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International Journal of Molecular... Jan 2024Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM).... (Review)
Review
Achieving glycemic control and sustaining functional pancreatic β-cell activity remains an unmet medical need in the treatment of type 2 diabetes mellitus (T2DM). Glucokinase activators (GKAs) constitute a class of anti-diabetic drugs designed to regulate blood sugar levels and enhance β-cell function in patients with diabetes. A significant progression in GKA development is underway to address the limitations of earlier generations. Dorzagliatin, a dual-acting GKA, targets both the liver and pancreas and has successfully completed two phase III trials, demonstrating favorable results in diabetes treatment. The hepato-selective GKA, TTP399, emerges as a strong contender, displaying clinically noteworthy outcomes with minimal adverse effects. This paper seeks to review the current literature, delve into the mechanisms of action of these new-generation GKAs, and assess their efficacy and safety in treating T2DM based on published preclinical studies and recent clinical trials.
Topics: Humans; Diabetes Mellitus, Type 2; Glucokinase; Pancreas; Glycemic Control; Drug-Related Side Effects and Adverse Reactions
PubMed: 38203742
DOI: 10.3390/ijms25010571 -
Frontiers in Physiology 2024GPCR-G protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of... (Review)
Review
GPCR-G protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-G protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP and releases DAG and IP. This IP increases intracellular Ca and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-G protein antibodies in GI smooth muscle, indicating the involvement of Gα protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active Gα proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by G proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY amino acids at ARD of TRPC5 binds with G protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for G and G pathway as G pathway increases intracellular Ca and the increased Ca facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (I) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-G protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.
PubMed: 38384797
DOI: 10.3389/fphys.2024.1362987 -
International Journal of Molecular... Oct 2023Bone homeostasis is regulated by the balanced actions of osteoblasts that form the bone and osteoclasts (OCs) that resorb the bone. Bone-resorbing OCs are differentiated... (Review)
Review
Bone homeostasis is regulated by the balanced actions of osteoblasts that form the bone and osteoclasts (OCs) that resorb the bone. Bone-resorbing OCs are differentiated from hematopoietic monocyte/macrophage lineage cells, whereas osteoblasts are derived from mesenchymal progenitors. OC differentiation is induced by two key cytokines, macrophage colony-stimulating factor (M-CSF), a factor essential for the proliferation and survival of the OCs, and receptor activator of nuclear factor kappa-B ligand (RANKL), a factor for responsible for the differentiation of the OCs. Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases, play an essential role in regulating the proliferation, differentiation, and function of OCs. ERKs have been known to play a critical role in the differentiation and activation of OCs. In most cases, ERKs positively regulate OC differentiation and function. However, several reports present conflicting conclusions. Interestingly, the inhibition of OC differentiation by ERK1/2 is observed only in OCs differentiated from RAW 264.7 cells. Therefore, in this review, we summarize the current understanding of the conflicting actions of ERK1/2 in OC differentiation.
Topics: Osteoclasts; Extracellular Signal-Regulated MAP Kinases; Osteoblasts; Cell Differentiation; Cytokines; Macrophage Colony-Stimulating Factor; RANK Ligand
PubMed: 37895023
DOI: 10.3390/ijms242015342 -
Chinese Herbal Medicines Jul 2023Natto is a soybean product fermented by natto bacteria. It is rich in a variety of amino acids, vitamins, proteins and active enzymes. It has a number of biological... (Review)
Review
Natto is a soybean product fermented by natto bacteria. It is rich in a variety of amino acids, vitamins, proteins and active enzymes. It has a number of biological activities, such as thrombolysis, prevention of osteoporosis, antibacterial, anticancer, antioxidant and so on. It is widely used in medicine, health-care food, biocatalysis and other fields. Natto is rich in many pharmacological active substances and has significant medicinal research value. This paper summarizes the pharmacological activities and applications of natto in and outside China, so as to provide references for further research and development of natto.
PubMed: 37538862
DOI: 10.1016/j.chmed.2023.02.005 -
Polymers Mar 2024Silica-supported chromium oxide catalysts, also named Phillips chromium catalysts (PCCs), provide more than half of the world's production of high- and medium-density... (Review)
Review
Silica-supported chromium oxide catalysts, also named Phillips chromium catalysts (PCCs), provide more than half of the world's production of high- and medium-density polyethylenes. PCCs are usually prepared in the Cr(VI)/SiO form, which is subjected to reductive activation. It has been explicitly proven that CO reduces Cr(VI) to Cr(II) species that initiate ethylene polymerization; ethylene activates Cr(VI) sites as well, but the nature of the catalytic species is complicated by the presence of the ethylene oxidation products. It is widely accepted that the catalytic species are of a Cr(III)-alkyl nature, but this common assumption faces the challenge of "extra" hydrogen: the formation of similar species under the action of even-electron reducing agents requires an additional H atom. Relatively recently, it was found that saturated hydrocarbons can also activate CrO/SiO, and alkyl fragments turn out to be bonded with a polyethylene chain. In recent years, there have been numerous experimental and theoretical studies of the structure and chemistry of PCCs at the different stages of preparation and activation. The use of modern spectral methods (such as extended X-ray absorption fine structure (EXAFS), X-ray absorption near-edge structure (XANES), and others); IR, UV-vis, EPR, and XAS spectroscopies; and theoretical approaches (DFT modeling, machine learning) clarified many essential aspects of the mechanisms of CrO/SiO activation and catalytic behavior. Overall, the Cosse-Arlman mechanism of polymerization on Cr(III)-alkyl centers is confirmed in many works, but its theoretical support required the development of nontrivial and contentious mechanistic concepts of Cr(VI)/SiO or Cr(II)/SiO activation. On the other hand, conflicting experimental data continue to be obtained, and certain mechanistic concepts are being developed with the use of outdated models. Strictly speaking, the main question of what type of catalytic species, Cr(II), Cr(III), or Cr(IV), comes into polymerization still has not received an unambiguous answer. The role of the chemical nature of the support-through the prism of the nature, geometry, and distribution of the active sites-is also not clear in depth. In the present review, we endeavored to summarize and discuss the recent studies in the field of the preparation, activation, and action of PCCs, with a focus on existing contradictions in the interpretation of the experimental and theoretical results.
PubMed: 38475365
DOI: 10.3390/polym16050681 -
Brain Communications 2023Many people with Tourette syndrome are able to volitionally suppress tics, under certain circumstances. To understand better the neural mechanisms that underlie this...
Many people with Tourette syndrome are able to volitionally suppress tics, under certain circumstances. To understand better the neural mechanisms that underlie this ability, we used functional magnetic resonance neuroimaging to track regional brain activity during performance of an intentional inhibition task. On some trials, Tourette syndrome and comparison participants internally chose to make or withhold a motor action (a button press), while on other trials, they followed 'Go' and 'NoGo' instructions to make or withhold the same action. Using representational similarity analysis, a functional magnetic resonance neuroimaging multivariate pattern analysis technique, we assessed how Tourette syndrome and comparison participants differed in neural activity when choosing to make or to withhold an action, relative to externally cued responses on Go and NoGo trials. Analyses were pre-registered, and the data and code are publicly available. We considered similarity of action representations within regions implicated as critical to motor action release or inhibition and to symptom expression in Tourette syndrome, namely the pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus and primary motor cortex. Strikingly, in the Tourette syndrome compared to the comparison group, neural activity within the pre-supplementary motor area displayed greater representational similarity across all action types. Within the pre-supplementary motor area, there was lower response-specific differentiation of activity relating to action and inhibition plans and to internally chosen and externally cued actions, implicating the region as a functional nexus in the symptomatology of Tourette syndrome. Correspondingly, patients with Tourette syndrome may experience volitional tic suppression as an effortful and tiring process because, at the top of the putative motor decision hierarchy, activity within the population of neurons facilitating action is overly similar to activity within the population of neurons promoting inhibition. However, not all pre-supplementary motor area group differences survived correction for multiple comparisons. Group differences in representational similarity were also present in the primary motor cortex. Here, representations of internally chosen and externally cued inhibition were more differentiated in the Tourette syndrome group than in the comparison group, potentially a consequence of a weaker voluntary capacity earlier in the motor hierarchy to suppress actions proactively. Tic severity and premonitory sensations correlated with primary motor cortex and caudate nucleus representational similarity, but these effects did not survive correction for multiple comparisons. In summary, more rigid pre-supplementary motor area neural coding across action categories may constitute a central feature of Tourette syndrome, which can account for patients' experience of 'unvoluntary' tics and effortful tic suppression.
PubMed: 37705680
DOI: 10.1093/braincomms/fcad224 -
Communications Biology Jul 2023The TWIK-related spinal cord K channel (TRESK, K18.1) is a K channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological...
The TWIK-related spinal cord K channel (TRESK, K18.1) is a K channel contributing to the maintenance of membrane potentials in various cells. Recently, physiological TRESK function was identified as a key player in T-cell differentiation rendering the channel a new pharmacological target for treatment of autoimmune diseases. The channel activator cloxyquin represents a promising lead compound for the development of a new class of immunomodulators. Identification of cloxyquin binding site and characterization of the molecular activation mechanism can foster the future drug development. Here, we identify the cloxyquin binding site at the M2/M4 interface by mutational scan and analyze the molecular mechanism of action by protein modeling as well as in silico and in vitro electrophysiology using different permeating ion species (K / Rb). In combination with kinetic analyses of channel inactivation, our results suggest that cloxyquin allosterically stabilizes the inner selectivity filter facilitating the conduction process subsequently activating hTRESK.
Topics: Potassium Channels; Binding Sites; Chloroquinolinols; Membrane Potentials
PubMed: 37464013
DOI: 10.1038/s42003-023-05114-4 -
Biomedicine & Pharmacotherapy =... Sep 2023Pyroptosis is a type of inflammatory cell death that is triggered by the formation of pores on the cell membrane by gasdermin (GSDM) family proteins. This process... (Review)
Review
Pyroptosis is a type of inflammatory cell death that is triggered by the formation of pores on the cell membrane by gasdermin (GSDM) family proteins. This process activates inflammasomes and leads to the maturation and release of proinflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Pyroptosis, a form of programmed cell death, has been found to be associated with various biomolecules such as caspases, granzymes, non-coding RNA (lncRNA), reactive oxygen species (ROS), and NOD-like receptor protein 3 (NLRP3). These biomolecules have been shown to play a dual role in cancer by affecting cell proliferation, metastasis, and the tumor microenvironment (TME), resulting in both tumor promotion and anti-tumor effects. Recent studies have found that Oridonin (Ori) has anti-tumor effects by regulating pyroptosis through various pathways. Ori can inhibit pyroptosis by inhibiting caspase-1, which is responsible for activating pyroptosis of the canonical pathway. Additionally, Ori can inhibit pyroptosis by inhibiting NLRP3, which is responsible for activating pyroptosis of the noncanonical pathway. Interestingly, Ori can also activate pyroptosis by activating caspase-3 and caspase-8, which are responsible for activating pyroptosis of the emerging pathway; Ori has been found to be effective in inhibiting pyroptosis by blocking the action of perforin, which is responsible for facilitating the entry of granzyme into cells and activating pyroptosis. Additionally, Ori plays a crucial role in regulating pyroptosis by promoting the accumulation of ROS while inhibiting the ncRNA and NLRP3 pathways. It is worth noting that all of these pathways ultimately regulate pyroptosis by influencing the cleavage of GSDM, which is a key factor in the process. These studies concludes that Ori has extensive anti-cancer effects that are related to its potential regulatory function on pyroptosis. The paper summarizes several potential ways in which Ori participates in the regulation of pyroptosis, providing a reference for further study on the relationship between Ori, pyroptosis, and cancer.
Topics: NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Reactive Oxygen Species; Inflammasomes; NLR Proteins
PubMed: 37329709
DOI: 10.1016/j.biopha.2023.115019 -
Best Practice & Research. Clinical... Oct 2023Epidemiological evidence shows that higher levels of physical activity reduce the relative risk of colon cancer by up to 20%. To design optimal physical activity... (Review)
Review
Epidemiological evidence shows that higher levels of physical activity reduce the relative risk of colon cancer by up to 20%. To design optimal physical activity interventions for primary prevention, it is important to understand how the specific characteristics of physical activity (type, intensity, overall volume) influence the magnitude of colon cancer risk reduction. Improving our understanding of the underlying biological mechanisms will also help to manipulate physical activity characteristics to precisely target mechanisms of action and identify populations most likely to benefit. This review synthesizes the best available evidence to explore how the type and dose of physical activity moderate the protective effect of physical activity on colon cancer.
Topics: Humans; Colorectal Neoplasms; Exercise; Colonic Neoplasms
PubMed: 37852708
DOI: 10.1016/j.bpg.2023.101841