Identification of activating transcription factor 6 (ATF6) as a novel prognostic biomarker and potential target in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is originating from oral mucosal epithelial cells. Autophagy plays a crucial role in cancer treatment by promoting cellular self-degradation and eliminating damaged components, thereby enhancing therapeutic efficacy. In this study, we aim to identify a novel autophagy-related biomarker to improve OSCC therapy. METHODS: We firstly utilized Cox and Lasso analyses to identify that ATF6 is associated with OSCC prognosis, and validated the results by Kaplan-Meier survival analysis. We further identified the downstream pathways and related genes by enrichment analysis and WGCNA analysis. Subsequently, we used short interfering RNA to investigate the effects of ATF6 knockdown on proliferation, migration, apoptosis, and autophagy in SCC-9 and SCC-15 cells through cell viability assay, transwell assay, EdU incorporation assay, flow cytometry analysis, western blot analysis and immunofluorescence analysis, etc. RESULTS: Bioinformatics analyses showed that ATF6 overexpression was associated with prognosis and detrimental to survival. In vitro studies verified that ATF6 knockdown reduced OSCC cell proliferation and migration. Mechanistically, ATF6 knockdown could promote cellular autophagy and apoptosis. CONCLUSION: We propose that ATF6 holds potential as a prognostic biomarker linked to autophagy in OSCC. This study provides valuable clues for further exploration of targeted therapy against OSCC.

Combination treatment with ferroptosis and autophagy inducers significantly inhibit the proliferation and migration of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC), a malignancy originating from mucosal epithelial cells. Currently, triggering apoptotic cell death with anticancer drugs is the main way to inhibit OSCC cells. However, the capability to trigger apoptosis in tumors is constrained by the intrinsic resistance of tumor cells to apoptosis, hampering its effectiveness. Thus, utilizing alternative modes of non-apoptotic cell death offers new therapeutic possibilities, such as using a drug combination strategy to simultaneously induce ferroptosis and autophagy has the potential to improve OSCC therapy. In this study, we found the ferroptosis inducer RSL3 has certain inhibitory effects on the proliferation and migration of OSCC cells. Interestingly, our studies showed that RSL3 is also associated with autophagy activation. Based on this finding, we tried to combine RSL3 with the autophagy inducer LYN-1604 to improve the therapeutic effect. The results demonstrated that simultaneous regulation of autophagy and ferroptosis significantly reduced the proliferation and migration of OSCC cells. Taken together, we demonstrated the therapeutic potential of RSL3 in OSCC cells and proposed that simultaneous activation of autophagy and ferroptosis have synergistic effects, which would provide valuable clues for further exploration of targeted therapy for OSCC.

Prognostic Value of Fatty Acid Metabolism-related Genes in Patients with Bladder Cancer.

INTRODUCTION: This study aimed to explore the expression profiles of fatty acid metabolism- related genes (FAMRGs) in patients with bladder cancer (BLCA). METHODS: The corresponding clinicopathological features of BLCA patients and RNA sequencing data were downloaded from TCGA and GSE13507. Univariate Cox regression was used to determine the prognostic value of FRGS in BLCA patients. LASSO regression analysis was then performed to select potential risk genes and eliminate genes that might overfit the model. Based on the independent prognostication-related FRGs, the nomogram survival model was established using the root mean square value of the R packet to predict the 1-year, 3-year, and 5-year survival rates of BLCA patients. By determining the area under the curve (AUC) value, the time-dependent receiver operating characteristic curve (ROC) was used to evaluate the prognostic efficiency of our model. RESULTS: A total of 243 DEFRGs were identified. Twenty FRGs were found to be related to the prognosis of BLCA in the TCGA database. Survival curves showed that high-risk patients had significantly shorter OS than low-risk cases (p < 0.001). The AUC of risk was 0.784, which was superior to age, sex, and stage, suggesting that the risk score was more favorable in predicting OS than traditional pathologic prognostic factors. The AUC was 0.757 at 1 year, 0.732 at 3 years, and 0.733 at 5 year-OS. CONCLUSION: In this study, we demonstrated that a FAMRG prognosis biomarker is associated with the tumor immune microenvironment in patients with BLCA.

Recent advances in aggregation-induced emission-active type I photosensitizers with near-infrared fluorescence: From materials design to therapeutic platform fabrication.

Near-infrared (NIR) fluorescence imaging-guided photodynamic therapy (PDT) technology plays an important role in treating various diseases and still attracts increasing research interests for developing novel photosensitizers (PSs) with outstanding performances. Conventional PSs such as porphyrin and rhodamine derivatives have easy self-aggregation properties in the physiological environment due to their inherent hydrophobic nature caused by their rigid molecular structure that induces strong intermolecular stacking π-π interaction, leading to serious fluorescence quenching and cytotoxic reactive oxygen species (ROS) reduction. Meanwhile, hypoxia is an inherent barrier in the microenvironment of solid tumors, seriously restricting the therapeutic outcome of conventional PDT. Aforementioned disadvantages should be overcome urgently to enhance the therapeutic effect of PSs. Novel NIR fluorescence-guided type I PSs with aggregation-induced emission (AIE), which features the advantages of improving fluorescent intensity and ROS generation efficiency at aggregation as well as outstanding oxygen tolerance, bring hope for resolving aforementioned problems simultaneously. At present, plenty of research works fully demonstrates the advancement of AIE-active PDT based on type I PSs. In this review, cutting-edge advances focusing on AIE-active NIR type I PSs that include the aspects of the photochemical mechanism of type I ROS generation, various molecular structures of reported type I PSs with NIR fluorescence and their design strategies, and typical anticancer applications are summarized. Finally, a brief conclusion is obtained, and the underlying challenges and prospects of AIE-active type I PSs are proposed.

Halogen-Modulated 2D Coordination Polymers for Efficient Hydrogen Peroxide Photosynthesis under Air and Pure Water Conditions.

H2 O2 is a widely used eco-friendly oxidant and a potential energy carrier. Photocatalytic H2 O2 production from water and O2 is an ideal approach with the potential to address the current energy crisis and environmental issues. Three zig-zag two-dimensional coordination polymers (2D CPs), named CuX-dptz, were synthesized by a rapid and facile method at room temperature, showing preeminent H2 O2 photoproduction performance under pure water and open air without any additives. CuBr-dptz exhibits a H2 O2 production rate high up to 1874 µmol g-1 h-1 , exceeding most reported photocatalysts under this condition, even comparable to those supported by sacrificial agents and O2 . The coordination environment of Cu can be modulated by halogen atoms (X=Cl, Br, I), which in turn affects the electron transfer process and finally determines the reaction activity. This is the first time that 2D CPs have been used for photocatalytic H2 O2 production in such challenging conditions, which provides a new pathway for the development of portable in situ H2 O2 photosynthesis devices.

Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy.

Metformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U-13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.

Discovery of a Dual-Target Inhibitor of CDK7 and HDAC1 That Induces Apoptosis and Inhibits Migration in Colorectal Cancer.

Aberrant expression or dysfunction of cyclin-dependent kinase 7(CDK7) and histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.

Targeting protein kinases for the treatment of Alzheimer's disease: Recent progress and future perspectives.

Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by memory impairment, mental retardation, impaired motor balance, loss of self-care and even death. Among the complex and diverse pathological changes in AD, protein kinases are deeply involved in abnormal phosphorylation of Tau proteins to form intracellular neuronal fiber tangles, neuronal loss, extracellular ß-amyloid (Aß) deposits to form amyloid plaques, and synaptic disturbances. As a disease of the elderly, the growing geriatric population is directly driving the market demand for AD therapeutics, and protein kinases are potential targets for the future fight against AD. This perspective provides an in-depth look at the role of the major protein kinases (GSK-3ß, CDK5, p38 MAPK, ERK1/2, and JNK3) in the pathogenesis of AD. At the same time, the development of different protein kinase inhibitors and the current state of clinical advancement are also outlined.

Dissecting the multifaced function of transcription factor EB (TFEB) in human diseases: From molecular mechanism to pharmacological modulation.

The transcription factor EB (TFEB) is a transcription factor of the MiT/TFE family that translocations from the cytoplasm to the nucleus in response to various stimuli, including lysosomal stress and nutrient starvation. By activating genes involved in lysosomal function, autophagy, and lipid metabolism, TFEB plays a crucial role in maintaining cellular homeostasis. Dysregulation of TFEB has been implicated in various diseases, including cancer, neurodegenerative diseases, metabolic diseases, cardiovascular diseases, infectious diseases, and inflammatory diseases. Therefore, modulating TFEB activity with agonists or inhibitors may have therapeutic potential. In this review, we reviewed the recently discovered regulatory mechanisms of TFEB and their impact on human diseases. Additionally, we also summarize the existing TFEB inhibitors and agonists (targeted and non-targeted) and discuss unresolved issues and future research directions in the field. In summary, this review sheds light on the crucial role of TFEB, which may pave the way for its translation from basic research to practical applications, bringing us closer to realizing the full potential of TFEB in various fields.

Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer.

Triple negative breast cancer (TNBC) is one of the most aggressive breast tumors, with a high rate of recurrence and metastasis as well as a poor prognosis. Consequently, it is urgent to find new targeted therapeutic strategies and development of corresponding drugs. Previous studies have shown that CDK12 inhibitors in combination with PARP1 inhibitors is able to induce synthetic lethality in TNBC cells. Here, we reported simultaneously inhibition of CDK12 and PARP1 by genetic or pharmacological approaches synergistically inhibited the proliferation of TNBC cells. Then, a series of small molecule inhibitors targeting both CDK12 and PARP1 were designed and synthesized. The new dual-target inhibitor (12e) showed potent inhibitory activity against CDK12 (IC50 = 285 nM) and PARP1 (IC50 = 34 nM), as well as good anti-proliferative effects in TNBC cell lines. Meanwhile, compound 12e showed favorable synergistic anti-tumor efficacy in cells and xenografts by inhibiting DNA damage repair, promoting cell cycle arrest and apoptosis. Taken together, we successfully synthesized the first effective CDK12-PARP1 dual inhibitor, which is expected to be an attractive therapeutic strategy for TNBC.

Wound healing rates and wound problems of conventional circumcision compared with ring circumcision: A meta-analysis.

A meta-analysis investigation was executed to measure the wound healing rates (WHRs) and wound problems (WPs) of conventional circumcision (CC) compared with ring circumcision (RC). A comprehensive literature investigation till March 2023 was applied and 2347 interrelated investigations were reviewed. The 16 chosen investigations enclosed 25 838 individuals, with circumcision, were in the chosen investigations' starting point, 3252 of them were RC, and 2586 were CC. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to compute the value of the WHRs and WPs of CC compared with RC by the dichotomous or continuous approaches and a fixed or random model. RC had a significantly lower wound infection rate (WIR) (OR, 0.58; 95% CI, 0.37-0.91, P = .002) and wound bleeding rate (WBR) (OR, 0.22; 95% CI, 0.12-0.42, P < .001) compared with those with CC. However, RC and CC had no significant difference in WHR (OR, 2.18; 95% CI, -0.73 to 5.09, P = .14), wound edema rate (WER) (OR, 1.11; 95% CI, 0.92-1.33, P = .28), and wound dehiscence rate (WDR) (OR, 0.98; 95% CI, 0.60-1.58, P = .93). RC had significantly lower WIR, and WBR, however, no significant difference in WHR, WER, and WDR compared with those with CC. However, care must be exercised when dealing with its values because of the low sample size of some of the nominated investigations for the meta-analysis.

Deciphering the multifunctional role of dual leucine zipper kinase (DLK) and its therapeutic potential in disease.

Dual leucine zipper kinase (DLK, MAP3K12), a serine/threonine protein kinase, plays a key role in neuronal development, as it regulates axon regeneration and degeneration through its downstream kinase. Importantly, DLK is closely related to the pathogenesis of numerous neurodegenerative diseases and the induction of ß-cell apoptosis that leads to diabetes. In this review, we summarize the current understanding of DLK function, and then discuss the role of DLK signaling in human diseases. Furthermore, various types of small molecule inhibitors of DLK that have been published so far are described in detail in this paper, providing some strategies for the design of DLK small molecule inhibitors in the future.

Development of JmjC-domain-containing histone demethylase (KDM2-7) inhibitors for cancer therapy.

Histone methylation is the most common histone modification and a highly dynamic regulator of gene transcription. Methylation of lysine residues can alter the structure of chromatin, helping to regulate DNA-based nuclear activities. Lysine demethylases control and maintain epigenetic factors that affect chromatin structure and cell characteristics. A variety of diseases, including malignant tumors, are connected to their dysregulation. Advances in biochemistry and pathogenesis have prompted the discovery of small molecule inhibitors and tool compounds that disrupt lysine demethylation. In this review, we focus on JmjC-domain-containing histone lysine demethylases (KDM2-7), discussing their structures and biological roles, representative inhibitors, and therapeutic potential in cancer therapy, and aiming to provide unique insights into the development of JmjC-KDM inhibitors.

Real-Time Monitoring of CAR-T Cell Efficiency through a Biorthogonal Cycloaddition Labeling Strategy.

Chimeric antigen receptors (CARs) recognizing tumor-associated antigens (TAAs) effectively target tumor cells without using the major histocompatibility complex (MHC). However, CARs have inaccurate dose determination in clinical practice, and the methods that can solve this problem often produce cytotoxic substances, such as green fluorescent protein (GFP) insertion. Therefore, in this study, we tried to anchor harmless fluorescent labels on CAR-T cell membranes using highly biologically compatible strain-promoted alkyne-azide cycloaddition (SPAAC) without any byproducts. Our conjugated fluorescent label was stable on the CAR-T cell surface for at least two weeks, with excellent light stability and metrology. Also, this method enabled the rapid quantification of the living CAR-T cells without affecting their activity. Thus, this method is a promising reliable strategy for accurately diagnosing and treating cancer.

Transcriptome-wide assessment of N6-methyladenosine modification identifies different gene expression and infection-associated pathways in Treponema pallidum-infected macrophage.

BACKGROUND: Treponema pallidum (Tp) is a widespread and destructive pathogen that leads to syphilis. As the acknowledged executor of host immunity, macrophage plays vital roles in combating the invasion and migration of Tp. However, the mechanisms of these processes are largely unknown, especially the critical driver genes and associated modifications. OBJECTIVE: We aimed to systematically dissect the global N6-methyladenosine (m6A) RNA modification patterns in Tp-infected macrophages. METHODS: The RNA of Tp-infected/non-infected macrophage was extracted, followed by mRNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing. Bioinformatics analysis was executed by m6A peaks and motifs identification, Gene ontology and signaling pathways analysis of differentially expressed genes, and comprehensive comparison. The m6A levels were measured by RNA Methylation Assay, and m6A modified genes were determined by qPCR. RESULTS: Totally, 2623 unique and 3509 common m6A peaks were proved along with related transcripts in Tp-infected macrophages. The common m6A-related genes were enriched in the signals of oxidative stress, cell differentiation, and angiogenesis, while unique genes in those of metabolism, inflammation, and infection. And differentially expressed transcripts revealed various biological processes and pathways associated with catabolic and infection. They also experienced comprehensive analysis due to hyper-/hypo-methylation. And the m6A level of macrophage was elevated, along with qPCR validation of specific genes. CONCLUSION: With a particular m6A transcriptome-wide map, our study provides unprecedented insights into the RNA modification of macrophage stimulated by Tp in vitro, which partially differs from other infections and may provide clues to explore the immune process for syphilis.

Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation.

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis. In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on. It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases. In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development. Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.

Unraveling the therapeutic potential of carbamoyl phosphate synthetase 1 (CPS1) in human diseases.

CPS1, the rate-limiting enzyme that controls the first reaction of the urea cycle, is responsible for converting toxic ammonia into non-toxic urea in mammals. While disruption of the functions of CPS1 leads to elevated ammonia and nerve damage in the body, mainly manifested as urea cycle disorder. Moreover, accumulating evidence has recently revealed that CPS1 is involved in a variety of human diseases, including CPS1D, cardiovascular disease, cancers, and others. In particular, CPS1 expression varies among cancers, being overexpressed in some cancers and downregulated in others, suggesting that CPS1 may be a promising cancer therapeutic target. In addition, some small-molecule inhibitors of CPS1 have been reported, which have not been confirmed experimentally in malignancies, meaning their future role is far from certain. In this review, we describe the structure and function of CPS1, highlight its important roles in various human diseases, and further discuss the potential diagnostic and therapeutic implications of small molecule compounds targeting CPS1.

A Comparison of the Clinical Outcomes of Thoracic Endovascular Repair for Acute Type B Aortic Dissection with Multichanneled and Double-Channeled Morphology.

In this study, we aim to investigate the clinical features and outcomes of multichanneled aortic dissection (MCAD) and double-channeled aortic dissection (DCAD) in acute type B aortic dissection (TBAD) patients who underwent thoracic endovascular aortic repair (TEVAR).In total, 479 consecutive acute TBAD patients treated with TEVAR from April 2002 to May 2020 were retrospectively enrolled in this study. The MCAD group was defined as those of multichanneled morphology by initial computed tomography angiography (CTA) (n = 61), whereas the DCAD group was defined as those with double-channeled morphology by initial CTA (n = 418). The clinical and morphological characteristics and short-term and long-term adverse events (30-day and > 30 days) were recorded and evaluated.No significant differences were noted between the 2 groups as regards demographics, comorbidity profiles, or initial feature of CTA. The incidence of true lumen compression was found to be significantly lower in the MCAD group compared with the DCAD group (8.2% versus 20.8%, P < 0.05). During the 65.37 ± 40.06 months of follow-up, there were no statistically significant differences in terms of 30-day mortality or the incidence of early adverse events between the 2 groups. The incidence rates of 5-year cumulative freedom from all-cause mortality and 5-year cumulative freedom from AD-related mortality were not significantly different between the MCAD and DCAD groups, whereas the 5-year cumulative freedom from adverse events were lower in the MCAD group compared to DCAD group (51.1% versus 72.5%, P < 0.05). In multivariate Cox regression models, only age > 60 years, pleural effusion, branch involvement, and length of the stent were independent predictors of mortality, whereas age > 60 years, pulse, pleural effusion, true lumen compression, widest diameter of the descending aorta, branch involvement, and length of stent were independent predictors of adverse aortic events.No significant difference was noted between the MCAD and DCAD groups in the 5-year mortality following, whereas patients with MCAD were found to have significantly lower AD-related events than patients with DCAD in long-term follow-up.

Graphene Oxide-Based Highly Sensitive Assay of Circulating MicroRNAs for Early Prediction of the Response to Neoadjuvant Chemotherapy in Breast Cancer.

The response to neoadjuvant chemotherapy (NAC) is highly correlated with survival in breast cancer (BC) patients. The early prediction of the response to NAC could facilitate treatment adjustments on a patient-by-patient basis, which would improve patient outcomes and survival. Conventional techniques used for detecting circulating microRNAs (miRNAs), which act as biomarkers for the early prediction of NAC efficacy in BC patients, are associated with limitations such as low sensitivity and specificity. We designed a highly sensitive graphene oxide (GO)-based qRT-PCR method for detecting miRNAs associated with the chemotherapeutic response in BC patients. The results showed that miRNA levels at both the baseline and end of the first NAC cycle could help distinguish NAC responders from NAC nonresponders; BC patients with lower plasma miRNA levels were more likely to achieve pathological complete remission. Thus, GO-based qRT-PCR could facilitate early prediction of NAC efficacy in BC patients.

Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report.

Multiple primary malignancies (MPMs) are defined as the coexistence of at least two unrelated primary malignancies in a single patient, with the tumors differing in their histology. MPMs in the same patient, when present within 6 months of the primary tumor diagnosis, are considered a synchronous occurrence. In this case report, we describe a 61-year-old man who presented with three distinct tumors concurrently in 2021: noninvasive urothelial carcinoma of the bladder, diffuse large B-cell lymphoma, and squamous cell carcinoma of the lung. We discuss the process of therapy and briefly review the literature. MPMs are increasing in incidence, requiring an interdisciplinary approach to diagnosis and treatment.