Small nucleolar RNA host gene 1 silence inhibits the lipopolysaccharide-induced microglial apoptosis and inflammation.

Microglia activation is an early mediator of neuroinflammation and a major contributor to spinal damage and motor dysfunction. This study was designed to investigate the role of small nucleolar RNA host gene 1 (SNHG1) on the apoptosis and inflammatory response of microglial cell BV-2 and its underlying molecular mechanism. The C5 lamina contusion-induced mouse model of spinal cord injury (SCI) was constructed. Mouse microglia BV2 was stimulated by lipopolysaccharide (LPS) to establish the in vitro model of SCI. The quantitative reverse transcription polymerase chain reaction method was used to quantify RNA expression levels. Enzyme-linked immunosorbent assays were used to quantify concentrations of inflammatory cytokines. Protein levels were assessed by western blotting, and apoptosis was assessed by flow cytometry. Dual luciferase reporter gene assay and RNA pull-down assay were conducted to investigate the binding relationships between molecules. Upregulation of SNHG1 and downregulation of miR-195-5p were observed in the spinal cords of SCI mouse model. LPS treatment led to elevation of SNHG1 expression in BV2 cells, as well as accelerated apoptosis and inflammation. Evident mitigation of LPS-induced BV2 cell damage was observed after SNHG1 knockdown. MiR-195-5p was identified as a target of SNHG1. Inhibition of miR-195-5p restored the impact of SNHG1 knockdown on cell damage of LPS-treated BV2 cells. Furthermore, miR-195-5p can target activating transcription factor-6 (ATF6). In summary, SNHG1 knockdown ameliorates LPS-induced microglial apoptosis and inflammatory response via the miR-195-5p/ATF6 axis, providing a novel direction for SCI treatment.

Discovery of diaminotriazine carboxamides as potent inhibitors of hematopoetic progenitor kinase 1.

Hematopoietic progenitor kinase 1 (HPK1), a member of mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of Ste20 serine/threonine kinases, is a negative regulator of T-cell receptor (TCR) signaling. Inactivating HPK1 kinase has been reported to be sufficient to elicit antitumor immune response. Therefore, HPK1 has attracted much attention as a promising target for tumor immunotherapy. A few of HPK1 inhibitors have been reported, and none of them have been approved for clinical applications. Hence, more effective HPK1 inhibitors are needed. Herein, a series of structurally novel diaminotriazine carboxamides were rationally designed, synthesized and evaluated for their inhibitory activity against HPK1 kinase. Most of them exhibited potent inhibitory potency against HPK1 kinase. In particular, compound 15b showed more robust HPK1 inhibitory activity than that of 11d developed by Merck in kinase activity assay (IC50 = 3.1 and 8.2 nM, respectively). The significant inhibitory potency against SLP76 phosphorylation in Jurkat T cells further confirmed the efficacy of compound 15b. In human peripheral blood mononuclear cell (PBMC) functional assays, compound 15b more significantly induced the production of interleukin 2 (IL-2) and interferon γ (IFN-γ) relative to 11d. Furthermore, 15b alone or in combination with anti-PD-1 antibodies showed potent in vivo antitumor efficacy in MC38 tumor-bearing mice. Compound 15b represents a promising lead for the development of effective HPK1 small-molecule inhibitors.

X-ray crystallography study and optimization of novel benzothiophene analogs as potent selective estrogen receptor covalent antagonists (SERCAs) with improved potency and safety profiles.

Endocrine therapy (ET) is a well-validated strategy for estrogen receptor α positive (ERα + ) breast cancer therapy. Despite the clinical success of current standard of care (SoC), endocrine-resistance inevitably emerges and remains a significant medical challenge. Herein, we describe the structural optimization and evaluation of a new series of selective estrogen receptor covalent antagonists (SERCAs) based on benzothiophene scaffold. Among them, compounds 15b and 39d were identified as two highly potent covalent antagonists, which exhibits superior antiproliferation activity than positive controls against MCF-7 cells and shows high selectivity over ERα negative (ERα-) cells. More importantly, their mode of covalent engagement at Cys530 residue was accurately illustrated by a cocrystal structure of 15b-bound ERαY537S (PDB ID: 7WNV) and intact mass spectrometry, respectively. Further in vivo studies demonstrated potent antitumor activity in MCF-7 xenograft mouse model and an improved safety profile. Collectively, these compounds could be promising candidates for future development of the next generation SERCAs for endocrine-resistant ERα + breast cancer.

Th1, Th2, and Th17 cells are dysregulated, but only Th17 cells relate to C-reactive protein, D-dimer, and mortality risk in Stanford type A aortic dissection patients.

BACKGROUND: T helper (Th) cells are closely involved in vascular inflammation, endothelial dysfunction, and atherogenesis, which are the hallmarks of aortic dissection (AD). This study aimed to evaluate the clinical value of Th1, Th2, and Th17 cell measurements in Stanford type A AD patients. METHODS: Stanford type A AD patients (N=80) and non-AD patients with chest pain (N = 40) were recruited. Then, Th1, Th2, and Th17 cells in peripheral blood CD4+ T cells from all participants were detected by flow cytometry. The 30-day mortality of Stanford type A AD patients was recorded. RESULTS: Th1 and Th17 cells were higher, while Th2 cells were lower in Stanford type A AD patients compared with non-AD patients (all p < 0.001). Meanwhile, Th1 cells (area under curve (AUC): 0.734, 95% confidence interval (CI): 0.640-0.828), Th2 cells (AUC: 0.841, 95% CI: 0.756-0.925), and Th17 cells (AUC: 0.898, 95% CI: 0.839-0.957) could distinguish Stanford type A patients from non-AD patients. Moreover, Th1 cells (p = 0.037) and Th17 cells (p = 0.001) were positively related to CRP, and Th17 cells (p = 0.039) were also positively associated with D-dimer in Stanford type A AD patients. Furthermore, Th17 cells were elevated in deaths compared with survivors (p = 0.001), also, it could estimate 30-day mortality risk in Stanford type A AD patients with an AUC of 0.741 (95% CI: 0.614-0.867), which was similar to the value of CRP (AUC: 0.771, 95% CI: 0.660-0.882), but lower than the value of D-dimer (AUC: 0.818, 95% CI: 0.722-0.913). CONCLUSION: Th1, Th2, and Th17 cells are dysregulated, but only the Th17 cells relate to CRP, D-dimer, and 30-day mortality risk in Stanford type A AD patients.

Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism.

Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

Circular RNA LARP4 correlates with decreased Enneking stage, better histological response, and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging microRNA-424 in osteosarcoma.

BACKGROUND: This study aimed to evaluate the association of circular RNA La-related RNA-binding protein 4 (circ-LARP4) with clinical features and prognosis in osteosarcoma patients, and further explore its effect on chemosensitivity in osteosarcoma cells. METHODS: Seventy-two osteosarcoma patients with Enneking stage IIA-IIB who underwent resection were consecutively enrolled, and then, tumor tissues and non-tumor tissues were obtained. Circ-LARP4 in tumor tissue/non-tumor tissue was detected by quantitative polymerase chain reaction. After circ-LARP4 overexpression and negative control overexpression plasmid transfection, relative cell viability (%) was evaluated by Cell Counting Kit-8 in MG63 cells treated by different concentrations of cisplatin, methotrexate, and doxorubicin, and IC50 was calculated. RESULTS: Circ-LARP4 was downregulated in tumor tissue compared with non-tumor tissue and had a good value in distinguishing tumor tissue from non-tumor tissue with an area under curve of 0.829 (95% CI: 0.762-0.859). Meanwhile, tumor circ-LARP4 was negatively correlated with the Enneking stage. After resection, circ-LARP4 high expression patients showed an increased tumor cell necrosis rate to adjuvant chemotherapy compared to circ-LARP4 low expression patients, and circ-LARP4 high expression correlated with prolonged disease-free survival and overall survival. In vitro experiments revealed that circ-LARP4 overexpression elevated the chemosensitivity of MG63 cells to cisplatin and doxorubicin but not methotrexate, with decreased cisplatin IC50 and doxorubicin IC50 concentrations than negative control. Besides, miR-424 overexpression attenuated the chemosensitivity in circ-LARP4 overexpression-treated MG63 cells. CONCLUSION: Circ-LARP4 high expression correlates with decreased Enneking stage and prolonged survival profiles, and it elevates chemosensitivity to cisplatin and doxorubicin via sponging miR-424 in osteosarcoma.

Comparison of the differentiation of dental pulp stem cells and periodontal ligament stem cells into neuron-like cells and their effects on focal cerebral ischemia.

Recent studies have reported an increasing incidence of ischemic stroke, particularly in younger age groups. Dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) are the most common stem cells acquired from the teeth of adults, even elderly people. However, there are no detailed reports on whether DPSCs or PDLSCs are suitable for the treatment of ischemic stroke. In this study, the in vitro differentiation of DPSCs and PDLSCs into neuron-like cells was evaluated. Then, we established a rat model of cerebral ischemia. DPSCs or PDLSCs were administered to animals, and the therapeutic effects of these two types of cells were investigated. The results showed that PDLSCs had a higher differentiation rate than DPSCs. Immunofluorescence studies showed that the expression of the neuronal differentiation marker Thy-1 was higher in PDLSCs than in DPSCs, and other gene markers of neuronal differentiation showed corresponding trends, which were confirmed by western blot analysis. In this process, the Notch and Wnt signaling pathways were inhibited and activated, respectively. Finally, rats with transient occlusion of the right middle cerebral artery were used as a model to assess the therapeutic effect of PDLSCs and DPSCs on ischemia. The results showed that rats in the PDLSC-treated group emitted significantly greater red fluorescence signal than the DPSC-treated group. PDLSC transplantation promoted the recovery of neurological function more effectively than DPSC transplantation. Hence, PDLSCs represent an autogenous source of adult mesenchymal stem cells with desirable biological properties and may be an ideal candidate for clinical applications.

A selenosemicarbazone complex with copper efficiently down-regulates the 90-kDa heat shock protein HSP90AA1 and its client proteins in cancer cells.

BACKGROUND: The 90-kDa heat shock protein HSP90AA1 is critical for the stability of several proteins that are important for tumor progression and thus, is a promising target for cancer therapy. Selenosemicarbazone metal complexes have been shown to possess anticancer activity through an unknown molecular mechanism. METHODS: The MTT assay, fluorescence-activated cell sorting, and fluorescent microscopy were used to analyze the mechanism of the anti-cancer activity of the selenosemicarbazone metal complexes. Additionally, RNA-seq was applied to identify transcriptional gene changes, and in turn, the signaling pathways involved in the process of 2-24a/Cu-induced cell death. Last, the expression of HSP90AA1, HSPA1A, PIM1, and AKT proteins in 2-24a/Cu-treated cells were investigated by western blot analysis. RESULTS: A novel selenosemicarbazone copper complex (2-24a/Cu) efficiently induced G2/M arrest and was cytotoxic in cancer cells. 2-24a/Cu significantly induced oxidative stress in cancer cells. Interestingly, although RNA-seq revealed that the transcription of HSP90AA1 was increased in 2-24a/Cu-treated cells, western blotting showed that the expression of HSP90AA1 protein was significantly decreased in these cells. Furthermore, down-regulation of HSP90AA1 led to the degradation of its client proteins (PIM1 and AKT1), which are also cancer therapy targets. CONCLUSION: Our results showed that 2-24a/Cu efficiently generates oxidative stress and down-regulates HSP90AA1 and its client proteins (PIM1, AKT1) in U2os and HeLa cells. These results demonstrate the potential application of this novel copper complex in cancer therapy.

Transmembrane protein TMEM97 and epigenetic reader BAHCC1 constitute an axis that supports pro-inflammatory cytokine expression.

Pro-inflammatory cytokine production by the retinal pigment epithelium (RPE) is a key etiology in retinal degenerative diseases, yet the underlying mechanisms are not well understood. TMEM97 is a scarcely studied transmembrane protein recently implicated in retinal degeneration. BAH domain coiled coil 1 (BAHCC1) is a newly discovered histone code reader involved in oncogenesis. A role for TMEM97 and BAHCC1 in RPE inflammation was not known. Here we found that they constitute a novel axis regulating pro-inflammatory cytokine expression in RPE cells. Transcriptomic analysis using a TMEM97-/- ARPE19 human cell line and the validation via TMEM97 loss- and gain-of-function revealed a profound role of TMEM97 in promoting the expression of pro-inflammatory cytokines, notably IL1ß and CCL2, and unexpectedly BAHCC1 as well. Moreover, co-immunoprecipitation indicated an association between the TMEM97 and BAHCC1 proteins. While TMEM97 ablation decreased and its overexpression increased NFκB (p50, p52, p65), the master transcription factor for pro-inflammatory cytokines, silencing BAHCC1 down-regulated NFκB and downstream pro-inflammatory cytokines. Furthermore, in an RPE-damage retinal degeneration mouse model, immunofluorescence illustrated down-regulation of IL1ß and CCL2 total proteins and suppression of glial activation in the retina of Tmem97-/- mice compared to Tmem97+/+ mice. Thus, TMEM97 is a novel determinant of pro-inflammatory cytokine expression acting via a previously unknown TMEM97- > BAHCC1- > NFκB cascade. SYNOPSIS: Retinal pigment epithelium (RPE) inflammation can lead to blindness. We identify here a previously uncharacterized cascade that underlies RPE cell production of pro-inflammatory cytokines. Specifically, transmembrane protein TMEM97 positively regulates the recently discovered histone code reader BAHCC1, which in turn enhances pro-inflammatory cytokine expression via the transcription factor NFκB.

Discovery of potent and selective c-Met inhibitors for MET-amplified hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is a prevalent and lethal malignancy worldwide. The MET gene, which encodes receptor tyrosine kinase c-Met, is aberrantly activated in various solid tumors, including non-small cell lung cancer and HCC. In this study, we identified a novel c-Met inhibitor 54 by virtual screening and structural optimization. Compound 54 showed potent c-Met inhibition with an IC50 value of 0.45 ± 0.06 nM. It also exhibited high selectivity among 370 kinases and potent anti-proliferative activity against MET-amplified HCC cells. Moreover, compound 54 displayed significant anti-tumor efficacy in vivo, making it a potential candidate for HCC treatment in future studies.

Comparison between percutaneous short-segment fixation and percutaneous vertebroplasty in treating Kummell's disease: A minimum 2-year follow-up retrospective study.

BACKGROUND: Percutaneous kyphoplasty (PKP) or percutaneous short-segment fixation (PSSF) is often used to treat Kummell's disease. However, it is not clear which treatment is better for patients. OBJECTIVE: To retrospectively compare the clinical efficacy of PVP and PSSF for the treatment of Kummell's disease. METHOD: 60 patients were involved in this research and the period of follow-up was at least 2 years. 27 of them were treated with PVP (Group I) and the rest who received PSSF (Group II). The visual analog scale (VAS) and radiographic indexes of each participant had been measured preoperatively as well as 1 week, 3 months, and 2 years postoperatively. Additionally, the Oswestry Disability Index (ODI) scores were assessed at the last time point. RESULTS: Comparing the two groups, no statistical significance was found among all parameters preoperatively. The time of operations and blood loss is less in Group I. At each time point after operation, the imaging indices in Group II are lower (P< 0.05). One week after treatments, the VAS scores are lower in Group I, and similarly, 3 months are the same (P< 0.05), while VAS are similar at the last time point. In the aspect of ODI scores, they are lower in Group II during long-term follow-up. CONCLUSION: For the treatment of Kummell's disease, both PVP and PSSF have been found to be effective. PVP can provide rapid pain relief with a shorter operation time. However, in cases with severe kyphosis deformity, PSSF should be given priority.

Serum YKL-40 in coronary heart disease: linkage with inflammatory cytokines, artery stenosis, and optimal cut-off value for estimating major adverse cardiovascular events.

Objective: YKL-40, previously known as chitinase-3-like protein 1 (CHI3L1), is an inflammation-related glycoprotein that promotes atherosclerosis, but its application and optimal cut-off value as a prognostic biomarker in coronary heart disease (CHD) require more clinical evidence. Thus, this prospective study aimed to evaluate the linkage of serum YKL-40 with disease features, inflammatory cytokines, and major adverse cardiovascular events (MACEs) in CHD patients. Methods: A total of 410 CHD patients were enrolled for serum YKL-40 determination via enzyme-linked immunosorbent assay. Meanwhile, serum YKL-40 levels in 100 healthy controls (HCs) were also quantified. Results: YKL-40 level was higher in CHD patients compared with that in HCs (P < 0.001). YKL-40 was positively linked with hyperlipidemia (P = 0.014), diabetes mellitus (P = 0.001), fasting blood glucose (P = 0.045), C-reactive protein (P < 0.001), the Gensini score (P < 0.001), and stenosis degree (graded by the Gensini score) (P < 0.001) in CHD patients. In addition, an elevated YKL-40 level was associated with increased levels of tumor necrosis factor alpha (P = 0.001), interleukin (IL)-1ß (P = 0.001), IL-6 (P < 0.001), and IL-17A (P = 0.002) in CHD patients. The 1-/2-/3-year cumulative MACE rates of CHD patients were 5.5%, 14.4%, and 25.0%, respectively. Regarding the prognostic capability, YKL-40 ≥100 ng/ml (the median cut-off value) (P = 0.003) and YKL-40 ≥150 ng/ml (the third interquartile cut-off value) (P = 0.021) reflected an elevated accumulating MACE rate, whereas accumulating MACE was not different between CHD patients with YKL-40 ≥80 and <80 ng/ml (the first interquartile cut-off value) (P = 0.083). Conclusion: Serum YKL-40 is positively linked with inflammatory cytokines and the Gensini score, whose high expression cut-off by 100 and 150 ng/ml estimates a higher MACE risk in CHD patients.

METTL3-mediated maturation of miR-192-5p targets ATG7 to prevent Schwann cell autophagy in peripheral nerve injury.

The inhibition of miR-192-5p can promote nerve repair in rats with peripheral nerve injury (PNI) but the precise mechanisms underlying this effect remain unclear. Schwann cell (SC) autophagy mediated by autophagy-related gene (ATG) proteins has a key role in PNI but it is uncertain whether miR-192-5p affects the involvement of SC autophagy in PNI. In this study, we investigated the impact of methyltransferase-like protein 3 (METTL3)/miR-192-5p/ATG7 on SC autophagy in a rat PNI model and in an SC oxygen and glucose deprivation model. The results revealed that METTL3 stimulated miR-192-5p maturation via m6A methylation to depress ATG7 and SC autophagy and aggravate PNI. These findings provide a new target and potential basis for the treatment of patients with PNI.

Nickel-Catalyzed Amidation of Aryl Alkynyl Acids with Tetraalkylthiuram Disulfides: A Facile Synthesis of Aryl Alkynyl Amides.

Nickel-catalyzed amidation of aryl alkynyl acids using tetraalkylthiuram disulfides as the amine source is described, affording a series of aryl alkynyl amides in good to excellent yields under mild conditions. This general methodology provides an alternative pathway for the synthesis of useful aryl alkynyl amides in an operationally simple manner, which shows its practical synthetic value in organic synthesis. The mechanism of this transformation was explored through control experiments and DFT calculations.

Online verification and management scheme of gateway meter flow in the power system by machine learning.

Currently, the calibration of electric energy meters often involves manual meter reading, dismantling inspection, or regular sampling inspection conducted by professionals. To improve work efficiency and verification accuracy, this research integrates machine learning into the scheme of online verification and management of gateway meter flow in the power system. The approach begins by applying the Faster Region Convolutional Neural Network (Faster-RCNN) model and the Single Shot MultiBox Detector (SSD) model to the recognition system for dial readings. Then, the collected measurement data is pre-processed, excluding data collected under light load conditions. Next, an estimation error model and a solution equation for the electricity meter are established based on the pre-processed data. The operation error of the electricity meter is estimated, and the estimation accuracy is verified using the limited memory recursive least squares algorithm (LMRLSA). Furthermore, business assistant decision-making is carried out by combining the remote verification results with the estimation outcomes. The proposed dial reading recognition system is tested using 528 images of meter readings, achieving an accuracy of 98.49%. In addition, the influence of various parameters on the error results of the electricity meter is also explored. The results demonstrate that a memory length ranging from 600 to 1,200 and a line loss error of less than 5% yield the most suitable accuracy for estimating the electricity meter error. Meanwhile, it is advisable to remove measurement data collected under light load to avoid unnecessary checks. The experiments manifest that the proposed algorithm can properly eliminate the influence of old measurement data on the error parameter estimation, thereby enhancing the accuracy of the estimation. The adjustment of the memory length ensures real-time performance in estimating meter errors and enables online monitoring. This research has certain reference significance for achieving the online verification and management of gateway meter flow in the power system.

Discovery of Potent, Selective, and Orally Bioavailable DYRK2 Inhibitors for the Treatment of Prostate Cancer.

Prostate cancer (PCa) seriously threatens male health, and targeting dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) has been verified to reduce PCa burden, while the research progress on the DYRK2 inhibitors was relatively slow. In this work, we discovered DYRK2 inhibitor 12 (IC50 = 9681 nM) through virtual screening. Subsequently, we performed systematic structural optimization to obtain 54 (IC50 = 14 nM). Compound 54 exhibited high selectivity among 215 kinases and significantly suppressed the proliferation and metastasis of PCa cells in vitro. Moreover, compound 54 displayed high safety, favorable bioavailability, and potent tumor growth inhibitory activity in vivo, which could be used as a potential candidate in the discovery of novel anti-PCa drugs.

Discovery of Potent DYRK2 Inhibitors with High Selectivity, Great Solubility, and Excellent Safety Properties for the Treatment of Prostate Cancer.

Prostate cancer (PCa) is a common male cancer with high incidence and mortality, and hormonal therapy as the major treatment for PCa patients is troubled by the inevitable resistance that makes us identify novel targets for PCa. Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) was found to be an effective target for the treatment of PCa, but the research on its inhibitors is rather little. In this work, a potent DYRK2 inhibitor 43 (IC50 = 0.6 nM) was acquired through virtual screening and structural optimization, which displayed high selectivity among 205 kinases; meanwhile, detailed interactions of 43 with DYRK2 were illustrated by the cocrystal. Furthermore, 43 possessed great water solubility (29.5 mg/mL), favorable safety properties (LD50 > 10,000 mg/kg), and potent anti-PCa activities, which could be used as a potential candidate in further preclinical studies.

GRK5 Deficiency in the Hippocampus Leads to Cognitive Impairment via Abnormal Microglial Alterations.

GRK5 is a member of the G protein-coupled receptor (GPCR) kinase family and is closely associated with heart and nervous system disease. It has been reported that GRK5 is closely related to cerebral nerve function and neurodegenerative diseases. However, the biological function of GRK5 in the brain and the influence of GRK5 deficiency on cognitive dysfunction associated with neurodegenerative diseases are unknown. Here, we reported that mice with reduced GRK5 in the hippocampus exhibit cognitive impairment and some Alzheimer's disease (AD)-related molecular pathologies, such as significant neuronal damage and loss, enhanced tau protein phosphorylation, and increased levels of Aß peptides in the hippocampus. Mechanistically, we observed that GRK5 is located in microglia and plays an essential role in maintaining the morphology and function of microglia. GRK5 deficiency elicits microglial morphology changes and proinflammatory-associated gene increases. In addition, transcriptional analysis of hippocampal tissues revealed striking changes in neuroactive ligand‒receptor interactions and TNF signaling in GRK5-deficient mice. In conclusion, our results further confirm the vital role of GRK5 in maintaining normal cognitive function in mice. This finding suggests a possible mechanism by which GRK5 maintains microglial homeostasis, and its loss may induce microglial function deficits and cause some AD-related molecular pathogenesis.

Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC.

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFRL858R/T790M/C797S mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFRdel19/T790M/C797S mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

Monitoring dynamic reactions of red blood cells to UHF electromagnetic waves radiation using a novel micro-imaging technology.

Multiple state-of-the-art techniques, such as multi-dimensional micro-imaging, fast multi-channel micro-spetrophotometry, and dynamic micro-imaging analysis, were used to dynamically investigate various effects of cell under the 900 MHz electromagnetic radiation. Cell changes in shape, size, and parameters of Hb absorption spectrum under different power density electromagnetic waves radiation were presented in this article. Experimental results indicated that the isolated human red blood cells (RBCs) do not have obviously real-time responses to the ultra-low density (15 µW/cm(2), 31 µW/cm(2)) electromagnetic wave radiation when the radiation time is not more than 30 min; however, the cells do have significant reactions in shape, size, and the like, to the electromagnetic waves radiation with power densities of 1 mW/cm(2) and 5 mW/cm(2). The data also reveal the possible influences and statistical relationships among living human cell functions, radiation amount, and exposure time with high-frequency electromagnetic waves. The results of this study may be significant on protection of human being and other living organisms against possible radiation affections of the high-frequency electromagnetic waves.