G protein-coupled receptor (GPCR) has been the primary therapeutic targets for many diseases. Agonists and antagonists of various GPCR are estimated to occupy approximately 35% of the drug market (1). Extracellular signals perceived by GPCR are transmitted via G proteins and trigger intracellular signaling cascades resulting in a plethora of physiological responses. G proteins usually are categorized into four main classical subfamilies according to their α subunits: Gαq/11, Gαs, Gαi/o, Gα12/13 (2). Main subunits Gαq/11, Gαs, Gαi/o and G12/13 are commonly thought to be coupled with phospholipase C (PLC), adenylyl cyclase activation, adenylyl cyclase inactivation, and other small GTPase families, respectively (3). Gαq/11 activates phospholipase Cβ pathway leading to intracellular Ca 2+ mobilization. Gαs and Gαi/o proteins regulate adenylyl cyclase activation and inhibition, respectively, which control intracellular cAMP level. Thus, G proteins are important signal transducing molecules for various cellular responses. Malfunction of GPCR signaling pathways are involved in many diseases, such as diabetes, cardiovascular diseases, and certain forms of cancers (4).

Small molecular chemicals targeting individual subtype of G proteins including Gs, Gi/o and Gq has been lacking, except for pertussis toxin being an established selective peptide inhibitor of the Gi/o protein. Recently, a cyclic depsipeptide compound YM-254890 isolated from culture broth of Chromobacterium sp. was reported as a selective inhibitor for the Gq protein by blocking GDP exchange of GTP on the α subunit of Gq complex. However, functional selectivity of YM-254890 towards various G proteins was not fully characterized, primarily due to its restricted availability before 2017. Here, using human coronary artery endothelial cells as a model, we performed a systemic pharmacological evaluation on the functional selectivity of YM- 254890 on multiple G protein-mediated receptor signaling. First, we confirmed that YM-254890, at 30 nM, abolished UTP-activated P2Y2 receptor- mediated Ca2+ signaling and ERK1/2 phosphorylation, indicating its potent inhibition on the Gq protein. However, we unexpectedly found that YM-254890 also significantly suppressed cAMP elevation and ERK1/2 phosphorylation induced by multiple Gs-coupled receptors including β2-adrenegic, adenosine A2 and PGI2 receptors. Surprisingly, although YM-254890 had no impact on CXCR4/Gi/o protein-mediated suppression of cAMP production, it abolished ERK1/2 activation. Further, no cellular toxicity was observed for YM-254890, and it neither affected A23187- or thapsigargin-induced Ca2+ signaling, nor forskolin-induced cAMP elevation and growth factor-induced MAPK signaling. We conclude that YM-254890 is not a selective inhibitor for Gq protein; instead, it acts as a broad spectrum inhibitor for Gq and Gs proteins and exhibits a biased inhibition on Gi/o signaling, without affecting non-GPCR-mediated cellular signaling.

Neurodegenerative disorders cause irreversible damage to the neurons and adversely affect the quality of life. Protein misfolding and their aggregation in specific parts of the brain, mitochondrial dysfunction, calcium load, proteolytic stress, and oxidative stress are among the causes of neurodegenerative disorders. In addition, altered metabolism has been associated with neurodegeneration as evidenced by reductions in glutamine and alanine in transient global amnesia patients, higher homocysteine-cysteine disulfide, and lower methionine decline in serum urea have been observed in Alzheimer’s disease patients. Neurodegeneration thus appears to be a culmination of altered metabolism. The study’s objective is to analyze various attributes like composition, physical properties of the protein, and factors like selectional and mutational forces, influencing codon usage preferences in a panel of genes involved directly or indirectly in metabolism and contributing to neurodegeneration. Various parameters, including gene composition, dinucleotide analysis, Relative synonymous codon usage (RSCU), Codon adaptation index (CAI), neutrality and parity plots, and different protein indices, were computed and analyzed to determine the codon usage pattern and factors affecting it. The correlation of intrinsic protein properties such as the grand average of hydropathicity index (GRAVY), isoelectric point, hydrophobicity, and acidic, basic, and neutral amino acid content has been found to influence codon usage. In genes up to 800 amino acids long, the GC3 content was highly variable, while GC12 content was relatively constant. An optimum CpG content is present in genes to maintain a high expression level as required for genes involved in metabolism. Also observed was a low codon usage bias with a higher protein expression level. Compositional parameters and nucleotides at the second position of codons played essential roles in explaining the extent of bias. Overall analysis indicated that the dominance of selection pressure and compositional constraints and mutational forces shape codon usage.

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Background: Streptococcus pneumonia had many serious serovars for which the vaccination was not yet developed, immunocompromised patients and patients with splenectomy were more susceptible to infection and sepsis by these organisms.Case presentation: We describe septic shock syndrome patient, who is diabetic with splenectomy, whose sepsis is caused by streptococcus pneumonia. The patient had a pneumococcal vaccination after having a splenectomy due to abdominal trauma five years ago. Strain 4 of streptococcus pneumonia caused the patient's septic shock. Results: Patient condition improved after 4 weeks of treatment with antibiotics, thrombolytic, renal replacement therapy and discharged in a good condition, no surgical procedures were needed apart of skin debridement of necrotized tissues. Conclusion: This instance demonstrates the necessity of considering illnesses caused by bacteria that patients have been immunized against when making a differential diagnosis because there are so many serovars present. Even though vaccine development has increased the development of vaccination for S. pneumonia serovars from 7 to 23 in the recent years, there is still a need for novel vaccines that can offer more generalized immunity against other serovars.