Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways.

Glucagon has emerged as a key regulator of extracellular amino acid (AA) homeostasis. Insufficient glucagon signaling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other AA sensors in α cell proliferation has not been described. Here, using both genders of mouse islets and glucagon receptor (gcgr)-deficient zebrafish (Danio rerio), we show α cell proliferation requires activation of the extracellular signal-regulated protein kinase (ERK1/2) by the AA-sensitive calcium sensing receptor (CaSR). Inactivation of CaSR dampened α cell proliferation, which was rescued by re-expression of CaSR or activation of Gq, but not Gi, signaling in α cells. CaSR was also unexpectedly necessary for mTORC1 activation in α cells. Furthermore, coactivation of Gq and mTORC1 induced α cell proliferation independent of hyperaminoacidemia. These results reveal another AA-sensitive mediator and identify pathways necessary and sufficient for hyperaminoacidemia-induced α cell proliferation.

In The Line of Treatment: A Systematic Review of Paroxysmal Supraventricular Tachycardia.

Paroxysmal supraventricular tachycardia (PSVT) is a common tachyarrhythmia, and an electrocardiogram is the best tool for making a diagnosis. If Valsalva maneuvers and carotid sinus massage do not give positive results, then the next choice is either adenosine or calcium channel blockers. At this time, adenosine is the drug of choice of treatment. Verapamil and diltiazem are the most commonly used calcium channel blockers (CCBs). This review aimed to compare the efficacy of both drugs in the treatment of PSVT. We utilized the databases PubMed Central and Medline by using keywords: "calcium channel blockers OR adenosine AND supraventricular tachycardia." In the end, we finalized 32 studies, including observational studies, literature reviews, systematic reviews/metanalysis, and randomized control trials. We included articles only in the English language and related to humans. Two authors completed the quality assessment and evaluation of bias according to specific guidelines. Only high-quality studies were included in this systematic review based on the cut-off score of seven or above. Calcium channel blockers have a longer half-life than adenosine and were previously used as the drug of choice in the treatment of PSVT. Calcium channel blockers are safe if given slowly; however, adenosine is safer and useful when an electrocardiogram is uncertain. We compared both drugs in certain aspects and found equal efficacy. Though safer, adenosine was found to have a higher cost and a higher probability of re-initiation arrhythmia compared to calcium channel blockers.

Cardiovascular Manifestations in Inflammatory Bowel Disease: A Systematic Review of the Pathogenesis and Management of Pericarditis.

Inflammatory bowel disease (IBD) is a chronic condition of the bowel that can be further categorized into ulcerative colitis and Crohn's disease. Rarely, this condition can be associated with pericarditis, which can be an extraintestinal manifestation of the disease or drug-induced. This review aims to determine the pathogenesis and management of pericarditis in IBD. In this review, the goal is to elucidate the pathogenesis of pericarditis in IBD and determine if pericarditis is an extraintestinal manifestation of IBD or a complication of current drug therapy used to manage IBD. Additionally, this review intends to explain the first-line management of pericarditis in IBD and explore the role of biologicals in attenuating pericarditis. An electronic search was conducted to identify relevant reports of pericarditis in IBD, and a quality assessment was conducted to identify high-quality articles according to the inclusion criteria. Full-text articles from inception to November 2020 were included, while non-English articles, gray literature, and animal studies were excluded. The majority of studies suggest that pericarditis arises as a complication of drug therapy by 5-aminosalicylic acid derivatives such as sulfasalazine, mesalamine, and balsalazide, and it occurs due to IgE-mediated allergic reactions, direct cardiac toxicity, cell-mediated hypersensitivity reactions, and humoral antibody response to therapy. Drug cessation or the initiation of a corticosteroid regimen seems to be the most effective means of managing pericarditis in IBD due to drug therapy or an extraintestinal manifestation.

The Importance of Sphingosine Kinase in Breast Cancer: A Potential for Breast Cancer Management.

Breast cancer management includes a combination of surgery, radiation therapy, and chemotherapy. While this management has proven effective, it is not perfect. To expand the umbrella of management to resistant breast cancer tumors, researchers have explored the idea of sphingosine kinase (SphK) and sphingosine-1-phosphate (S1P) as a potential target for treatment. In this article, we review the mechanism of the sphingosine kinase/sphingosine-1-phosphate (SphK/S1P) axis along with its effect on the tumor microenvironment (TME) and compounds that have been studied inhibiting the SphK/S1P axis. We searched for relevant articles in the last five years in Medline and PubMed Central. Inclusion criteria, exclusion criteria, and quality checklists were applied to identify the most relevant articles. We compiled the information that has been summarized in the respective tables and figures provided in this review. The metabolism of sphingolipids was summarized, followed by the SphK/S1P upregulation in breast cancer cells. The variety of effects by upregulation of SphK led to an increase in inflammation, growth, and metastasis in breast cancer tumors. The increase in S1P also impacted the TME, including the cells and surrounding tissue, allowing the breast tumors to thrive. The final point made was a summary of the compounds and drugs that inhibited the SphK/S1P axis. They have proven their effectiveness and show even greater efficacy in combination with docetaxel and doxorubicin in preclinical studies. In conclusion, what is known about the SphK/S1P axis within breast cancer cells is immense but incomplete as we summarize what is known so far. Having a complete picture will allow a faster transition to application in the clinical field but clinical trials have not commenced as of yet.

The D-form of a novel heparan binding peptide decreases cytomegalovirus infection in vivo and in vitro.

Human cytomegalovirus (HCMV) infection in utero can lead to congenital sensory neural hearing loss and mental retardation. Reactivation or primary infection can increase the morbidity and mortality in immune suppressed transplant recipients and AIDS patients. The current standard of care for HCMV disease is nucleoside analogs, which can be nephrotoxic. In addition resistance to current treatments is becoming increasingly common. In an effort to develop novel CMV treatments, we tested the effectiveness of the D-form of a novel heparan sulfate binding peptide, p5RD, at reducing infection of ganciclovir (GCV) resistant HCMVs in vitro and MCMV in vivo. HCMV infection was reduced by greater than 90% when cells were pretreated with p5RD. Because p5RD acts by a mechanism unrelated to those used by current antivirals, it was effective at reducing GCV resistant HCMVs by 85%. We show that p5RD is resistant to common proteases and serum inactivation, which likely contributed to its ability to significantly reduced infection of peritoneal exudate cells and viral loads in the spleen and the lungs in vivo. The ability of p5RD to reduce HCMV infectivity in vitro including GCV resistant HCMVs and MCMV infection in vivo suggests that this peptide could be a novel anti-CMV therapeutic.

Coalescence-Induced Jumping of Multiple Condensate Droplets on Hierarchical Superhydrophobic Surfaces.

Coalescence-induced jumping of condensate droplets from a superhydrophobic surface with hierarchical micro/nanoscale roughness is quantitatively characterized. Experimental observations show that the condensate droplet jumping is induced by coalescence of multiple droplets of different sizes, and that the coalesced droplet trajectories typically deviate from the surface normal. A depth-from-defocus image processing technique is developed to track the out-of-plane displacement of the jumping droplets, so as to accurately measure the droplet size and velocity. The results demonstrate that the highest jumping velocity is achieved when two droplets coalesce. The jumping velocity decreases gradually with an increase in the number of coalescing droplets, despite the greater potential surface energy released upon coalescence. A general theoretical model that accounts for viscous dissipation, surface adhesion, line tension, the initial droplet wetting states, and the number and sizes of the coalescing droplets is developed to explain the trends of droplet jumping velocity observed in the experiments.