ARTICLE | doi:10.20944/preprints202007.0582.v1
Online: 24 July 2020 (11:58:41 CEST)
Semaglutide is a glucagon-like peptide 1 analog used for the treatment of patients with type 2 diabetes mellitus. With 94% sequence similarity to human GLP-1, semaglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist, which binds directly to GLP-1R, causing various beneficial downstream effects that reduce blood glucose. Practically, it is favourable for semaglutide to bind not just directly, but also tighter, to its receptor GLP-1R. Therefore, incorporating currently available experimental structural data of semaglutide-GLP-1R, this short article reports for the first time that biophysically, semaglutide is able to bind tighter to GLP-1R with just a simple Val27-Arg28 exchange in its peptide backbone.
REVIEW | doi:10.20944/preprints202011.0684.v1
Online: 27 November 2020 (11:24:40 CET)
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from the gut upon nutrient stimulation and regulate postprandial metabolism. These hormones are known as classical incretin hormones and are responsible for a major part of postprandial insulin release. The incretin effect is severely reduced in patients with type 2 diabetes, but it was discovered that administration of GLP-1 agonists was capable of normalizing glucose control in these patients. Over the last decades, much research has been focused on the development of incretin-based therapies for type 2 diabetes. These therapies include incretin receptor agonists and inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-4. Especially the development of diverse GLP-1 receptor agonists has shown immense success, whereas studies of GIP monotherapy in patients with type 2 diabetes have consistently been disappointing. Interestingly, both GIP-GLP-1 co-agonists and GIP receptor antagonists administered in combination with GLP-1R agonists appear to be efficient with respect to both weight loss and control of diabetes, although the molecular mechanisms behind these effects remain unknown. This review describes our current knowledge of the two incretin hormones and the development of incretin-based therapies for treatment of type 2 diabetes.
REVIEW | doi:10.20944/preprints202004.0224.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: substance P,; NK-1R,; AML,; Aprepitant,; anti-leukemic,; apoptosis,; non-solid tumor
Online: 14 April 2020 (15:19:45 CEST)
Acute myeloid leukemia (AML) is an incurable hematological malignancy. To treat the disease successfully, new therapeutic strategies are urgently needed. One of these strategies can be the use of neurokinin-1 receptor (NK-1R) antagonists (e.g., aprepitant), because the substance P (SP)/NK-1R system is involved in cancer progression, including AML. AML patients show an up-regulation of the NK-1R mRNA expression; human AML cell lines show immunoreactivity for both SP and the NK-1R (it is overexpressed: the truncated isoform is more expressed than the full-length form) and, via this receptor, SP and NK-1R antagonists (aprepitant, in a concentration-dependent manner) respectively exert a proliferative action or an antileukemic effect (apoptotic mechanisms are triggered by promoting oxidative stress via mitochondrial Ca++ overload). Aprepitant inhibits the formation of AML cell colonies and, in combination with chemotherapeutic drugs, is more effective in inducing cytotoxic effects and AML cell growth blockade. NK-1R antagonists also exert an antinociceptive effect in myeloid leukemia-induced bone pain. The antitumor effect of aprepitant is diminished when the NF-κB pathway is overactivated and the damage induced by aprepitant in cancer cells is higher than that exerted in non-cancer cells. Thus, the SP/NK-1R system is involved in AML and aprepitant is a promising antitumor strategy against this hematological malignancy. In this review, the involvement of this system in solid and non-solid tumors (in particular in AML) is up-dated and the use of aprepitant as an anti-leukemic strategy for the treatment of AML is also mentioned (a dose of aprepitant (> 20 mg/kg/day) for a period of time according to the response to treatment is suggested).
REVIEW | doi:10.20944/preprints202006.0135.v1
Subject: Medicine & Pharmacology, Gastroenterology Keywords: enteric nervous system; ENS; gastrointestinal tract; GI; glucagon-like peptide 2; GLP-2
Online: 11 June 2020 (11:58:03 CEST)
The gastrointestinal (GI) tract is innervated by the enteric nervous system (ENS), an extensive neuronal network that traverses along its walls. Due to local reflex circuits, the ENS is capable of functioning with and without input from the central nervous system. The functions of the ENS range from the propulsion of food to nutrient handling, blood flow regulation and immunological defense. Records of it first being studied emerged in the early 19th century when the submucosal and myenteric plexuses were discovered. This was followed by extensive research and further delineation of its development, anatomy, and function during the next two centuries. The morbidity and mortality associated with the underdevelopment, infection or inflammation of the ENS highlights its importance and the need for us to completely understand its normal function. This review will provide a general overview of the ENS to date and connect specific GI disorders such as short bowel syndrome with neuronal pathophysiology. Exciting opportunities in which the ENS could be used as a therapeutic target for common GI diseases will also be highlighted, as the further unlocking of such mechanisms could open the door to more therapy-related advances, and ultimately change our approach to GI disorders.
REVIEW | doi:10.20944/preprints202004.0103.v1
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: Coronavirus; SARS-CoV-2; Medical Laboratory; Resource-limited setting, Good Laboratory Practice (GLP)
Online: 7 April 2020 (12:11:35 CEST)
The 2019 Coronavirus pandemic which was initially referred to as 2019-nCoV, was first identified in Wuhan, China. Early response from the Chinese government included quarantine of infected persons, isolation and total lockdown of Wuhan province to prevent further spread. With the spread of the disease across national borders and declaration of the disease as a global pandemic, there has been a robust response by the international community to contain this deadly virus and prevent its further spread worldwide. Africa is not left out of this rampaging pandemic with documented cases in over 40 countries and still rising. Although extensive studies have been carried out on the novel SARS-CoV-2 on its pathogenesis, mode of infection and virulence but much is still unknown. However, potentially infectious samples are received routinely in the medical laboratory for analysis. This technical note reviews good laboratory practice (GLP) and processes across the different specialities of Medical Laboratory practice that should minimize the risk of infection to laboratory staff especially in resource-limited settings.