Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

A novel perspective on the preventive treatment of hydrazine compound-induced liver injury: Isoniazid liver injury as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Anethum graveolens L. (dill), which has been used as a medicine, spice and aromatic plant since ancient times, is not only a traditional Chinese medicines but also an important medicinal and functional food in Europe and Central and South Asia. In ethnomedicine, dill reportedly exerts a protective effect on the liver and has been widely used as a traditional medicine for the treatment of jaundice in the liver and spleen and inflammatory gout diseases in Saudi Arabia. Furthermore, studies have found that dill can regulate the NAT2 enzyme, and this plant was thus selected to study its alleviating effect on isoniazid liver injury. AIM OF THE STUDY: The purpose of this study was to explore the effect of dill on alleviating liver injury induced by hydrazine compounds represented by isoniazid through the use of network pharmacology combined with in vivo and in vitro experimental verifications. MATERIALS AND METHODS: First, we screened the key targets of dill in the treatment of liver injury through the use of network pharmacology; we then performed GO and KEGG pathway enrichment analyses using the DAVID database. We also verified the alleviative and anti-inflammatory effects of dill on isoniazid liver injury in rats by animal experiments. We further investigated the modulating effect of dill on the enzymatic activity of NAT2, a common metabolizing enzyme of hydrazine compounds. RESULTS: A total of 111 key targets were screened through network pharmacology. In vivo experiments showed that dill reduced the amount of inflammatory factors produced by isoniazid, such as IL-10, IL-1ß, TNF-α and IL-6, restored the levels of ALT, AST, r-GT, AKP and TBA in vivo, and attenuated isoniazid liver injury. Both in vivo and vitro results indicated that dill could regulate the expression of NAT2 enzymes. CONCLUSIONS: The results tentatively demonstrate that dill can alleviate isoniazid liver injury through multiple components, targets and pathways and exerts a regulatory effect on the NAT2 enzyme, and these findings thus provide new ideas for subsequent studies on hydrazide liver injury--reducing the risk of hydrazide-induced liver injury through anti-inflammation and regulation of NAT2 enzymes.

Scientific Evidences of Calorie Restriction and Intermittent Fasting for Neuroprotection in Traumatic Brain Injury Animal Models: A Review of the Literature.

It has widely been accepted that food restriction (FR) without malnutrition has multiple health benefits. Various calorie restriction (CR) and intermittent fasting (IF) regimens have recently been reported to exert neuroprotective effects in traumatic brain injury (TBI) through variable mechanisms. However, the evidence connecting CR or IF to neuroprotection in TBI as well as current issues remaining in this research field have yet to be reviewed in literature. The objective of our review was therefore to weigh the evidence that suggests the connection between CR/IF with recovery promotion following TBI. Medline, Google Scholar and Web of Science were searched from inception to 25 February 2022. An overwhelming number of results generated suggest that several types of CR/IF play a promising role in promoting post-TBI recovery. This recovery is believed to be achieved by alleviating mitochondrial dysfunction, promoting hippocampal neurogenesis, inhibiting glial cell responses, shaping neural cell plasticity, as well as targeting apoptosis and autophagy. Further, we represent our views on the current issues and provide thoughts on the future direction of this research field.

Stability and Bifurcation Analysis of a Diffusive miR-9/Hes1 Network With Time Delay.

In this paper, a model of miR-9/Hes1 interaction network involving one time delay and diffusion effect under the Neumann boundary conditions is studied. First of all, the stability of the positive equilibrium and the existence of local Hopf bifurcation and Turing-Hopf bifurcation are investigated by analyzing the associated characteristic equation. Second, a algorithm for determining the direction, stability and period of the corresponding bifurcating periodic solutions is presented. The obtained results suggest that the quiescent progenitors (high steady-state Hes1) can be easily excited into oscillation by time delay whereas the differentiated state (low steady-state Hes1) is basically unaffected, and the integrated effect of delay and diffusion can induce the occurrence of spatially inhomogeneous patterns. More importantly, spatially homogeneous/inhomogeneous periodic solutions can exist simultaneously when the diffusion coefficients of Hes1 mRNA and Hes1 protein are appropriately small, conversely, there is only spatially homogeneous periodic solutions. Intriguingly, both temporal patterns and spatial-temporal patterns show that time delay can prompt Hes1 protein to shift from the high concentration state to the low concentration one ("ON" → "OFF"), where Hes1 protein shows low level whereas miR-9 shows high level. Finally, some numerical examples are presented to verify and visualize theoretical results.

Operation overview of a biological waste treatment system during the 4-crew 180-day integrated experiment in the controlled ecological life support system (CELSS).

Waste management and treatment is vital to health care and material circulation, especially in the Controlled Ecological Life Support System (CELSS) with finite resources for long-duration manned space missions. A closed ecological-cycle integrated 4-crew 180-day experiment platform was established to investigate the key technologies such as effective cultivation of higher plant, water treatment and recycling, waste management and treatment. In this study, generated waste during the integrated experiment was classified as renewable and non-renewable waste. The renewable waste including all crew feces and part of inedible plant biomass were treated in a biological system where the aerobic composting technology was utilized. The performance in relation to degradation effect, phytotoxicity and nutrient evaluation was examined during the continuous 180 days. The long-term operation results displayed that 96.26 kg feces and 74.4 kg wheat straw were treated, and 90.6 kg compost product was discharged in nine batches. The microbial community variation was analyzed and Firmicutes, Actinobacteria and Proteobacteria enriched in the compost. The phytotoxicity of compost was examined by seed germination index (GI) and GI of Chinese cabbage ranged from 88% to 132% for all batches. Compared to grown in vermiculite only, the lettuce yield increased 19% when grown in a mixture of vermiculite and processed compost. The summary of this work will be helpful to facilitate future applications of aerobic composting technology as the bio-based waste treatment technology in CELSS.

Efficacy of Longdan Xiegan Decoction on the Treatment of Eczema: A Systematic Review and Meta-Analysis.

BACKGROUND: Longdan Xiegan decoction (LDXGD) has been widely used in the treatment of eczema. In recent years, randomized controlled trials (RCTs) of LDXGD for the treatment of eczema have gradually increased. Most of the results show that LDXGD is effective in treating eczema. However, whether these conclusions are reliable or not requires meta-analysis. OBJECTIVE: This study aimed to systematically evaluate the clinical efficacy of LDXGD in the treatment of eczema. MATERIALS AND METHODS: Seven electronic databases, including PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biomedical Literature on Disc (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and Chinese Science and Technology Periodical Database (VIP) were systematically searched from their inception until January 2021. Risk of bias was assessed using criteria from the Cochrane Collaboration and meta-analysis was conducted on the screened literature data using Review Manage (RevMan 5.3). Then, to assess the quality of evidence, the GRADE criteria was adopted. RESULTS: 14 RCTs with 1080 participants were identified. Meta-analysis indicated that compared with western medicine (WM), the cure rate and the total effective rate of LDXGD in treating eczema were higher. Meanwhile, the recurrence rate and the levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF-α) after treatment were lower. The adverse reaction was reported in 5 out of 14 studies without significant statistical difference. According to GRADE criteria, the quality of evidence was low for all outcomes except for the cure rate (moderate-quality evidence) and the total effective rate (moderate-quality evidence). CONCLUSION: The clinical efficacy of LDXGD in the treatment of eczema was more effective compared with the one of conventional WM alone. However, due to the limitation of the quality of the included studies, additional studies are required to further confirm these results.

Study on Lubrication Characteristics of Metal Liquid Film Based on Electromagnetic-Elastic Mechanics-Hydrodynamics Multiphysics Coupling Model.

In an electromagnetic rail launcher, a metal liquid film is created at the armature/rail (A/R) contact interface. It has a significant impact on electromagnetic launch performance. In this paper, an electromagnetic-elastic mechanics-hydrodynamics multi physics coupling model is established in consideration of the metal liquid film's own acceleration, magnetic pressure and dynamic changes in film thickness. Based on this model, the lubricating characteristics of magnetic pressure and fluid pressure distribution, film thickness distribution and velocity distribution of the metal liquid film were studied. When the velocity of the metal liquid film is very fast, and the magnetic pressure is reduced, it may fail to maintain stability and rupture, which may be an important reason for the transition. Finally, this paper analyzes the lubrication effect of the metal liquid film, and points out that when we want strictly to control the muzzle velocity, the lubrication effect of the metal liquid film must be considered.

Systematic Review of Herbal Tea (a Traditional Chinese Treatment Method) in the Therapy of Chronic Simple Pharyngitis and Preliminary Exploration about Its Medication Rules.

BACKGROUND: Chronic simple pharyngitis (CSP) is a common clinical chronic respiratory inflammation with persistent and intransigent symptoms. We analyzed the clinical data to find the evidence that herbal tea, a traditional Chinese medicine treatment in China, could improve the symptoms of CSP patients in a simple way. METHODS: We systematically reviewed the clinical data of randomized controlled treatments from April 2019 and evaluated the results using the improved Jadad scale and the Cochrane bias risk assessment tool. RevMan 5.3 software was used for chart analysis. In addition, we used Excel to conduct frequency statistics on Chinese herbs from included articles and analyze its medication rules. RESULTS: Among the collection of 161 articles, 6 RCTs published in Chinese journals were included in this review. The methodological quality of the treatments was low, and most of them only provide diagnostic criteria. Inclusion and exclusion criteria were not specified, and none of the 6 RCTs used the blind method on the result evaluator. Furthermore, only one RCT evaluated the baseline level variance. For these reasons, we did not make a network meta-analysis. CONCLUSIONS: The traditional Chinese herbs involved in herbal tea did have ingredients to alleviate CSP symptoms. However, our research showed that the current research could not draw any credible conclusions on the curative effect of herbal tea, which indicated that the overall level of TCM clinical research needs to be improved to evaluate the efficacy of herbal tea.

In situ formation of nanoscale zero-value iron on fish-scale-based porous carbon for Cr(VI) adsorption.

Magnetic carbon materials that have nanoscale zero-valent iron (nZVI) supported on fish scale based hierarchical lamellar porous carbon (FHLC) is reported in this study. The nZVI on FHLC was in the form of body-centered-cubic iron (Fe) crystal. Although it was demonstrated that the specific surface area (SBET), total pore volume (Vt) and micropore volume (Vm) of the FHLC decreased with the increase of Fe contents, a certain amount of addition of iron nanoparticles on FHLC enhances the Cr(VI) adsorption properties. The as-prepared material shows faster adsorption rate and higher maximum adsorption capacity (357.14 mg/g) compared to bare FHLC (344.83 mg/g). In addition, this magnetic carbon material exhibits a high saturated magnetization (16.49 emu/g). It is indicated that the as-prepared carbon material not only can be used to remove Cr(VI) efficiently but also shows excellent magnetic separation performance from wastewater.

A study of the kinetics and isotherms for Cr(VI) adsorption in a binary mixture of Cr(VI)-Ni(II) using hierarchical porous carbon obtained from pig bone.

Cr(VI) adsorption in a binary mixture Cr(VI)-Ni(II) using the hierarchical porous carbon prepared from pig bone (HPC) was investigated. The various factors affecting adsorption of Cr(VI) ions from aqueous solutions such as initial concentration, pH, temperature and contact time were analyzed. The results showed excellent efficiency of Cr(VI) adsorption by HPC. The kinetics and isotherms for Cr(VI) adsorption from a binary mixture Cr(VI)-Ni(II) by HPC were studied. The adsorption equilibrium described by the Langmuir isotherm model is better than that described by the Freundlich isotherm model for the binary mixture in this study. The maximum adsorption capacity was reliably found to be as high as 192.68 mg/g in the binary mixture at pH 2. On fitting the experimental data to both pseudo-first- and second-order equations, the regression analysis of the second-order equation gave a better R² value.