Impact of cathepsin K-induced proteoglycans degradation on dentin collagen.

OBJECTIVES: This study aimed to investigate the effects of cathepsin K (catK) on proteoglycans (PGs) and the subsequent impacts on dentin collagen degradation. MATERIALS AND METHODS: Demineralized dentin samples were prepared and divided into the following groups: deionized water (DW), 0.1 U/mL chondroitinase ABC (C-ABC), and 1 µM odanacatib (ODN). Then, they were immersed for 48 h and then incubated in 1 mL of PBS (pH=5.5) at 37 °C for 5 d. Glycosaminoglycan (GAG) were examined to explore the degradation of PGs by catK. To determine the effect of catK-mediated PGs on dentin collagen degradation, hydroxyproline (HYP) assays, assessment of the degree of dentin crosslinking, and scanning electron microscopy (SEM) were assessed. Statistical analysis was conducted using one-way ANOVA followed by Tukey's tests or Welch's ANOVA followed by Dunnett's tests at a significance level of 0.05. RESULTS: The production of GAG was significantly lower in the ODN group than in the DW group (P < 0.05), revealing that PG degradation was reduced in dentin after ODN treatment. Additionally, ODN treatment minimized the gaps in collagen fibers, improved fiber arrangement, and significantly increased the degree of collagen crosslinking, subsequently reducing the total amount of collagen fiber degradation in the dentin (P < 0.05). CONCLUSIONS: CatK-mediated degradation of PGs negatively impacted the stability of collagen fibers, promoted gaps, led to a less organized arrangement of dentin collagen fibers, ultimately increasing collagen degradation.

Effectiveness and feasibility of nerve real-time monitoring and intermittent monitoring in endoscopic thyroidectomy: A multicenter retrospective cohort study of 1621 patients.

BACKGROUND: Protecting recurrent laryngeal nerve (RLN) and external branch of the superior laryngeal nerve (EBSLN), a crucial indicator for assessing the quality of thyroid surgery, poses a challenge in endoscopic thyroidectomy. The aim of this study was to investigate the effectiveness and feasibility of nerve real-time monitoring and intermittent monitoring in endoscopic thyroidectomy. METHODS: In this retrospective cohort study, patients underwent endoscopic thyroidectomy were included, and the characteristics and outcomes of real-time monitoring and intermittent monitoring groups were compared. Thereafter, the outcomes of four surgical types (unilateral lobectomy, total thyroidectomy, unilateral lobectomy + lymph node dissection (LND), and total thyroidectomy + LND) were compared in both groups. RESULTS: A total of 1621 patients were enrolled. Compared to intermittent monitoring group, real-time monitoring group significantly shortened operation durations in the four surgical types (30.8 ± 6.1 min vs. 35.7 ± 5.7 min, 54.7 ± 4.4 min vs. 59.1 ± 5.2 min, 39.3 ± 4.6 min vs. 42.0 ± 4.7 min, 59.1 ± 4.9 min vs. 66.0 ± 5.8 min, respectively). As for surgical complications, compared to intermittent monitoring group, real-time monitoring group had lower rates of transient vocal cord paralysis among the four surgical types (0.0% vs. 3.3%, 0.0% vs. 4.0%, 0.8% vs. 3.2%, 2.8% vs. 6.7%, respectively), and lower rates of EBSLN injury (1.1% vs. 4.4%, 0.0% vs. 12.0%, 0.8% vs. 3.8%, 0.9% vs. 4.8%, respectively). Clinicopathologic characteristics and postoperative inflammatory reactions were similarly paralleled in both groups. CONCLUSION: Implementation of real-time monitoring in endoscopic thyroidectomy effectively protects the RLN and EBSLN while shortening operation duration, demonstrating its feasibility and efficacy in enhancing nerve protection and surgical efficiency.

Gut hormone multi-agonists for the treatment of type 2 diabetes and obesity: advances and challenges.

The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagon-like peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field.

miR-4739 promotes epithelial-mesenchymal transition and angiogenesis in "driver gene-negative" non-small cell lung cancer via activating the Wnt/ß-catenin signaling.

PURPOSE: "Driver gene-negative" non-small cell lung cancer (NSCLC) currently has no approved targeted drug, due to the lack of common actionable driver molecules. Even though miRNAs play crucial roles in various malignancies, their roles in "driver gene-negative" NSCLC keep unclear. METHODS: miRNA expression microarrays were utilized to screen miRNAs associated with "driver gene-negative" NSCLC malignant progression. Quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH) were employed to validate the expression of miR-4739, and its correlation with clinicopathological characteristics was analyzed in tumor specimens using univariate and multivariate analyses. The biological functions and underlying mechanisms of miR-4739 were investigated both in vitro and in vivo. RESULTS: our research demonstrated, for the first time, that miR-4739 was substantially increased in "driver gene-negative" NSCLC tumor tissues and cell lines, and overexpression of miR-4739 was related to clinical staging, metastasis, and unfavorable outcomes. Functional experiments discovered that miR-4739 dramatically enhanced tumor cell proliferation, migration, and metastasis by promoting the epithelial-to-mesenchymal transition (EMT). Meanwhile, miR-4739 can be transported from cancer cells to the site of vascular epithelial cells through exosomes, consequently facilitating the proliferation and migration of vascular epithelial cells and inducing angiogenesis. Mechanistically, miR-4739 can activate Wnt/ß-catenin signaling both in tumor cells and vascular epithelial cells by targeting Wnt/ß-catenin signaling antagonists APC2 and DKK3, respectively. CONCLUSION: Our work identifies a valuable oncogene, miR-4739, that accelerates malignant progression in "driver gene-negative" NSCLC and serves as a potential therapeutic target for this group of tumors.

Design, synthesis, and evaluation of antitumor activity of novel C-6 sulfhydryl-substituted and 20-substituted derivatives of celastrol.

Celastrol has been identified as a potential candidate for anticancer drug development. In this study, 28 novel celastrol derivatives with C-6 sulfhydryl substitution and 20-substitution were designed and synthesized, and their antiproliferative activity against human cancer cells and non-malignant human cells was evaluated, with cisplatin and celastrol being used as controls. The results showed that most of the derivatives had enhanced in vitro anticancer activity compared to the parent compound celastrol. Specifically, derivative 2f demonstrated the most potent inhibitory potential and selectivity against HOS with an IC50 value of 0.82 µM. Our study provides new insights into the structure-activity relationship of celastrol and suggests that compound 2f may be a promising drug candidate for the treatment of osteosarcoma.

Discovery of a potent and long-acting Xenopus GLP-1-based GLP-1/glucagon/Y2 receptor triple agonist.

The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y2 receptors, aiming for superior weight loss and better glycemic control. The strategy for constructing such a unimolecular triple agonist peptide is the conjugation of the GLP-1R/GCGR dual-agonistic moiety and PYY moiety via maleimide-thiol specific reaction. A novel triple agonist peptide, 3b, was identified via stepwise structure optimization, long-acting modification and in vitro receptor screens. Peptide 3b exhibited potent and balanced GCGR and GLP-1R activities as well as potent and highly selective Y2R activity. Peptide 3b potently reduced food intake without triggering nausea associated behavior in kaolin consumption and conditioned taste aversion assays. In diet induced obesity (DIO) mice, a lower dose of 3b achieved significantly better effects on lipid metabolism, body weight, and glycemic control than higher dose of GLP-1R mono-agonist, GLP-1R/GCGR dual agonist and GLP-1R/Y2R dual agonist counterparts. Collectively, these data support the therapeutic potential of our GLP-1R/GCGR/Y2R triple agonist 3b as a novel anti-obesity and anti-diabetic agent. Targeting GLP-1R, GCGR and Y2R with unimolecular triple agonist peptide offers a route to develop new obesity and T2DM treatments.

A GLP-1/glucagon (GCG)/CCK2 receptors tri-agonist provides new therapy for obesity and diabetes.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCK2 ) dual agonists have been shown to restore pancreas function and improve glycaemic control in preclinical studies. We describe, for the first time, the beneficial effects of GLP-1/glucagon receptor and GLP-1/CCK2 dual agonists, which can be integrated into one peptide, resulting in significant anti-diabetes and anti-obesity effectiveness. EXPERIMENTAL APPROACH: The in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCK2 tri-agonist (xGLP/GCG/gastrin) against GLP-1, GCG, CCK1 and CCK2 receptors was determined on cells expressing the corresponding receptors by cAMP accumulation or ERK1/2 phosphorylation assays. The in vivo anti-diabetes and anti-obesity effects of this tri-agonist xGLP/GCG/gastrin were studied in both db/db and diet induced obesity (DIO) mice. KEY RESULTS: xGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCK2 tri-agonist. In DIO mice, the metabolic benefits of xGLP-1/GCG/gastrin, such as reduction of body weight and hepatic lipid contents were significantly better than those of the peptide ZP3022 (GLP-1/CCK-2 dual agonist) and liraglutide. In a short-term study in db/db mice, xGLP/GCG/gastrin treatment had considerable effects, increasing islet numbers, islet areas and insulin content. In a long-term treatment study using db/db mice, xGLP-1/GCG/gastrin showed a significantly and sustained improvement in glucose tolerance and glucose control compared with that of liraglutide, ZP3022, cotadutide (GLP-1/GCG dual agonist) and xGLP/GCG-15. CONCLUSIONS AND IMPLICATIONS: These results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Peptide-based long-acting co-agonists of GLP-1 and cholecystokinin 1 receptors as novel anti-diabesity agents.

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. It was documented previously that co-administration of a cholecystokinin receptor-1 receptor (CCK-1R) agonist with a glucagon-like peptide-1 receptor (GLP-1R) agonist exerted improved effects on metabolic improvements in obese rodents. Here, we reported a series of novel GLP-1R/CCK-1R co-agonists constructed by linking the C-terminus of a GLP-1R agonist (native GLP-1 or Xenopus GLP-1) to the N-terminus of a CCK-1R selective agonist NN9056. The stability of co-agonists was further enhanced by introducing an albumin binding motif. In vitro functional assays revealed that the co-agonists retained full agonism potency on GLP-1R and CCK-1R. Particularly, 2a and 2c showed higher hypoglycemic and insulinotropic activities than NN9056 and semaglutide. The glucose-lowering durations and PK profiles of 2a and 2c were comparable to those of semaglutide. Desirably, in diet induced obesity (DIO) mice, 2a and 2c exhibited superior metabolic benefits to NN9056 and semaglutide in reducing food intake, inducing body weight loss, and regulating lipid metabolism. In short- and long-term studies in diabetic db/db mice, 2a and 2c showed enhanced effects on HbA1c, glucose tolerance, and pancreas function restoration compared with semaglutide. Importantly, no side effects, toxicities, or pancreatic inflammation were caused by 2a and 2c treatments. These preclinical studies suggest that the pharmacological effects of CCK-1 and GLP-1 pathways can be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer.

Metastasis is responsible for the high mortality rate of lung cancer, but its underlying molecular mechanisms are poorly understood. Here, we demonstrated that the expression of diacylglycerol kinase alpha (DGKA) was elevated in the metastatic lesions of non-small cell lung cancer (NSCLC) and correlated with poor survival. Mechanistic studies revealed a direct physical interaction as well as a mutual regulation among DGKA, proto-oncogene tyrosine-protein kinase Src (SRC), and focal adhesion kinase 1 (FAK) proteins. The C-terminal domain of DGKA was responsible for the SRC SH3 domain binding, while the catalytic domain of DGKA interacted with the FREM domain of FAK. DGKA phosphorylated the SRC protein at Tyr416 and the FAK protein at Tyr397 to form and activate the DGKA/SRC/FAK complex, thus initiating the downstream WNT/ß-catenin and VEGF signaling pathways, promoting epithelial-mesenchymal transition (EMT) and angiogenesis, and resulting in the metastasis of NSCLC. DGKA knockdown inhibited the invasive phenotype of NSCLC cells in vitro. Pharmacologic ablation of DGKA inhibited the metastasis of NSCLC cells in vivo, and this was reversed by the overexpression of DGKA. These results suggested that DGKA was a potential prognostic biomarker as well as a promising therapeutic target for NSCLC, especially when there was lymphatic or distant metastasis.

Nucleoporin 93 mediates ß-catenin nuclear import to promote hepatocellular carcinoma progression and metastasis.

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating ß-catenin translocation. In addition, we found that Nup93 interacted with ß-catenin directly, independent of importin. Furthermore, LEF1 and ß-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-ß-catenin pathway for HCC therapeutics.

Identification and structure-activity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.

Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure-activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.

Relapsed/refractory multiple myeloma-transformed plasma-cell leukemia successfully treated with daratumumab followed by autologous stem cell transplantation.

Daratumumab is a humanized anti-CD38 IgG1 monoclonal antibody which could be used for multiple myeloma (MM). MM with plasma-cell leukemia (PCL) transformation is highly aggressive and is resistant to conventional therapy. Novel therapeutics are needed for PCL, and daratumumab may play role. We report a case of relapsed/refractory multiple myeloma (RRMM)-transformed PCL successfully treated with daratumumab. The case was a 42-year-old man who was diagnosed with MM 2 years ago and relapsed after six cycles of bortezomib-based chemotherapy. The patient rapidly developed hyperleukocytosis and disseminated intravascular coagulation, and was diagnosed with PCL. Daratumumab-based therapy was tried and the case miraculously obtained complete remission (CR) after four doses of a weekly infusion of daratumumab. Finally the patient received autologous hematopoietic stem-cell transplantation (auto-HSCT) and maintained CR. Moreover, we monitored the immune cell dynamics by flow cytometry (FCM) during daratumumab-based treatment. The immune cell subset analysis revealed significant down-regulation of CD38+ natural killer (NK) cells, regulatory T cells (Tregs) and regulatory B cells (Bregs). Meanwhile cytotoxic T-lymphocyte expansion was observed. In conclusion, daratumumab could rapidly decrease tumor burden, improve the condition of the PCL patient, and serve as a bridging salvage chemotherapy for further chimeric antigen recptor T cell therapy (Car-T) or HSCT, which could potentially improve patient survival. The immune cell dynamic findings in this case suggest that the immunomodulatory mechanism may contribute to the antimyeloma effect of daratumumab.

Design of novel Xenopus GLP-1-based dual glucagon-like peptide 1 (GLP-1)/glucagon receptor agonists.

Dual activation of the glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) has the potential to lead to an effective therapy for the treatment of diabetes and obesity. Here, we report the discovery of a series of peptides with dual activity on GLP-1R and GCGR that were discovered by rational design. Structural elements of oxyntomodulin (OXM), glucagon or exendin-4 were engineered into the selective GLP-1R agonist Xenopus GLP-1 (xGLP-1) on the basis of sequence analysis, resulting in hybrid peptides with potent dual activity at GLP-1R and GCGR. Further modifications with fatty acid resulted in a novel metabolically stable peptide (xGLP/GCG-15) with enhanced and balanced GLP-1R and GCGR activations. This lead peptide was further explored pharmacologically in both db/db and diet-induced obesity (DIO) rodent models. Chronic administration of xGLP/GCG-15 significantly induced hypoglycemic effects and body weight loss, improved glucose tolerance, and normalized lipid metabolism, adiposity, and liver steatosis in relevant rodent models. These preclinical studies suggest that xGLP/GCG-15 has potential for development as a novel anti-obesity and/or anti-diabetic candidate. Considering the equal effects of xGLP/GCG-15 and the clinical candidate MEDI0382 on reverse hepatic steatosis, it may also be explored as a new therapy for nonalcoholic steatohepatitis (NASH) in the future.

Development of Furo[2,3-b]quinoline Derivatives with Anti-Breast Cancer Property by Targeting Topoisomerase II.

A number of novel furo[2,3-b]quinoline derivatives were designed and synthesized by introducing different substituted anilines and phenols to C4-position of furo[2,3-b]quinoline. All target compounds were evaluated in vitro against two human breast cancer cell lines (MCF-7 and MDA-MB-231) and one normal breast cell (MCF-10A) by MTT (3-[4,5-dimethylthylthiazol-2-yl]-2,5 diphenyltetrazolium broide, Thiazolyl blue) method. Most derivatives showed significant cytotoxic activity on the two breast cancer cells with IC50 values in the range of (5.60-26.24 µM) and a certain selectivity, especially in the inhibition of MDA-MB-231. More notably, they were less toxic to normal breast cell (MCF-7-10A). Compound I7 could be considered as an ideal selective candidate for further study. Mechanism studies showed that I7 could inhibit the proliferation of cells by arresting MDA-MB-231 cell cycle at G2/M phase. Overall, as a novel furo[2,3-b]quinoline derivative, I7 exhibited an excellent inhibitory effect in MDA-MB-231 cell and was worthy of in-depth study.

CD8dimCD3+ lymphocytes in fever patients might be biomarkers of active EBV infection and exclusion indicator of T-LGLL.

Background: Massive monoclonal or oligoclonal expansion of CD8+ T cells is a notable feature of primary infections of the Epstein-Barr virus (EBV). However, the clinical significance of this expansion is not clear. Results: An increase in the CD8dimCD3+ lymphocyte subset in patients with active EBV infection was due to caspase-8-dependent apoptosis was found using flow cytometry in this study. The number of these cells was associated with the illness severity. Pan-T-cell antigen and receptor analyses were also compared in patients with active EBV infections and T-cell large granular lymphocytic leukemia to provide additional diagnostic information. Conclusion: The increase in CD8dimCD3+ cells could be a biomarker of active EBV infection and an exclusion indicator of T-cell large granular lymphocytic leukemia with flow cytometric analysis.

Stapled and Xenopus Glucagon-Like Peptide 1 (GLP-1)-Based Dual GLP-1/Gastrin Receptor Agonists with Improved Metabolic Benefits in Rodent Models of Obesity and Diabetes.

Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving ß-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases ß-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life (t1/2) is short, and its body weight reducing activity is limited. Here, we report the discovery of a series of novel GLP-1R/CCK-2R dual agonists. Starting from Xenopus GLP-1, dual cysteine mutation was conducted followed by covalent side chain stapling and albumin binder incorporation, resulting in a stabilized secondary structure, increased agonist potency, and improved stability. Further C-terminal conjugation of gastrin-6 generated GLP-1R/CCK-2R dual agonists, among which 6a and 6b showed higher stability and hypoglycemic activity than liraglutide and ZP3022. Desirably, 6a and 6b exhibited prominent metabolic benefits in diet-induced obesity mice without causing nausea responses and exerted considerable effects on ß-cell restoration in db/db mice. These preclinical studies suggest the potential role of GLP-1R/CCK-2R dual agonists as effective agents for treating diabetes and related metabolic disorders.

Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-ß aggregation against Alzheimer's disease.

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-ß aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC50 values in the nanomolar, and exhibited a moderate inhibition of amyloid-ß aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC50 = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC50 = 141 nM, SI > 355), and exhibited good inhibitory activity against Aß1-42 aggregation (40.78%, 25 µM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.

HIF-1ɑ-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/ß-catenin and Notch signaling.

Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1ɑ was identified as the transcription mediator of miR-1275. Activation of Wnt/ß-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/ß-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/ß-catenin and Notch pathways, including DKK3, SFRP1, GSK3ß, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/ß-catenin and Notch signaling pathways. Thus, HIF-1ɑ-regulated miR-1275 might be a potential therapeutic target for LUAD.

Combined evaluation of the expression status of CD155 and TIGIT plays an important role in the prognosis of LUAD (lung adenocarcinoma).

The interaction between CD155 and its high-affinity ligand TIGIT is being increasingly investigated in various solid tumors. However, the prognostic significance of CD155 and TIGIT in lung adenocarcinoma (LUAD) remains unclear. In this study, immunohistochemistry was applied in 334 LUAD cases to evaluate the expression of CD155 and TIGIT. Western blotting was conducted in 5 paired primary LUAD and adjacent normal lung tissues. Our results reveal that CD155 and TIGIT are overexpressed in LUAD tissues and that aberrant overexpression is closely correlated with poor clinical outcomes (P < 0.01). The multivariate model also shows that CD155 expression is an independent risk factor for LUAD (RR, 1.34; P = 0.036). Moreover, patients expressing high CD155 and TIGIT simultaneously presented shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) (P < 0.01). These findings suggest that CD155 and TIGIT can make up a prognosticating tool to predict clinical outcomes, thereby contributing to personalized medical care in LUAD.