelating capacity and inhibition of lipid peroxidation were studied in addition to the assessment of haemolytic activity and erythrocyte membrane stabilizing activity (EMSA). Chemical characterization of SSME were performed by high performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). RESULTS: The results indicate that SSME possess potent antioxidant activity with IC50 value of 113.06 ± 5.67 µg/ml, 63.93 ± 4.16 µg/ml and 142.14 ± 6.13 µg/ml for hydroxyl radical, superoxide radical and hypochlorous acid, respectively. HPLC analysis revealed presence of different phenolic secondary metabolites such as gallic acid, ferulic acid, p-coumaric acid, syringic acid, myricetin, quercetin etc. GC-MS analysis displayed the predominance of γ-sitosterol, vitamin E and squalene in SSME. CONCLUSION: The present study provides a convincing evidence that S. sylvestre not only possess potent antioxidant activity but also can be used as a source of natural bioactive phytochemicals in the future.

Emission, speciation, and evaluation of impacts of non-methane volatile organic compounds from open dump site.

Surface emission from Dhapa, the only garbage disposal ground in Kolkata, is a matter of concern to the local environment and also fuels the issues of occupational and environmental health. Surface emission of the Dhapa landfill site was studied using a flux chamber measurement for nonmethane volatile organic compounds (NMVOCs). Eighteen noncarbonyl volatile organic compounds (VOCs) and 14 carbonyl VOCs, including suspected and known carcinogens, were found in appreciable concentrations. The concentrations of the target species in the flux chamber were found to be significantly higher for most of the species in summer than winter. Surface emission rate of landfill gas was estimated by using two different approaches to assess the applicability for an open landfill site. It was found that the emissions predicted using the model Land GEM version 3.02 is one to two orders less than the emission rate calculated from flux chamber measurement for the target species. Tropospheric ozone formation has a serious impact for NMVOC emission. The total ozone-forming potential (OFP) of the Dhapa dumping ground considering all target NMVOCs was estimated to be 4.9E+04 and 1.2E+05 g/day in winter and summer, respectively. Also, it was found that carbonyl VOCs play a more important role than noncarbonyl VOCs for tropospheric ozone formation. Cumulative cancer risk estimated for all the carcinogenic species was found to be 2792 for 1 million population, while the total noncancer hazard index (HI) was estimated to be 246 for the occupational exposure to different compounds from surface emission to the dump-site workers at Dhapa. Implications: This paper describes the real-time surface emission of NMVOCs from an open municipal solid waste (MSW) dump site studied using a flux chamber. Our study findings indicate that while planning for new landfill site in tropical meteorology, real-time emission data must be considered, rather than relying on modeled data. The formation of tropospheric ozone from emitted NMVOC has also been studied. Our result shows how an open landfill site acts as a source and adds to the tropospheric ozone for the airshed of a metropolitan city.

Alterations in Circadian Rhythms, Sleep, and Physical Activity in COVID-19: Mechanisms, Interventions, and Lessons for the Future.

Although the world is acquitting from the throes of COVID-19 and returning to the regularity of life, its effects on physical and mental health are prominently evident in the post-pandemic era. The pandemic subjected us to inadequate sleep and physical activities, stress, irregular eating patterns, and work hours beyond the regular rest-activity cycle. Thus, perturbing the synchrony of the regular circadian clock functions led to chronic psychiatric and neurological disorders and poor immunological response in several COVID-19 survivors. Understanding the links between the host immune system and viral replication machinery from a clock-infection biology perspective promises novel avenues of intervention. Behavioral improvements in our daily lifestyle can reduce the severity and expedite the convalescent stage of COVID-19 by maintaining consistent eating, sleep, and physical activity schedules. Including dietary supplements and nutraceuticals with prophylactic value aids in combating COVID-19, as their deficiency can lead to a higher risk of infection, vulnerability, and severity of COVID-19. Thus, besides developing therapeutic measures, perpetual healthy practices could also contribute to combating the upcoming pandemics. This review highlights the impact of the COVID-19 pandemic on biological rhythms, sleep-wake cycles, physical activities, and eating patterns and how those disruptions possibly contribute to the response, severity, and outcome of SARS-CoV-2 infection.

Telomerase: a nexus between cancer nanotherapy and circadian rhythm.

Cancer represents a complex disease category defined by the unregulated proliferation and dissemination of anomalous cells within the human body. According to the GLOBOCAN 2020 report, the year 2020 witnessed the diagnosis of approximately 19.3 million new cases of cancer and 10.0 million individuals succumbed to the disease. A typical cell eventually becomes cancerous because of a long-term buildup of genetic instability and replicative immortality. Telomerase is a crucial regulator of cancer progression as it induces replicative immortality. In cancer cells, telomerase inhibits apoptosis by elongating the length of the telomeric region, which usually protects the genome from shortening. Many nanoparticles are documented as being available for detecting the presence of telomerase, and many were used as delivery systems to transport drugs. Furthermore, telomere homeostasis is regulated by the circadian time-keeping machinery, leading to 24-hour rhythms in telomerase activity and TERT mRNA expression in mammals. This review provides a comprehensive discussion of various kinds of nanoparticles used in telomerase detection, inhibition, and multiple drug-related pathways, as well as enlightens an imperative association between circadian rhythm and telomerase activity from the perspective of nanoparticle-based anticancer therapeutics.

AagingBase: a comprehensive database of anti-aging peptides.

The process of aging is an intrinsic and inevitable aspect of life that impacts every living organism. As biotechnological advancements continue to shape our understanding of medicine, peptide therapeutics have emerged as a promising strategy for anti-aging interventions. This is primarily due to their favorable attributes, such as low immunogenicity and cost-effective production. Peptide-based treatments have garnered widespread acceptance and interest in aging research, particularly in the context of age-related therapies. To effectively develop anti-aging treatments, a comprehensive understanding of the physicochemical characteristics of anti-aging peptides is essential. Factors such as amino acid composition, instability index, hydrophobic areas and other relevant properties significantly determine their efficacy as potential therapeutic agents. Consequently, the creation of 'AagingBase', a comprehensive database for anti-aging peptides, aims to facilitate research on aging by leveraging the potential of peptide therapies. AagingBase houses experimentally validated 282 anti-aging peptides collected from 54 research articles and 236 patents. Employing state-of-the-art computational techniques, the acquired sequences have undergone rigorous physicochemical calculations. Furthermore, AagingBase presents users with various informative analyses highlighting atomic compositions, secondary structure fractions, tertiary structure, amino acid compositions and frequencies. The database also offers advanced search and filtering options and similarity search, thereby aiding researchers in understanding their biological functions. Hence, the database enables efficient identification and prioritization of potential peptide candidates in geriatric medicine and holds immense potential for advancing geriatric medicine research and innovations. AagingBase can be accessed without any restriction. Database URL: https://project.iith.ac.in/cgntlab/aagingbase/.

Circadian medicine for aging attenuation and sleep disorders: Prospects and challenges.

Aging causes progressive deterioration of daily rhythms in behavioral and metabolic processes and disruption in the regular sleep-wake cycle. Circadian disruption is directly related to diverse age-induced health abnormalities. Rising evidence from various organisms shows that core clock gene mutations cause premature aging, reduced lifespan, and sleeping irregularities. Improving the clock functions and correcting its disruption by pharmacological interventions or time-regulated feeding patterns could be a novel avenue for effective clinical management of aging and sleep disorders. To this end, many drugs for sleep disorders and anti-aging compounds interact with the core clock machinery and alter the circadian output. Evaluation of dosing time-dependency and circadian regulation of drug metabolism for therapeutic improvement of the existing drugs is another fundamental facet of chronomedicine. Multiple studies have demonstrated dose-dependent manipulation of the circadian period and phase-shifting by pharmacologically active compounds. The chronobiology research field is gradually moving towards the development of novel therapeutic strategies based on targeting the molecular clock or dosing time-oriented medications. However, such translational research ventures would require more experimental evidence from studies on humans. This review discusses the impact of circadian rhythms on aging and sleep, emphasizing the potentiality of circadian medicine in aging attenuation and sleep disorders.

Circadian biology to advance therapeutics for mood disorders.

Mood disorders account for a significant global disease burden, and pharmacological innovation is needed as existing medications are suboptimal. A wide range of evidence implicates circadian and sleep dysfunction in the pathogenesis of mood disorders, and there is growing interest in these chronobiological pathways as a focus for treatment innovation. We review contemporary evidence in three promising areas in circadian-clock-based therapeutics in mood disorders: targeting the circadian system informed by mechanistic molecular advances; time-tailoring of medications; and personalizing treatment using circadian parameters. We also consider the limitations and challenges in accelerating the development of new circadian-informed pharmacotherapies for mood disorders.

Systems Biology of COVID-19 and Human Diseases: Beyond a Bird's Eye View, and Toward One Health.

As we gaze into the future beyond the current coronavirus disease 2019 (COVID-19) pandemic, there is a need to rethink our priorities in planetary health, research funding, and, importantly, the concepts and unchecked assumptions by which we attempt to understand health and prevent illness. Next-generation quantitative omics technologies promise a more profound and panoptic understanding of the dynamic pathophysiological processes and their aberrations in diverse diseased conditions. Systems biology research is highly relevant for COVID-19, a systemic disease affecting multiple organs and biological pathways. In addition, expanding the concept of health beyond humans so as to capture the importance of ecosystem health and recognizing the interdependence of human, animal, and plant health are enormously relevant and timely in the current historical moment of the pandemic. Notably, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing COVID-19, can affect our body clock, and the circadian aspects of this viral infection and host immunity need to be considered for its effective clinical management. Finally, we need to rethink and expand beyond the false binaries such as humans versus nature, and deploy multiomics systems biology research if we intend to design effective, innovative, and socioecological planetary health interventions to prevent future pandemics and ecological crises. We argue here that juxtaposing ecology and human health sciences scholarship is one of the key emerging tenets of 21st-century integrative biology.

The Promises of Proteomics and Metabolomics for Unravelling the Mechanism and Side Effect Landscape of Beta-Adrenoceptor Antagonists in Cardiovascular Therapeutics.

Cardiovascular medicine witnessed notable advances for the past decade. Multiomics research offers a new lens for precision/personalized medicine for existing and emerging drugs used in the cardiovascular clinic. Beta-blockers are vital in treating hypertension and chronic heart failure. However, clinical use of beta-blockers is also associated with side effects and person-to-person variations in their pharmacokinetics and pharmacodynamics. A comprehensive understanding of the mechanisms that underpin the side effect landscape of beta-blockers is imperative to optimize their therapeutic value. In addition, current research emphasizes the circadian clock's vital roles in regulating pharmacological parameters. Administration of the beta-blockers at specific dosing times could potentially improve their effectiveness and reduce their toxic effects. The rapid development of mass spectrometry technologies with chemical proteomics and thermal proteome profiling methods has also substantially advanced our understanding of underlying side effects mechanisms by unbiased deconvolution of drug targets and off-targets. Metabolomics is steadily demonstrating its utility for conducting mechanistic and toxicological analyses of pharmacological compounds. This article discusses the promises of cutting-edge proteomics and metabolomics approaches to investigate the molecular targets, mechanism of action, adverse effects, and dosing time dependency of beta-blockers.

A comprehensive rhythmicity analysis of host proteins and immune factors involved in malaria pathogenesis to decipher the importance of host circadian clock in malaria.

Background: Circadian rhythms broadly impact human health by regulating our daily physiological and metabolic processes. The circadian clocks substantially regulate our immune responses and susceptibility to infections. Malaria parasites have intrinsic molecular oscillations and coordinate their infection cycle with host rhythms. Considering the cyclical nature of malaria, a clear understanding of the circadian regulations in malaria pathogenesis and host responses is of immense importance. Methods: We have thoroughly investigated the transcript level rhythmic patterns in blood proteins altered in falciparum and vivax malaria and malaria-related immune factors in mice, baboons, and humans by analyzing datasets from published literature and comprehensive databases. Using the Metascape and DAVID platforms, we analyzed Gene Ontology terms and physiological pathways associated with the rhythmic malaria-associated host immune factors. Results: We observed that almost 50% of the malaria-associated host immune factors are rhythmic in mice and humans. Overlapping rhythmic genes identified in mice, baboons, and humans, exhibited enrichment (Q < 0.05, fold-enrichment > 5) of multiple physiological pathways essential for host immune and defense response, including cytokine production, leukocyte activation, cellular defense, and response, regulation of kinase activity, B-cell receptor signaling pathway, and cellular response to cytokine stimulus. Conclusions: Our analysis indicates a robust circadian regulation on multiple interconnected host response pathways and immunological networks in malaria, evident from numerous rhythmic genes involved in those pathways. Host immune rhythms play a vital role in the temporal regulation of host-parasite interactions and defense machinery in malaria.

Investigation of serum proteome alterations in human glioblastoma multiforme.

Glioblastoma multiforme (GBM) or grade IV astrocytoma is the most common and lethal adult malignant brain tumor. The present study was conducted to investigate the alterations in the serum proteome in GBM patients compared to healthy controls. Comparative proteomic analysis was performed employing classical 2DE and 2D-DIGE combined with MALDI TOF/TOF MS and results were further validated through Western blotting and immunoturbidimetric assay. Comparison of the serum proteome of GBM and healthy subjects revealed 55 differentially expressed and statistically significant (p <0.05) protein spots. Among the identified proteins, haptoglobin, plasminogen precursor, apolipoprotein A-1 and M, and transthyretin are very significant due to their functional consequences in glioma tumor growth and migration, and could further be studied as glioma biomarkers and grade-specific protein signatures. Analysis of the lipoprotein pattern indicated elevated serum levels of cholesterol, triacylglycerol, and low-density lipoproteins in GBM patients. Functional pathway analysis was performed using multiple software including ingenuity pathway analysis (IPA), protein analysis through evolutionary relationships (PANTHER), database for annotation, visualization and integrated discovery (DAVID), and GeneSpring to investigate the biological context of the identified proteins, which revealed the association of candidate proteins in a few essential physiological pathways such as intrinsic prothrombin activation pathway, plasminogen activating cascade, coagulation system, glioma invasiveness signaling, and PI3K signaling in B lymphocytes. A subset of the differentially expressed proteins was applied to build statistical sample class prediction models for discrimination of GBM patients and healthy controls employing partial least squares discriminant analysis (PLS-DA) and other machine learning methods such as support vector machine (SVM), Decision Tree and Naïve Bayes, and excellent discrimination between GBM and control groups was accomplished.

Mycogenesis of gold nanoparticles using a phytopathogen Alternaria alternata.

The development of an eco-friendly and reliable process for the synthesis of gold nanomaterials (AuNPs) using microorganisms is gaining importance in the field of nanotechnology. In the present study, AuNPs have been synthesized by bio-reduction of chloroauric acid (HAuCl(4)) using the fungal culture filtrate (FCF) of Alternaria alternata. The synthesis of the AuNPs was monitored by UV-visible spectroscopy. The particles thereby obtained were characterized by UV, dynamic light scattering (DLS), X-ray diffraction (XRD), energy dispersive X-ray (EDX) analysis, Fourier transform infrared (FTIR) spectroscopy, atomic force microscopy (AFM) and transmission electron microscopy (TEM). Energy-dispersive X-ray study revealed the presence of gold in the nanoparticles. Fourier transform infrared spectroscopy confirmed the presence of a protein shell outside the nanoparticles which in turn also support their stabilization. Treatment of the fungal culture filtrate with aqueous Au(+) ions produced AuNPs with an average particle size of 12 ± 5 nm. This proposed mechanistic principal might serve as a set of design rule for the synthesis of nanostructures with desired architecture and can be amenable for the large scale commercial production and technical applications.