Role of protein arginine methyltransferase 1 in obesity-related metabolic disorders: Research progress and implications.

Obesity has become a major global problem that significantly confers an increased risk of developing life-threatening complications, including type 2 diabetes mellitus, fatty liver disease and cardiovascular diseases. Protein arginine methyltransferases (PRMTs) are enzymes that catalyse the methylation of target proteins. They are ubiquitous in eukaryotes and regulate transcription, splicing, cell metabolism and RNA biology. As a key, epigenetically modified enzyme, protein arginine methyltransferase 1 (PRMT1) is involved in obesity-related metabolic processes, such as lipid metabolism, the insulin signalling pathway, energy balance and inflammation, and plays an important role in the pathology of obesity-related metabolic disorders. This review summarizes recent research on the role of PRMT1 in obesity-related metabolic disorders. The primary objective was to comprehensively elucidate the functional role and regulatory mechanisms of PRMT1. Moreover, this study attempts to review the pathogenesis of PRMT1-mediated obesity-related metabolic disorders, thereby offering pivotal information for further studies and clinical treatment.

Entrainment degree of globally coupled Winfree oscillators under external forcing.

We consider globally connected coupled Winfree oscillators under the influence of an external periodic forcing. Such systems exhibit many qualitatively different regimes of collective dynamics. Our aim is to understand this collective dynamics and, in particular, the system's capability of entrainment to the external forcing. To quantify the entrainment of the system, we introduce the entrainment degree, that is, the proportion of oscillators that synchronize to the forcing, as the main focus of this paper. Through a series of numerical simulations, we study the entrainment degree for different inter-oscillator coupling strengths, external forcing strengths, and distributions of natural frequencies of the Winfree oscillators, and we compare the results for the different cases. In the case of identical oscillators, we give a precise description of the parameter regions where oscillators are entrained. Finally, we use a mean-field method, based on the Ott-Antonsen ansatz, to obtain a low-dimensional description of the collective dynamics and to compute an approximation of the entrainment degree. The mean-field results turn out to be strikingly similar to the results obtained through numerical simulations of the full system dynamics.

Design, synthesis, and biological evaluation of new B-RafV600E kinase inhibitors.

The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study.

The regulatory role of m6A methylation modification in metabolic syndrome pathogenesis and progression.

Metabolic syndromes are characterized by various complications caused by disrupted glucose and lipid metabolism, which are major factors affecting the health of a population. However, existing diagnostic and treatment strategies have limitations, such as the lack of early diagnostic and therapeutic approaches, variability in patient responses to treatment, and cost-effectiveness. Therefore, developing alternative solutions for metabolic syndromes is crucial. N6-methyladenosine (m6A) is one of the most abundant modifications that determine the fate of RNA. m6A modifications are closely associated with metabolic syndrome development and present novel prospects for clinical applications. Aberrant m6A modifications have been detected during inflammatory infiltration, apoptosis, autophagy, iron sagging, necrosis, and scorching during metabolic syndrome pathogenesis and progression. However, few reviews have systematically described the correlation between m6A modifications and these factors concerning metabolic syndrome pathogenesis and progression. This study summarizes the m6A methylation regulators and their roles in metabolic syndrome development, highlighting the potential of m6A modification as a biomarker in metabolic disorders.

HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial.

Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

A Systematic Government-Driven Green Development Transformation Strategy with Chinese Characteristics: The Case Study of the Xining Metropolitan Area.

In the 21st century, the tension between economic growth, resources and the environment in countries around the world is increasing, and the sustainable development of the economy and society is under great pressure. Green development has become the only way for countries to promote sustainable development. Generally, capitalist countries achieve their green development goals through increasingly strict environmental protection regulations, technological upgrading, industrial upgrading and global transfer based on market mechanisms and legal environments. Evidently, this green development strategy relies on the core position of Western countries in the global technological leadership and the global division of labor. However, limited in terms of their economic strength and by technical barriers, how can developing countries, led by China, in the marginal position in the global market competition, carry out green development transformation? In line with the "high-quality development" strategy, governments at all levels in China are actively exploring green development strategies with their own characteristics. Based on the Second Tibetan Plateau Scientific Expedition and Research and the face-to-face interview method, this paper summarizes a new strategy of systematic government-driven green development combining internal and external factors in the underdeveloped areas of inland China, which has gradually formed in the Xining metropolitan area (XMA) in the past 20 years. This strategy has the following characteristics: Firstly, during the period of rapid growth, the XMA areas have promoted each other through new urbanization and new industrialization and jointly promoted the formation of a green development turn in the new era. Secondly, the government is the core actor and driving force of China's regional green development and has gradually formulated and implemented a series of policy systems during this development. Restricted by local economic backwardness and low industrial profits, the implementation of green government policies tends to be mandatory. The majority of urban residents and rural people support this transformation because they have benefited from the transformation process. Thirdly, this green development strategy is reflected in many aspects, such as industry, ecology, the environment, space and transportation, and is part of a systematic, green-oriented transformation. Fourthly, the advantages of the socialist system with Chinese characteristics are the guarantee of the green development strategy. It is noteworthy that this kind of green development transformation requires a large amount of "additional" investment and the "rapid" upgrade of the industry. Therefore, it requires more time and the understanding and assistance of all sectors of society.

Identification of novel B-RafV600E inhibitors employing FBDD strategy.

B-Raf kinase is the key point in a main branch of mitogen-activated protein kinase pathways and some of its mutations, such as the V600E mutation, lead to the persistent activation of ERK signaling and the trigger of severe diseases, including melanoma and other somatic cancers. Several potent drugs have been approved to treat B-Raf-related tumors, however, cases of resistance and relapse have been reported universally. Hence, differential scaffolds are in need to alleviate the scarcity of drugs and benefit the therapy of B-Raf-mutant cancers. Herein we report our recent work on the construction of novel B-RafV600E inhibitors employing fragment-based drug design strategy. In this research, we decomposed known inhibitors to fragments and rebuilt new candidates using these blocks according to the evaluation of their potential. Lead compounds were synthesized after selection by means of virtual screening and molecular dynamics validation. Afterwards, we tested the pharmacological efficiency of these entities both in vitro and in vivo utilizing A375 xenograft model. The results favored our rational design intention and hinted this new kind of inhibitors might be helpful in the further explorations of potent agents.