Unveiling the Noncanonical Activation Mechanism of Cdks: Insights From Recent Structural Studies

The Cyclin-dependent kinases (CDKs) play crucial roles in a range of essential cellular processes. While the classical two-step activation mechanism is generally applicable to cell cycle-related CDKs, both CDK7 and CDK8, involved in transcriptional regulation, adopt distinct mechanisms for kinase activation. In both cases, binding to their respective cyclin partners results in only partial activity, while their full activation requires the presence of an additional subunit. Recent structural studies of these two noncanonical kinases have provided unprecedented insights into their activation mechanisms, enabling us to understand how the third subunit coordinates the T-loop stabilization and enhances kinase activity. In this review, we summarize the structure and function of CDK7 and CDK8 within their respective functional complexes, while also describing their noncanonical activation mechanisms. These insights open new avenues for targeted drug discovery and potential therapeutic interventions in various diseases related to CDK7 and CDK8

Pure spin current generation in a Rashba-Dresselhaus quantum channel

We demonstrate a spin pump to generate pure spin current of tunable intensity and polarization in the absence of charge current. The pumping functionality is achieved by means of an ac gate voltage that modulates the Rashba constant dynamically in a local region of a quantum channel with both static Rashba and Dresselhaus spin-orbit interactions. Spin-resolved Floquet scattering matrix is calculated to analyze the whole scattering process. Pumped spin current can be divided into spin-preserved transmission and spin-flip reflection parts. These two terms have opposite polarization of spin current and are competing with each other. Our proposed spin-based device can be utilized for non-magnetic control of spin flow by tuning the ac gate voltage and the driving frequency.Comment: 6 pages, 3 figure

Biological actions and molecular effects of resveratrol, pterostilbene, and 3′-hydroxypterostilbene

AbstractStilbenes are a class of polyphenolic compounds, naturally found in a wide variety of dietary sources such as grapes, berries, peanuts, red wine, and some medicinal plants. There are several well-known stilbenes including trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene. The core chemical structure of stilbene compounds is 1,2-diphenylethylene. Recently, stilbenes have attracted extensive attention and interest due to their wide range of health-beneficial effects such as anti-inflammation, -carcinogenic, -diabetes, and -dyslipidemia activities. Moreover, accumulating in vitro and in vivo studies have reported that stilbene compounds act as inducers of multiple cell-death pathways such as apoptosis, cell cycle arrest, and autophagy for chemopreventive and chemotherapeutic agents in several types of cancer cells. The aim of this review is to highlight recent molecular findings and biological actions of trans-resveratrol, pterostilbene, and 3′-hydroxypterostilbene

Targeted deletion of GSNOR in hepatocytes of mice causes nitrosative inactivation of O6-alkylguanine-DNA alkyltransferase and increased sensitivity to genotoxic diethylnitrosamine

S-nitrosoglutathione reductase (GSNOR), a ubiquitously expressed protein central to the control of protein S-nitrosylation, plays critical roles in many biological systems. We showed recently that GSNOR is often deficient in human hepatocellular carcinoma and that germ line deletion of the GSNOR gene in mice causes hepatocellular carcinoma through S-nitrosylation and proteasomal degradation of the key DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT). We report here the generation of mice with targeted deletion of GSNOR in hepatocytes or in cells of the hematopoietic lineage. We found that during inflammatory responses induced by intraperitoneal injection of diethylnitrosamine (DEN) or lipopolysaccharide, the amount of liver AGT was not changed in mice with GSNOR deletion in hematopoietic cells but was almost completely depleted in mice with GSNOR deletion in hepatocytes. In livers of DEN-challenged mice, GSNOR deletion in hepatocytes but not hematopoietic cells resulted in an increase in phosphorylated histone H2AX, a well-established marker of DNA double-strand breaks. Hepatocyte deletion of GSNOR increased DEN-induced mortality, which was abolished in mice deficient in both GSNOR and inducible nitric oxide synthase. Thus, protection of AGT and resistance to nitrosamine-induced genotoxicity critically depends on GSNOR in hepatocytes. In addition, our findings suggest that nitrosative inactivation of AGT from GSNOR deficiency might sensitize cancerous cells to alkylating drugs in cancer treatment

Citrus flavonoids and the intestinal barrier: Interactions and effects.

peer reviewedThe intestinal barrier plays a central role in sustaining gut homeostasis and, when dysfunctional, may contribute to diseases. Dietary flavonoids derived from Citrus genus represent one of the main naturally occurring phytochemicals with multiple potential benefits for the intestinal barrier function. In the intestine, citrus flavonoids (CFs) undergo ingestion from the lumen, biotransformation in the epithelial cells and/or crosstalk with luminal microbiota to afford various metabolites that may in turn exert protective actions on gut barrier along with their parental compounds. Specifically, the health-promoting properties of CFs and their metabolic bioactives for the intestinal barrier include their capacity to (a) modulate barrier permeability; (b) protect mucus layer; (c) regulate intestinal immune system; (d) fight against oxidative stress; and (e) positively shape microbiome and metabolome. Notably, local effects of CFs can also generate systemic benefits, for instance, improvement of gut microbial dysbiosis helpful to orchestrate gut homeostasis and leading to alleviation of systemic dysmetabolism. Given the important role of the intestinal barrier in overall health, further understanding of underlying action mechanisms and ultimate health effects of CFs as well as their metabolites on the intestine is of great significance to future application of citrus plants and their bioactives as dietary supplements and/or functional ingredients in medical foods

Major adverse cardiovascular events of enzalutamide versus abiraterone in prostate cancer: a retrospective cohort study.

Background While the cardiovascular risks of androgen receptor pathway inhibitors have been studied, they were seldom compared directly. This study compares the risks of major adverse cardiovascular events (MACE) between enzalutamide and abiraterone among prostate cancer (PCa) patients. Methods Adult PCa patients receiving either enzalutamide or abiraterone in addition to androgen deprivation therapy in Hong Kong between 1 December 1999 and 31 March 2021 were identified in this retrospective cohort study. Patients who switched between enzalutamide and abiraterone, initiated abiraterone used without steroids, or experienced prior cardiac events were excluded. Patients were followed-up until 30 September 2021. The primary outcomes were MACE, a composite of stroke, myocardial infarction (MI), Heart failure (HF), or all-cause mortality and a composite of adverse cardiovascular events (CACE) not including all-cause mortality. The secondary outcomes were individual components of MACE. Inverse probability treatment weighting was used to balance covariates between treatment groups. Results In total, 1015 patients were analyzed (456 enzalutamide users and 559 abiraterone users; mean age 70.6 ± 8.8 years old) over a median follow-up duration of 11.3 (IQR: 5.3–21.3) months. Enzalutamide users had significantly lower risks of 4P-MACE (weighted hazard ratio (wHR) 0.71 [95% confidence interval (CI) 0.59–0.86], p < 0.001) and CACE (wHR 0.63 [95% CI: 0.42–0.96], p = 0.031), which remained consistent in multivariable analysis. Such an association may be stronger in patients aged ≥65 years or without diabetes mellitus and was independent of bilateral orchidectomy. Enzalutamide users also had significantly lower risks of MI (wHR 0.57 [95% CI: 0.33–0.97], p = 0.040) and all-cause mortality (wHR 0.71 [95% CI: 0.59–0.85], p < 0.001). Conclusion Enzalutamide was associated with lower cardiovascular risks than abiraterone in PCa patients

Association between duration of gonadotrophin-releasing hormone agonist use and cardiovascular risks: A population-based competing-risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

Post-stroke upper limb recovery is correlated with dynamic resting-state network connectivity

Motor recovery is still limited for people with stroke especially those with greater functional impairments. In order to improve outcome, we need to understand more about the mechanisms underpinning recovery. Task-unbiased, blood flow–independent post-stroke neural activity can be acquired from resting brain electrophysiological recordings and offers substantial promise to investigate physiological mechanisms, but behaviourally relevant features of resting-state sensorimotor network dynamics have not yet been identified. Thirty-seven people with subcortical ischaemic stroke and unilateral hand paresis of any degree were longitudinally evaluated at 3 weeks (early subacute) and 12 weeks (late subacute) after stroke. Resting-state magnetoencephalography and clinical scores of motor function were recorded and compared with matched controls. Magnetoencephalography data were decomposed using a data-driven hidden Markov model into 10 time-varying resting-state networks. People with stroke showed statistically significantly improved Action Research Arm Test and Fugl-Meyer upper extremity scores between 3 weeks and 12 weeks after stroke (both P < 0.001). Hidden Markov model analysis revealed a primarily alpha-band ipsilesional resting-state sensorimotor network which had a significantly increased life-time (the average time elapsed between entering and exiting the network) and fractional occupancy (the occupied percentage among all networks) at 3 weeks after stroke when compared with controls. The life-time of the ipsilesional resting-state sensorimotor network positively correlated with concurrent motor scores in people with stroke who had not fully recovered. Specifically, this relationship was observed only in ipsilesional rather in contralesional sensorimotor network, default mode network or visual network. The ipsilesional sensorimotor network metrics were not significantly different from controls at 12 weeks after stroke. The increased recruitment of alpha-band ipsilesional resting-state sensorimotor network at subacute stroke served as functionally correlated biomarkers exclusively in people with stroke with not fully recovered hand paresis, plausibly reflecting functional motor recovery processes

Statin use and mortality risk in Asian patients with prostate cancer receiving androgen deprivation therapy: A population-based cohort study

Background This study aimed to examine the associations between the use of statins concurrent with androgen deprivation therapy (ADT) and the risks of mortality in Asian patients diagnosed with prostate cancer (PCa). Methods Adult patients (≥18 years old) diagnosed with PCa who were receiving any form of ADT and were being treated at public hospitals in Hong Kong from December 1999 to March 2021 were retrospectively identified, with follow-up conducted until September 2021. Patients who had received medical castration for <180 days without subsequent bilateral orchidectomy, those who had used statins concurrently with ADT for <180 days, and those with missing baseline total cholesterol levels were excluded. Statin users were defined as individuals who had used statins for ≥180 days concurrent with ADT, while non-users were those who had not used any statins. PCa-related mortality was the primary outcome, while all-cause mortality served as the secondary outcome. Inverse probability treatment weighting was employed to balance the covariates. Results A total of 4920 patients were included, consisting of 2578 statin users and 2342 non-users (mean age 76.1 ± 8.2 years). Over a mean follow-up period of 4.2 ± 3.3 years, it was observed that statin users had significantly lower risks of both PCa-related mortality (weighted hazard ratio [wHR] 0.56 [95% confidence interval (CI) 0.48, 0.65], p < 0.001) and all-cause mortality (wHR 0.57 [95% CI 0.51, 0.63], p < 0.001), regardless of the type of ADT used. Notably, these associations were more pronounced among patients with less advanced PCa, as indicated by the absence of androgen receptor antagonist or chemotherapy usage (p value for interaction <0.001 for both outcomes). Conclusion(s) The use of statins concurrent with ADT was associated with reduced mortality risks among Asian patients with PCa. These findings suggest the need for additional research to explore the potential role of statins in the treatment of PCa patients

Nobiletin Prevents Trimethylamine Oxide-Induced Vascular Inflammation via Inhibition of the NF-κB/MAPK Pathways.

peer reviewedDietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways