A comprehensive review on signaling attributes of serine and serine metabolism in health and disease.

Serine is a metabolite with ever-expanding metabolic and non-metabolic signaling attributes. By providing one­carbon units for macromolecule biosynthesis and functional modifications, serine and serine metabolism largely impinge on cellular survival and function. Cancer cells frequently have a preference for serine metabolic reprogramming to create a conducive metabolic state for survival and aggressiveness, making intervention of cancer-associated rewiring of serine metabolism a promising therapeutic strategy for cancer treatment. Beyond providing methyl donors for methylation in modulation of innate immunity, serine metabolism generates formyl donors for mitochondrial tRNA formylation which is required for mitochondrial function. Interestingly, fully developed neurons lack the machinery for serine biosynthesis and rely heavily on astrocytic l-serine for production of d-serine to shape synaptic plasticity. Here, we recapitulate recent discoveries that address the medical significance of serine and serine metabolism in malignancies, mitochondrial-associated disorders, and neurodegenerative pathologies. Metabolic control and epigenetic- and posttranslational regulation of serine metabolism are also discussed. Given the metabolic similarities between cancer cells, neurons and germ cells, we further propose the relevance of serine metabolism in testicular homeostasis. Our work provides valuable hints for future investigations that will lead to a deeper understanding of serine and serine metabolism in cellular physiology and pathology.

Retinoic acid signaling in development and differentiation commitment and its regulatory topology.

Retinoic acid (RA), the derivative of vitamin A/retinol, is a signaling molecule with important implications in health and disease. It is a well-known developmental morphogen that functions mainly through the transcriptional activity of nuclear RA receptors (RARs) and, uncommonly, through other nuclear receptors, including peroxisome proliferator-activated receptors. Intracellular RA is under spatiotemporally fine-tuned regulation by synthesis and degradation processes catalyzed by retinaldehyde dehydrogenases and P450 family enzymes, respectively. In addition to dictating the transcription architecture, RA also impinges on cell functioning through non-genomic mechanisms independent of RAR transcriptional activity. Although RA-based differentiation therapy has achieved impressive success in the treatment of hematologic malignancies, RA also has pro-tumor activity. Here, we highlight the relevance of RA signaling in cell-fate determination, neurogenesis, visual function, inflammatory responses and gametogenesis commitment. Genetic and post-translational modifications of RAR are also discussed. A better understanding of RA signaling will foster the development of precision medicine to improve the defects caused by deregulated RA signaling.

Unlocking gut microbiota potential of dairy cows in varied environmental conditions using shotgun metagenomic approach.

Food security and environmental pollution are major concerns for the expanding world population, where farm animals are the largest source of dietary proteins and are responsible for producing anthropogenic gases, including methane, especially by cows. We sampled the fecal microbiomes of cows from varying environmental regions of Pakistan to determine the better-performing microbiomes for higher yields and lower methane emissions by applying the shotgun metagenomic approach. We selected managed dairy farms in the Chakwal, Salt Range, and Patoki regions of Pakistan, and also incorporated animals from local farmers. Milk yield and milk fat, and protein contents were measured and correlated with microbiome diversity and function. The average milk protein content from the Salt Range farms was 2.68%, with an average peak milk yield of 45 litters/head/day, compared to 3.68% in Patoki farms with an average peak milk yield of 18 litters/head/day. Salt-range dairy cows prefer S-adenosyl-L-methionine (SAMe) to S-adenosyl-L-homocysteine (SAH) conversion reactions and are responsible for low milk protein content. It is linked to Bacteroides fragilles which account for 10% of the total Bacteroides, compared to 3% in the Patoki region. The solid Non-Fat in the salt range was 8.29%, whereas that in patoki was 6.34%. Moreover, Lactobacillus plantarum high abundance in Salt Range provided propionate as alternate sink to [H], and overcoming a Methanobrevibacter ruminantium high methane emissions in the Salt Range. Furthermore, our results identified ruminant fecal microbiomes that can be used as fecal microbiota transplants (FMT) to high-methane emitters and low-performing herds to increase farm output and reduce the environmental damage caused by anthropogenic gases emitted by dairy cows.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

The variation in promoter sequences of the Akt3 gene between cow and buffalo revealed different responses against mastitis.

BACKGROUND: Serine/threonine kinase 3 (AKT3) is a protein-coding gene that is associated with several cattle immune diseases including different tumors and cancers. The objective of this study was to investigate the differences in structures and functions of AKT3 of cow and buffalo cattle. METHODS: The sequence differences of gene-coding sequence (CDS) and core promoter region of AKT3 in cow and buffalo were analyzed by using bioinformatics tools and PCR sequencing. Also, the functional analysis of promoter regulating gene expression by RT-PCR was performed using 500 Holstein cows and buffalos. And, evaluation of AKT3 inflammatory response to the lipopolysaccharide (LPS)-induced mastitis was performed between both species. RESULTS: The results revealed the variation in 6 exons out of 13 exons of the two species of CDS. Also, 4 different regions in 3-kb promoters of the AKT3 gene were significantly different between cow and buffalo species, in which cow's AKT3 promoter sequence region was started from - 371 to - 1247, while in buffalo, the sequence was started from - 371 to - 969 of the promoter crucial region. Thus, the promoter was overexpressed in cows compared to buffaloes. As a result, significant differences (P < 0.05) between the two species in the AKT3 gene expression level related to the LPS stimulation in their mammary epithelial cell line. CONCLUSIONS: This study emphasized the great importance of the structural differences of AKT3 between the animal species on their different responses against immune diseases like mastitis.

Immune Evasion Strategies of Pathogens in Macrophages: the Potential for Limiting Pathogen Transmission.

Preventing pathogen transmission to a new host is of major interest to the immunologist and could benefit from a detailed investigation of pathogen immune evasion strategies. The first line of defense against pathogen invasion is provided by macrophages. When they sense pathogens, macrophages initiate signals to inflammatory and pro-inflammatory cytokines through pattern recognition receptors (PRRs) subsequently mediating phagocytosis and inflammation. The macrophage immune machinery classically includes two subsets: the activated M1 and the activated M2 that respond accordingly in diverse immune challenges. The lipid and glycogen metabolic pathways work together with the lysosome to help the mature phagosome to degrade and eliminate intracellular pathogens in macrophages. The viral evasion strategies are even more complex due to the interplay between autophagy and apoptosis. However, pathogens evolve several strategies to camouflage themselves against immune responses in order to ensure their survival, replication and transmission. These strategies include the muting of PRRs initiated inflammatory responses, attenuation of M1 and/or induction of M2 macrophages, suppression of autophago-lysosomal formation, interference with lipid and glycogen metabolism, and viral mediation of autophagy and apoptosis cross-talk to enhance viral replication. This review focuses on pathogen immune evasion methods and on the strategies used by the host against camouflaged pathogens.

CRISPR/Cas9 therapeutics: a cure for cancer and other genetic diseases.

Cancer is caused by a series of alterations in genome and epigenome mostly resulting in activation of oncogenes or inactivation of cancer suppressor genes. Genetic engineering has become pivotal in the treatment of cancer and other genetic diseases, especially the formerly-niche use of clustered regularly interspaced short palindromic repeats (CRISPR) associated with Cas9. In defining its superior use, we have followed the recent advances that have been made in producing CRISPR/Cas9 as a therapy of choice. We also provide important genetic mutations where CRISPRs can be repurposed to create adaptive immunity to fight carcinomas and edit genetic mutations causing it. Meanwhile, challenges to CRISPR technology are also discussed with emphasis on ability of pathogens to evolve against CRISPRs. We follow the recent developments on the function of CRISPRs with different carriers which can efficiently deliver it to target cells; furthermore, analogous technologies are also discussed along CRISPRs, including zinc-finger nuclease (ZFN) and transcription activator-like effector nucleases (TALENs). Moreover, progress in clinical applications of CRISPR therapeutics is reviewed; in effect, patients can have lower morbidity and/or mortality from the therapeutic method with least possible side-effects.

Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Modulates Interferon-ß Expression Mainly Through Attenuating Interferon-Regulatory Factor 3 Phosphorylation.

Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) that emerged from classic PRRSV causes more severe damage to the swine industry. The earlier reports indicating inhibition of interferon-ß (IFN-ß) expression by PRRSV through total blockage of IFN-regulatory factor 3 (IRF3) nuclear translocation made us investigate the mechanism of IFN-ß expression in HP-PRRSV infection. For this purpose, the IRF3 nuclear translocation in the control group [Poly (I:C)] and test group [Poly (I:C)+HP-PRRSV] was detected by immunofluorescence, and the results showed that IRF3 nuclear translocation in cells with PRRSV was weaker than cells without PRRSV, which was different from the previous study. In addition, the IFN-ß mRNA and protein expression was observed to be inhibited by HP-PRRSV along with decreased IRF3 mRNA and total protein, and IRF3 nuclear translocation of test group was suppressed in MARC-145 and porcine alveolar macrophage cells in comparison with the control group. The quantity of phosphorylated IRF3 protein was also reduced after HP-PRRSV infection. However, CREB-binding protein (CBP) expression did not change between the control and test group. These results indicate that the inhibition of IFN-ß expression is mainly due to the quantitative change in the amount of phosphorylated IRF3 in the cytoplasm, but not dependent on the complete blockage of IRF3 nuclear translocation or the restraining of CBP expression in the nucleus by HP-PRRSV.

SUMOylation: A link to future therapeutics.

SUMOylation, much of a similar process like ubiquitination catches attention across various research groups as a potential therapeutic target to fight various infectious and cancerous diseases. This idea take its strength from recent reports which unearth the molecular mechanisms of SUMOylation and its involvement in important diseases distributed across various kingdoms. At the beginning SUMOylation was considered a process affected only by viral diseases but subsequent reports enlighten its role in diseases caused by bacteria as well. This enhances the SUMOylation canvas and demanded more in-depth study of the process. The present review is an attempt to study the regulatory mechanism of genes when the natural SUMOylation pathway is disturbed, the cross-talk among SUMOylation and other post translational modifications, the role of miRNAs in controlling the function of transcripts, loading of RNA species into exosomes and the possible SUMOylation related therapeutic targets.

Recent developments in therapeutic protein expression technologies in plants.

Infectious diseases and cancers are some of the commonest causes of deaths throughout the world. The previous two decades have witnessed a combined endeavor across various biological sciences to address this issue in novel ways. The advent of recombinant DNA technologies has provided the tools for producing recombinant proteins that can be used as therapeutic agents. A number of expression systems have been developed for the production of pharmaceutical products. Recently, advances have been made using plants as bioreactors to produce therapeutic proteins directed against infectious diseases and cancers. This review highlights the recent progress in therapeutic protein expression in plants (stable and transient), the factors affecting heterologous protein expression, vector systems and recent developments in existing technologies and steps towards the industrial production of plant-made vaccines, antibodies, and biopharmaceuticals.