Cellular Actions Research Articles

Metabolic Regulation of Inflammation: Exploring the Potential Benefits of Itaconate in Autoimmune Disorders.

Itaconic acid and its metabolites have demonstrated significant therapeutic potential in various immune diseases. Originating from the tricarboxylic acid cycle in immune cells, itaconic acid can modulate immune responses, diminish inflammation, and combat oxidative stress. Recent research has uncovered multiple mechanisms through which itaconic acid exerts its effects, including the inhibition of inflammatory cytokine production, activation of anti-inflammatory pathways, and modulation of immune cell function by regulating cellular metabolism. Cellular actions are influenced by the modulation of metabolic pathways, such as inhibiting succinate dehydrogenase (SDH) activity or glycolysis, activation of nuclear-factor-E2-related factor 2 (Nrf2), boosting cellular defences against oxidative stress, and suppression of immune cell inflammation through the NF-κB pathway. This comprehensive review discusses the initiation, progression, and mechanisms of action of itaconic acid and its metabolites, highlighting their modulatory effects on various immune cell types. Additionally, it examines their involvement in immune disease like rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, and autoimmune hepatitis, offering greater understanding for creating new therapies for these ailments.

Explore the Role of the Sphingosine-1-Phosphate Signalling as a Novel Promising Therapeutic Target for the Management of Parkinson's Disease.

Sphingosine-1-phosphate (S1P) is a cellular signalling molecule derived from sphingosine, which is a pro-apoptotic sphingolipid. Sphingolipids control various cellular actions like growth, homeostasis, and stress-related responses. The main sources of S1P in our body are erythrocytes. S1P controls both cellular mediators and other second messengers intracellularly. The S1P receptor also helps in inflammatory and neuroprotective effects (required to manage of Parkinson's). A large number of anti-Parkinson drugs are available, but still, there is a need for more effective and safer drugs. S1P and its receptors could be targeted as novel drugs due to their involvement in neuro-inflammation and Parkinson's. The present review effort to explore the biological role of S1P and related receptors, for their possible involvement in PD; furthermore. Overall, S1P and other related metabolizing enzymes have significant therapeutic opportunities for Parkinson's disease along with other neurological disorders.

Effects of imidazole derivatives on cellular proliferation and apoptosis in myeloid leukemia.

Acute promyelocytic leukemia (APL) is the sub-type of Acute myeloid leukemia (AML) which is described by differentiation block at promyelocytic stage and t(15; 17) translocation with All trans retinoic acid (ATRA) and arsenic trioxide (ATO) as standard treatments. Chronic myeloid leukemia (CML) translocation t (19; 22) causes a rise in granulocytes and their immature precursors in the blood. Different mutations cause resistance to first-line tyrosine kinase therapies in CML. Beside drug resistance, leukemia stem cells (LSC) are critical resources for relapse and resistance in APL and CML. The drug toxicity and resistant profile associated with LSC and current therapeutics of APL and CML necessitate the development of new therapies. Imidazoles are heterocyclic nitrogen compounds with diverse cellular actions. The purpose of this research was to assess the anti-leukemic properties of four novel imidazole derivatives including L-4, L-7, R-35, and R-NIM04. Pharmacological and biochemical approaches were used which showed that all four imidazole derivatives interfere with the NB4 cells proliferation, an APL cell line, while only L-7 exhibit anti-proliferative activity against K562 cells, a CML cell line. The anti-proliferative effect of imidazole derivatives was linked to apoptosis induction. Further real-time polymerase chain reaction (RT-PCR) analysis revealed downregulation of AXL-Receptor Tyrosine Kinase (AXL-RTK) and target genes of Wnt/beta-catenin pathway like c-Myc, Axin2 and EYA3. An additive effect was observed after combinatorial treatment of L-7 with standard drugs ATRA or Imatinib on the proliferation of NB4 and K562 cells respectively which was related to further downregulation of target genes of Wnt/beta catenin pathway. Imidazole derivatives significantly reduce proliferation of NB4 and K562 cells by inducing apoptosis, down regulating of AXL-RTK and Wnt/β-catenin target genes.

Re-Assessing the Role of Platelet Activating Factor and Its Inflammatory Signaling and Inhibitors in Cancer and Anti-Cancer Strategies.

Since 2000s, we have outlined the multifaceted role of inflammation in several aspects of cancer, via specific inflammatory mediators, including the platelet activating factor (PAF) and PAF-receptor (PAFR) related signaling, which affect important inflammatory junctions and cellular interactions that are associated with tumor-related inflammatory manifestations. It is now well established that disease-related unresolved chronic inflammatory responses can promote carcinogenesis. At the same time, tumors themselves are able to promote their progression and metastasis, by triggering an inflammation-related vicious cycle, in which PAF and its signaling play crucial role(s), which usually conclude in tumor growth and angiogenesis. In parallel, new evidence suggests that PAF and its signaling also interact with several inflammation-related cancer treatments by inducing an antitumor immune response or, conversely, promoting tumor recurrence. Within this review article, the current knowledge and future perspectives of the implication of PAF and its signaling in all these important aspects of cancer are thoroughly re-assessed. The potential beneficial role of PAF-inhibitors and natural or synthetic modulators of PAF-metabolism against tumors, tumor progression and metastasis are evaluated. Emphasis is given to natural and synthetic molecules with dual anti-PAF and anti-cancer activities (Bio-DAPAC-tives), with proven evidence of their antitumor potency through clinical trials, as well as on metal-based anti-inflammatory mediators that constitute a new class of potent inhibitors. The way these compounds may promote anti-tumor effects and modulate the inflammatory cellular actions and immune responses is also discussed. Limitations and future perspectives on targeting of PAF, its metabolism and receptor, including PAF-related inflammatory signaling, as part(s) of anti-tumor strategies that involve inflammation and immune response(s) for an improved outcome, are also evaluated.

Involvement of mitogen- and stress-activated protein kinase 1 in BMP-6–induced chondrocyte differentiation

Bone morphogenetic proteins (BMPs) are involved in several cellular responsive actions, such as development, cell differentiation, and apoptosis, via their specific transmembrane receptors. In particular, BMPs promote the differentiation and maturation of bone and cartilage from mesenchymal stem cells. Based on comprehensive analyses performed with a large number of antibodies, mitogen- and stress-activated protein kinase (MSK)1 was found to be immediately phosphorylated in the mouse chondrocyte precursor cell line, ATDC5, upon BMP-6 stimulation. The overexpression and knockdown of MSK1 in ATDC5 cells also enhanced and suppressed BMP-6-induced chondrocyte differentiation, respectively. Similar to ATDC5 cells, an exvivo organ culture system using mouse embryonic metatarsal bones also demonstrated that BMP-6-mediated MSK1 activation might play a role in chondrocyte differentiation. Using several inhibitors, the p38 kinase pathway was confirmed to be implicated in BMP-6-induced phosphorylation of MSK1. Furthermore, MSK1 mutants lacking kinase activities and those lacking serine/threonine residues targeted by p38 kinase severely impaired their ability to potentiate BMP-6-induced chondrogenic differentiation of ATDC5 cells. Interestingly, a loss-of-function study for Smad4 perturbed BMP-6-induced phosphorylation of p38 kinase to inhibit BMP-6-mediated chondrocyte differentiation via MSK1 activation. Overall, both Smad-dependent and independent pathways require BMP-6-induced chondrocyte differentiation via MSK1 activation in ATDC5 cells.

MicroRNAs role in telomere length maintenance and telomerase activity in tumor cells.

MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of thehuman telomerase reverse transcriptase(hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells.Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.

Molecular nociceptive mechanisms in migraine: The migraine cascade.

This review will explore the categorization of migraine-provoking molecules, their cellular actions, site of action and potential drug targets based on the migraine cascade model. Personal experience and literature. Migraine impacts over 1 billion people worldwide but is underfunded in research. Recent progress, particularly through the human and animal provocation model, has deepened our understanding of its mechanisms. This model have identified endogenous neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) that induces controlled migraine-like attacks leading to significant discoveries of their role in migraine. This knowledge led to the development of CGRP-inhibiting drugs; a groundbreaking migraine treatment now accessible globally. Also a PACAP-inhibiting drug was effective in a recent phase II trial. Notably, rodent studies have shed light on pain pathways and the mechanisms of various migraine-inducing substances identifying novel drug targets. This is primarily done by using selective inhibitors that target specific signaling pathways of the known migraine triggers leading to the hypothesized cellular cascade model of migraine. The model of migraine presents numerous opportunities for innovative drug development. The future of new migraine treatments is limited only by the investment from pharmaceutical companies.

The conjugation of tigerinin-1r with modified gastric inhibitory polypeptide enhanced its cellular uptake and metabolic actions

The conjugation of tigerinin-1r with modified gastric inhibitory polypeptide enhanced its cellular uptake and metabolic actions

Integrating inverse reinforcement learning into data-driven mechanistic computational models: a novel paradigm to decode cancer cell heterogeneity

Cellular heterogeneity is a ubiquitous aspect of biology and a major obstacle to successful cancer treatment. Several techniques have emerged to quantify heterogeneity in live cells along axes including cellular migration, morphology, growth, and signaling. Crucially, these studies reveal that cellular heterogeneity is not a result of randomness or a failure in cellular control systems, but instead is a predictable aspect of multicellular systems. We hypothesize that individual cells in complex tissues can behave as reward-maximizing agents and that differences in reward perception can explain heterogeneity. In this perspective, we introduce inverse reinforcement learning as a novel approach for analyzing cellular heterogeneity. We briefly detail experimental approaches for measuring cellular heterogeneity over time and how these experiments can generate datasets consisting of cellular states and actions. Next, we show how inverse reinforcement learning can be applied to these datasets to infer how individual cells choose different actions based on heterogeneous states. Finally, we introduce potential applications of inverse reinforcement learning to three cell biology problems. Overall, we expect inverse reinforcement learning to reveal why cells behave heterogeneously and enable identification of novel treatments based on this new understanding.

A tail of their own: regulation of cardiolipin and phosphatidylinositol fatty acyl profile by the acyltransferase LCLAT1.

Cardiolipin and phosphatidylinositol along with the latter's phosphorylated derivative phosphoinositides, control a wide range of cellular functions from signal transduction, membrane traffic, mitochondrial function, cytoskeletal dynamics, and cell metabolism. An emerging dimension to these lipids is the specificity of their fatty acyl chains that is remarkably distinct from that of other glycerophospholipids. Cardiolipin and phosphatidylinositol undergo acyl remodeling involving the sequential actions of phospholipase A to hydrolyze acyl chains and key acyltransferases that re-acylate with specific acyl groups. LCLAT1 (also known as LYCAT, AGPAT8, LPLAT6, or ALCAT1) is an acyltransferase that contributes to specific acyl profiles for phosphatidylinositol, phosphoinositides, and cardiolipin. As such, perturbations of LCLAT1 lead to alterations in cardiolipin-dependent phenomena such as mitochondrial respiration and dynamics and phosphoinositide-dependent processes such as endocytic membrane traffic and receptor signaling. Here we examine the biochemical and cellular actions of LCLAT1, as well as the contribution of this acyltransferase to the development and specific diseases.

Rafting on the Evidence for Lipid Raft-like Domains as Hubs Triggering Environmental Toxicants' Cellular Effects.

The plasma membrane lipid rafts are cholesterol- and sphingolipid-enriched domains that allow regularly distributed, sub-micro-sized structures englobing proteins to compartmentalize cellular processes. These membrane domains can be highly heterogeneous and dynamic, functioning as signal transduction platforms that amplify the local concentrations and signaling of individual components. Moreover, they participate in cell signaling routes that are known to be important targets of environmental toxicants affecting cell redox status and calcium homeostasis, immune regulation, and hormonal functions. In this work, the evidence that plasma membrane raft-like domains operate as hubs for toxicants' cellular actions is discussed, and suggestions for future research are provided. Several studies address the insertion of pesticides and other organic pollutants into membranes, their accumulation in lipid rafts, or lipid rafts' disruption by polychlorinated biphenyls (PCBs), benzo[a]pyrene (B[a]P), and even metals/metalloids. In hepatocytes, macrophages, or neurons, B[a]P, airborne particulate matter, and other toxicants caused rafts' protein and lipid remodeling, oxidative changes, or amyloidogenesis. Different studies investigated the role of the invaginated lipid rafts present in endothelial cells in mediating the vascular inflammatory effects of PCBs. Furthermore, in vitro and in vivo data strongly implicate raft-localized NADPH oxidases, the aryl hydrocarbon receptor, caveolin-1, and protein kinases in the toxic mechanisms of occupational and environmental chemicals.

Chemical and cell antioxidant activity of amaranth flour and beverage after simulated gastrointestinal digestion. Role of peptides

The potential of peptides generated by simulated gastrointestinal digestion (SGID) of two products derived from Amaranthus manteggazianus seeds, flour (F) and beverage (B), to exert peroxyl scavenging activity (ORAC) and antioxidant action on intestinal cells was studied. B was prepared by solubilisation of seed proteins, with the addition of gums and the application of a pasteurization treatment. The gastrointestinal digests FD and BD showed some differences in the peptide/polypeptide composition. The SGID produced increased ORAC activity for both samples, with some differences in the ORAC of the whole digests BD and FD and of some gel filtration fractions. Bioaccessible fractions (FDdbs and BDdbs) were obtained after treatment with cholestyramine resin to remove bile salts due to their cytotoxicity and oxidative effect. BDdbs presented a greater ORAC potency (IC50: 0.05 ± 0.01 and 0.008 ± 0.004 mg protein/ml for FDdbs and BDdbs, respectively). These fractions showed low cytotoxicity values (measured by LDH release) and produced high intracellular ROS inhibition (around 80 %), increased the SOD activity and the GSH content, with no effect on GPx activity in Caco2-TC7 cells exposed to H2O2. Several fractions with MM < 2.2 kDa presented also these cellular actions; fractions from FD induced higher increases in GSH concentration. Amaranth flour and a processed matrix like the beverage are shown as sources of bioactive peptides with potential cell antioxidant activity.

Estradiol receptors inhibit long-term potentiation in the dorsomedial striatum.

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation in ex vivo brain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrus stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus did not exhibit LTP. Furthermore, antagonists of ERα or GPER rescued LTP in estrus females and agonists of ERα or GPER reduced LTP in diestrus females. In males, activating ERα but not GPER reduced LTP. These results uncover an inhibitory action of estradiol receptors on cellular learning in the DMS and suggest a cellular mechanism underlying the impairment in certain types of DMS-based learning observed in the presence of high estradiol. Due to the dorsal striatum's role in drug addiction, these findings may provide a mechanism underlying an estradiol-mediated progression from goal-directed to habitual drug use.Significance StatementThis study examined the role of the female reproductive cycle and female sex hormones in synaptic plasticity, a cellular process that underlies learning behavior, in a brain region involved in goal-directed learning. Synaptic plasticity was similar between male mice and female mice in the low estradiol phase of the cycle. In contrast, female mice in a high estradiol phase of the cycle did not exhibit synaptic plasticity. The effect of estradiol was mediated by two of the three estradiol receptors found in the brain. The results have implications for the role of the female reproductive cycle in the development of drug addiction, which involves a progression from goal-directed learning to habit-based learning as drug use switches from recreational to compulsive.

Cellular Responses and Targets in Food Spoilage Yeasts Exposed to Antifungal Prenylated Isoflavonoids.

Prenylated isoflavonoids are phytochemicals with promising antifungal properties. Recently, it was shown that glabridin and wighteone disrupted the plasma membrane (PM) of the food spoilage yeast Zygosaccharomyces parabailii in distinct ways, which led us to investigate further their modes of action (MoA). Transcriptomic profiling with Z. parabailii showed that genes encoding transmembrane ATPase transporters, including Yor1, and genes homologous to the pleiotropic drug resistance (PDR) subfamily in Saccharomyces cerevisiae were upregulated in response to both compounds. Gene functions involved in fatty acid and lipid metabolism, proteostasis, and DNA replication processes were overrepresented among genes upregulated by glabridin and/or wighteone. Chemogenomic analysis using the genome-wide deletant collection for S. cerevisiae further suggested an important role for PM lipids and PM proteins. Deletants of gene functions involved in biosynthesis of very-long-chain fatty acids (constituents of PM sphingolipids) and ergosterol were hypersensitive to both compounds. Using lipid biosynthesis inhibitors, we corroborated roles for sphingolipids and ergosterol in prenylated isoflavonoid action. The PM ABC transporter Yor1 and Lem3-dependent flippases conferred sensitivity and resistance, respectively, to the compounds, suggesting an important role for PM phospholipid asymmetry in their MoAs. Impaired tryptophan availability, likely linked to perturbation of the PM tryptophan permease Tat2, was evident in response to glabridin. Finally, substantial evidence highlighted a role of the endoplasmic reticulum (ER) in cellular responses to wighteone, including gene functions associated with ER membrane stress or with phospholipid biosynthesis, the primary lipid of the ER membrane. IMPORTANCE Preservatives, such as sorbic acid and benzoic acid, inhibit the growth of undesirable yeast and molds in foods. Unfortunately, preservative tolerance and resistance in food spoilage yeast, such as Zygosaccharomyces parabailii, is a growing challenge in the food industry, which can compromise food safety and increase food waste. Prenylated isoflavonoids are the main defense phytochemicals in the Fabaceae family. Glabridin and wighteone belong to this group of compounds and have shown potent antifungal activity against food spoilage yeasts. The present study demonstrated the mode of action of these compounds against food spoilage yeasts by using advanced molecular tools. Overall, the cellular actions of these two prenylated isoflavonoids share similarities (at the level of the plasma membrane) but also differences. Tryptophan import was specifically affected by glabridin, whereas endoplasmic reticulum membrane stress was specifically induced by wighteone. Understanding the mode of action of these novel antifungal agents is essential for their application in food preservation.

New medications development for smoking cessation

Diseases associated with nicotine dependence in the form of habitual tobacco use are a major cause of premature death in the United States. The majority of tobacco smokers will relapse within the first month of attempted abstinence. Smoking cessation agents increase the likelihood that smokers can achieve long-term abstinence. Nevertheless, currently available smoking cessation agents have limited utility and fail to prevent relapse in the majority of smokers. Pharmacotherapy is therefore an effective strategy to aid smoking cessation efforts but considerable risk of relapse persists even when the most efficacious medications currently available are used. The past decade has seen major breakthroughs in our understanding of the molecular, cellular, and systems-level actions of nicotine in the brain that contribute to the development and maintenance of habitual tobacco use. In parallel, large-scale human genetics studies have revealed allelic variants that influence vulnerability to tobacco use disorder. These advances have revealed targets for the development of novel smoking cessation agents. Here, we summarize current efforts to develop smoking cessation therapeutics and highlight opportunities for future efforts.

Crosstalk Between the Nervous System and Systemic Organs in Acute Brain Injury.

Organ crosstalk is a complex biological communication between distal organs mediated via cellular, soluble, and neurohormonal actions, based on a two-way pathway. The communication between the central nervous system and peripheral organs involves nerves, endocrine, and immunity systems as well as the emotional and cognitive centers of the brain. Particularly, acute brain injury is complicated by neuroinflammation and neurodegeneration causing multiorgan inflammation, microbial dysbiosis, gastrointestinal dysfunction and dysmotility, liver dysfunction, acute kidney injury, and cardiac dysfunction. Organ crosstalk has become increasingly popular, although the information is still limited. The present narrative review provides an update on the crosstalk between the nervous system and systemic organs after acute brain injury. Future research might help to target this pathophysiological process, preventing the progression toward multiorgan dysfunction in critically ill patients with brain injury.

Anticancer activities of tocotrienols: A Systematic Scoping Review

Background: The increasing number of cancer cases requires developing newer approaches to treat this disease. One approach uses natural compounds with known anticancer effects, such as tocotrienols. Many cell-based and animal-model studies found that tocotrienols possess potent anticancer activities. However, the exact molecular regulatory mechanism through which tocotrienols exert anticancer actions remains unclear. Methods: This scoping review analysed data from original research articles reporting on the anticancer effects of tocotrienols on human cancer cell lines published in the last seven years (January 2015 and September 2021) using a systematic scoping review approach. From the initial 619 research papers [ProQuest (n= 61), PubMed (n= 84), Embase (n = 148), Ovid Medline (n =53), Scopus (n = 137), Web of Science (n =136)] identified using pre-defined keywords, only 37 articles met the inclusion and exclusion criteria for this review. Human cancers commonly studied in the 37 research articles include breast, lung, prostate and colorectal cancer cell lines. Results: The analysis showed that exposing human cancer cell lines to tocotrienols triggered common anticancer mechanisms such as activation of apoptosis and inhibition of proliferation, angiogenesis and cell migration through regulation of key regulatory genes and proteins involved in these pathways. Conclusions: The findings show that tocotrienols regulate a number of biomarkers that induce cell death and regulate cell cycle in various types of human cancer cells. Further targeted studies are required to map the definite pathways by which T3 exerts their action and to better understand the cellular actions and the regulatory pathways.

General anesthetic action profile on the human prefrontal cortex cells through comprehensive single-cell RNA-seq analysis

The cellular and molecular actions of general anesthetics to induce anesthesia state and also cellular signaling changes for subsequent potential "long term" effects remain largely elusive. General anesthetics were reported to act on voltage-gated ion channels and ligand-gated ion channels. Here we used single-cell RNA-sequencing complemented with whole-cell patch clamp and calcium transient techniques to examine the gene transcriptome and ion channels profiling of sevoflurane and propofol, both commonly used clinically, on the human fetal prefrontal cortex (PFC) mixed cell cultures. Both propofol and sevoflurane at clinically relevant dose/concentration promoted "microgliosis" but only sevoflurane decreased microglia transcriptional similarity. Propofol and sevoflurane each extensively but transiently (<2h) altered transcriptome profiling across microglia, excitatory neurons, interneurons, astrocytes and oligodendrocyte progenitor cells. Utilizing scRNA-seq as a robust and high-through put tool, our work may provide a comprehensive blueprint for future mechanistic studies of general anesthetics in clinically relevant settings.

Optimisation Models for Pathway Activity Inference in Cancer.

With advances in high-throughput technologies, there has been an enormous increase in data related to profiling the activity of molecules in disease. While such data provide more comprehensive information on cellular actions, their large volume and complexity pose difficulty in accurate classification of disease phenotypes. Therefore, novel modelling methods that can improve accuracy while offering interpretable means of analysis are required. Biological pathways can be used to incorporate a priori knowledge of biological interactions to decrease data dimensionality and increase the biological interpretability of machine learning models. A mathematical optimisation model is proposed for pathway activity inference towards precise disease phenotype prediction and is applied to RNA-Seq datasets. The model is based on mixed-integer linear programming (MILP) mathematical optimisation principles and infers pathway activity as the linear combination of pathway member gene expression, multiplying expression values with model-determined gene weights that are optimised to maximise discrimination of phenotype classes and minimise incorrect sample allocation. The model is evaluated on the transcriptome of breast and colorectal cancer, and exhibits solution results of good optimality as well as good prediction performance on related cancer subtypes. Two baseline pathway activity inference methods and three advanced methods are used for comparison. Sample prediction accuracy, robustness against noise expression data, and survival analysis suggest competitive prediction performance of our model while providing interpretability and insight on key pathways and genes. Overall, our work demonstrates that the flexible nature of mathematical programming lends itself well to developing efficient computational strategies for pathway activity inference and disease subtype prediction.

A Status Review on Health-Promoting Properties and Global Regulation of Essential Oils.

Since ancient times, essential oils (EOs) have been known for their therapeutic potential against many health issues. Recent studies suggest that EOs may contribute to the regulation and modulation of various biomarkers and cellular pathways responsible for metabolic health as well as the development of many diseases, including cancer, obesity, diabetes, cardiovascular diseases, and bacterial infections. During metabolic dysfunction and even infections, the immune system becomes compromised and releases pro-inflammatory cytokines that lead to serious health consequences. The bioactive compounds present in EOs (especially terpenoids and phenylpropanoids) with different chemical compositions from fruits, vegetables, and medicinal plants confer protection against these metabolic and infectious diseases through anti-inflammatory, antioxidant, anti-cancer, and anti-microbial properties. In this review, we have highlighted some targeted physiological and cellular actions through which EOs may exhibit anti-inflammatory, anti-cancer, and anti-microbial properties. In addition, it has been observed that EOs from specific plant sources may play a significant role in the prevention of obesity, diabetes, hypertension, dyslipidemia, microbial infections, and increasing breast milk production, along with improvements in heart, liver, and brain health. The current status of the bioactive activities of EOs and their therapeutic effects are covered in this review. However, with respect to the health benefits of EOs, it is very important to regulate the dose and usage of EOs to reduce their adverse health effects. Therefore, we specified that some countries have their own regulatory bodies while others follow WHO and FAO standards and legislation for the use of EOs.