Three-Month Excessive Body Weight Loss < 37.7% as a Predictor of Mid-term Suboptimal Outcomes Postlaparoscopic Sleeve Gastrectomy: Risk Factors and the Impact of Neutrophil-to-Lymphocyte Ratio on Adipocyte Function.

INTRODUCTION: This study aimed to evaluate the impact of achieving < 37.7% excess body-weight loss (EBWL) within 3 months of postlaparoscopic sleeve gastrectomy (LSG) on clinical outcomes and its correlation with adipocyte function. METHODS: Patients (n = 176) who underwent LSG between January 2019 and January 2023 were included. Weight loss and status of health markers were monitored postoperatively. The cohort was stratified based on EBWL < 37.7% at 3 months or not. Variables including neutrophil-to-lymphocyte ratio (NLR), insulin resistance, and comorbidities were analyzed. Omental visceral and subcutaneous adipose tissue samples were used to analyze the differences in adipocyte function by western blot. RESULTS: Patients with EBWL < 37.7% at 3 months post-LSG (suboptimal group) comprised less likelihood of achieving ≥ 50% EBWL than those who achieved ≥ 37.7% EBWL (optimal group) at 6 months (42.55% vs. 95.52% in optimal group, p < 0.001), 12 months (85.11% vs. 99.25% in optimal group, p < 0.001) and 24 months (77.14% vs. 94.74% in optimal group, p = 0.009) post-LSG. High BMI (OR = 1.222, 95% CI 1.138-1.312, p < 0.001), NLR ≥ 2.36 (OR = 2.915, 95% CI 1.257-6.670, p = 0.013), and female sex (OR = 3.243, 95% CI 1.306-8.051, p = 0.011) significantly predicted EBWL < 37.7% at 3 months post-LSG. Patients with NLR ≥ 2.36 had significantly lower adipose triglyceride lipase in omental fat (p = 0.025). CONCLUSION: EBWL < 37.7% at 3 months post-LSG is a strong predictor of subsequent suboptimal weight loss. High BMI, NLR ≥ 2.36, and female sex are risk factors in predicting EBWL < 37.7% at 3 months post-LSG. These findings may offer a reference to apply adjuvant weight loss medications to patients who are predisposed to suboptimal outcomes.

N-Benzylated 5-Hydroxybenzothiophene-2-carboxamides as Multi-Targeted Clk/Dyrk Inhibitors and Potential Anticancer Agents.

Numerous studies have reported that Dyrk1A, Dyrk1B, and Clk1 are overexpressed in multiple cancers, suggesting a role in malignant disease. Here, we introduce a novel class of group-selective kinase inhibitors targeting Dyrk1A, Dyrk1B, and Clk1. This was achieved by modifying our earlier selective Clk1 inhibitors, which were based on the 5-methoxybenzothiophene-2-carboxamide scaffold. By incorporating a 5-hydroxy group, we increased the potential for additional hydrogen bond interactions that broadened the inhibitory effect to include Dyrk1A and Dyrk1B kinases. Within this series, compounds 12 and 17 emerged as the most potent multi-kinase inhibitors against Dyrk1A, Dyrk1B, and Clk1. Furthermore, when assessed against the most closely related kinases also implicated in cancer, the frontrunner compounds revealed additional inhibitory activity against Haspin and Clk2. Compounds 12 and 17 displayed high potency across various cancer cell lines with minimal effect on non-tumor cells. By examining the effect of these inhibitors on cell cycle distribution, compound 17 retained cells in the G2/M phase and induced apoptosis. Compounds 12 and 17 could also increase levels of cleaved caspase-3 and Bax, while decreasing the expression of the antiapoptotic Bcl-2 protein. These findings support the further study and development of these compounds as novel anticancer therapeutics.

Guizhi Fuling Wan ameliorates concanavalin A-induced autoimmune hepatitis in mice.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated hepatic disease associated with intense complications. AIH is more common in females and needs effective drugs to treat. Guizhi Fuling Wan (GZFLW) is a traditional Chinese herbal formula used to treat various gynecologic diseases. In this study, we aim to extend the new use of GZFLW for AIH. METHODS: The tandem MS-based analysis was used to identify secondary metabolites in GZFLW. Therapeutic effects of GZFLW were tested in a concanavalin A (Con A)-induced AIH model in mice. Ethnopharmacological mechanisms underlying the antiapoptotic, antioxidant, and immunomodulatory protective effects were determined. RESULTS: Oral administration of GZFLW attenuates AIH in a Con A-induced hepatotoxic model in vivo. The tandem MS-based analysis identified 15 secondary metabolites in GZFLW. The Con A-induced AIH syndromes, including hepatic apoptosis, inflammation, reactive oxygen species accumulation, function failure, and mortality, were significantly alleviated by GZFLW in mice. Mechanistically, GZFLW restrained the caspase-dependent apoptosis, restored the antioxidant system, and decreased pro-inflammatory cytokine production in the livers of Con A-treated mice. Besides, GZFLW repressed the Con A-induced hepatic infiltration of inflammatory cells, splenic T cell activation, and splenomegaly in mice. CONCLUSIONS: Our findings demonstrate the applicable potential of GZFLW in treating AIH. It prompts further investigation of GZFLW as a treatment option for AIH and possibly other hepatic diseases.

Ribociclib leverages phosphodiesterase 4 inhibition in the treatment of neutrophilic inflammation and acute respiratory distress syndrome.

INTRODUCTION: Overwhelming neutrophil activation and oxidative stress significantly contribute to acute respiratory distress syndrome (ARDS) pathogenesis. However, the potential of repurposing ribociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor used clinically in cancer treatment, for treating neutrophilic ARDS remains uncertain. This study illustrated the ability and underlying mechanism of ribociclib for treating ARDS and neutrophilic inflammation. METHODS: Primary human neutrophils were used to determine the therapeutic effects of ribociclib on respiratory bursts, chemotactic responses, and inflammatory signaling. In vitro and silico analyses were performed to determine the underlying molecular mechanisms. The potential of ribociclib repurposing was evaluated using an in vivo ARDS model in lipopolysaccharide (LPS)-primed mice. RESULTS: We found that treatment using ribociclib markedly limited overabundant oxidative stress (reactive oxygen species [ROS]) production and chemotactic responses (integrin levels and adhesion) in activated human neutrophils. Ribociclib was also shown to act as a selective inhibitor of phosphodiesterase 4 (PDE4), thereby promoting the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway, leading to the inhibition of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) phosphorylation, and calcium influx. Notably, prophylactic administration and post-treatment with ribociclib ameliorated neutrophil infiltration, lung inflammation, accumulation of oxidative stress, pulmonary destruction, and mortality in mice with LPS-induced ARDS. CONCLUSION: We demonstrated for the first time that ribociclib serves as a novel PDE4 inhibitor for treating neutrophilic inflammation and ARDS. The repurposing ribociclib and targeting neutrophilic PDE4 offer a potential off-label alternative for treating lung lesions and other inflammatory conditions.

Unlocking the Potential of Octocoral-Derived Secondary Metabolites against Neutrophilic Inflammatory Response.

Inflammation is a critical defense mechanism that is utilized by the body to protect itself against pathogens and other noxious invaders. However, if the inflammatory response becomes exaggerated or uncontrollable, its original protective role is not only demolished but it also becomes detrimental to the affected tissues or even to the entire body. Thus, regulating the inflammatory process is crucial to ensure that it is resolved promptly to prevent any subsequent damage. The role of neutrophils in inflammation has been highlighted in recent decades by a plethora of studies focusing on neutrophilic inflammatory diseases as well as the mechanisms to regulate the activity of neutrophils during the overwhelmed inflammatory process. As natural products have demonstrated promising effects in a wide range of pharmacological activities, they have been investigated for the discovery of new anti-inflammatory therapeutics to overcome the drawbacks of current synthetic agents. Octocorals have attracted scientists as a plentiful source of novel and intriguing marine scaffolds that exhibit many pharmacological activities, including anti-inflammatory effects. In this review, we aim to provide a summary of the neutrophilic anti-inflammatory properties of these marine organisms that were demonstrated in 46 studies from 1995 to the present (April 2023). We hope the present work offers a comprehensive overview of the anti-inflammatory potential of octocorals and encourages researchers to identify promising leads among numerous compounds isolated from octocorals over the past few decades to be further developed into anti-inflammatory therapeutic agents.

Perceived Stress Mediating the Association Between Mindfulness and Resilience Among Registered Nurses.

Purpose: Resilience continues to be an important concept in the nursing profession due to its significant role in personal healthcare, patients' healthcare, and leadership. The present study examined the mediating role of perceived stress in the association between mindfulness and resilience among registered nurses in order to understand their importance among those in the Taiwanese nursing profession. Materials and Methods: Between October and November 2021, a total of 816 registered nurses participated in a cross-sectional survey including psychometric measures assessing perceived stress (Chinese Perceived Stress Scale-10), mindfulness (Chinese Mindful Attention Awareness Scale), and resilience (Chinese Questionnaire of Resilience). Results: Results indicated that perceived stress mediated the association between mindfulness and resilience (standardized coefficient = 0.251, p<0.001), although there was no significant association between mindfulness and resilience (standardized coefficient = 0.042, p=0.16). This suggests that perceived stress may function as both distress and eustress because mindfulness was not directly associated with resilience but indirectly via perceived stress. Conclusion: Nurses and their administrators should focus on different ways of coping with stress so that they become more resilient in facing other stressors. Future studies may be conducted to examine the mediating role of perceived stress in the association between other coping strategies and resilience among registered nurses.

Chemometric-guided chemical marker selection: A case study of the heat-clearing herb Scrophularia ningpoensis.

The selection of medicinal plants' chemical markers focuses on bioactivity as the primary goal, followed by the nature of secondary metabolites, their stability, and availability. However, herbal medicines are valued for their complex and holistic pharmacological effects. A correct chemical marker can be carefully selected by a systematic clarification of their chemical-biological relationships. In the current study, the multi-informative molecular networking (MIMN) approach was employed to construct the anti-inflammatory metabolomic pattern of a heat-clearing herb, Scrophularia ningpoensis Hemsl. (S. ningpoensis). The MIMN molecular families characterized by cinnamic acid glycosides showed a higher bioactivity score compared with the other two major chemical classes (iridoid glycosides and iridoid-cinnamic acid glycosides). The Global Natural Product Social Molecular Networking (GNPS) and Reaxys database were used to assist in the putative annotation of eighteen metabolites from the bioactive and non-bioactive molecular families. The anti-inflammatory validation step was based on the detection of reactive oxygen species (ROS) generation by activated human neutrophils. All compounds from the bioactive MIMN molecular families dose-dependently inhibited the total ROS generation promoted by fMLF (IC50: 0.04-0.42 µM), while the compounds from non-bioactive MIMN clusters did not show any significant anti-inflammatory effect. The ROS-dependent anti-inflammatory activity of these cinnamic acid glycosides was attributed to their oxygen radical scavenging ability. The most abundant cinnamic acid glycoside, angoroside C (IC50: 0.34 µM) was suggested to be selected as a chemical marker for S. ningpoensis. In this study, the MIMN platform was applied to assist in the chemical marker selection of S. ningpoensis. The correct selection of markers will aid in the compilation and revision of herbal monographs and pharmacopeias resulting in the precise analysis and classification of medicinal plants on a scientific basis.

Sinulariaone A: a novel diterpenoid with a 13-membered carbocyclic skeleton from an octocoral Sinularia species.

Chemical composition screening of an octocoral identified as Sinularia species led to the isolation of a novel diterpenoid, sinulariaone A (1), featuring a 13-membered carbocyclic skeleton. The structure of 1 was established by spectroscopic elucidation, computed calculation, and X-ray diffraction analysis. Moreover, a single-crystal X-ray diffraction analysis of chlorofurancembranoid B (2), obtained in our previous study from the same octocoral species, was reported for the first time to demonstrate the absolute configuration. Diterpenoid 1 showed cytotoxicity towards human promyelocytic leukemia HL-60 cells, with an IC50 value of 38.01 µM.

Palbociclib blocks neutrophilic phosphatidylinositol 3-kinase activity to alleviate psoriasiform dermatitis.

BACKGROUND AND PURPOSE: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. EXPERIMENTAL APPROACH: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. KEY RESULTS: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation. CONCLUSIONS AND IMPLICATIONS: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.

Hinokitiol Inhibits the Viability of Oral Squamous Carcinoma Cells by Inducing Apoptosis and Autophagy.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is one of the deadliest cancers, with approximately ~500,000 new diagnosed cases and 145,000 deaths worldwide, per year. The incidence of new cases continues to increase in developing countries. This study aimed to investigate the effect of hinokitiol on cell viability in OSCC cells. MATERIALS AND METHODS: The anticancer effect and mechanism of action of hinokitiol in OSCC cells were analyzed by cell viability assays and cell cycle analysis using flow cytometry, while apoptosis and autophagy-related protein expression was measured using western blot. RESULTS: The results showed that hinokitiol concentration-dependently reduced the viability of SCC4 and SCC25 cells by downregulating the levels of cell-cycle mediators, such as cyclin B1, cyclin D1 and cyclin-dependent kinase-1 (CDK1). Furthermore, hinokitiol promoted apoptosis in SCC25 cells based on the presence of active cleaved caspase-3. Hinokitiol also induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and the expression of the sequestosome-1 (p62/SQSTM). CONCLUSION: Hinokitiol exhibits anti-proliferation activity and has pro-apoptotic effects on OSCC cell lines.

Carnosic acid inhibits reactive oxygen species-dependent neutrophil extracellular trap formation and ameliorates acute respiratory distress syndrome.

AIMS: Infiltration of activated neutrophils into the lungs is a hallmark of acute respiratory distress syndrome (ARDS). Neutrophilic inflammation, particularly neutrophil extracellular traps (NETs), is proposed as a useful target for treating ARDS. Carnosic acid (CA) is a food additive; however, its anti-neutrophilic activity in the treatment of ARDS has not been well established. The hypothesis of present study is to confirm that CA alleviates ARDS by suppressing neutrophilic inflammation and oxidative damage. MAIN METHODS: Generation of superoxide anions and reactive oxygen species (ROS), induction of elastase degranulation, and formation of NETs by human neutrophils were assayed using spectrophotometry, flow cytometry, and immunofluorescent microscopy. Immunoblotting was performed to determine the cellular mechanisms involved. Cell-free radical systems were used to test antioxidant activities. The therapeutic effect of CA was evaluated in a lipopolysaccharide (LPS)-induced ARDS mouse model. KEY FINDINGS: CA greatly reduced superoxide anion production, ROS production, elastase release, cluster of differentiation 11b expression, and cell adhesion in activated human neutrophils. Mechanistic studies have demonstrated that CA suppresses phosphorylation of extracellular regulated kinase and c-Jun N-terminal kinase in activated neutrophils. CA effectively scavenges reactive oxygen and nitrogen species, but not superoxide anions. This is consistent with the finding that CA is effective against ROS-dependent NET formation. CA treatment significantly improved pulmonary neutrophil infiltration, oxidative damage, NET formation, and alveolar damage in LPS-induced mice. SIGNIFICANCE: Our data suggested the potential application of CA for neutrophil-associated ARDS therapy.

Discovery of novel 5-methoxybenzothiophene hydrazides as metabolically stable Clk1 inhibitors with high potency and unprecedented Clk1 isoenzyme selectivity.

Clk1 kinase is a key modulator of the pre-mRNA alternative splicing machinery which has been proposed as a promising target for treatment of various tumour types, Duchenne's muscular dystrophy and viral infections such as HIV-1 and influenza. Most reported Clk1 inhibitors showed significant co-inhibition of Clk2 and Clk4 in particular, which limits their usefulness for deciphering the individual roles of the Clk1 isoform in physiology and disease. Herein, we present a new 5-methoxybenzothiophene scaffold, enabling for the first time selective inhibition of Clk1 even among the isoenzymes. The 3,5-difluorophenyl and 3,5-dichlorophenyl derivatives 26a and 27a (Clk1 IC50 = 1.4 and 1.7 nM, respectively) showed unprecedented selectivity factors of 15 and 8 over Clk4, and selectivity factors of 535 and 84 over Clk2. Furthermore, 26a and 27a exhibited good growth inhibitory activity in T24 cancer cells and long metabolic half-lives of almost 1 and 6.4 h, respectively. The overall favorable profile of our new Clk1 inhibitors suggests that they may be used in in vivo disease models or as probes to unravel the physiological or pathogenic roles of the Clk1 isoenzyme.

MS/MS Molecular Networking Unveils the Chemical Diversity of Biscembranoid Derivatives, Neutrophilic Inflammatory Mediators from the Cultured Soft Coral Sarcophyton trocheliophorum.

Biscembranoids are the distinctive tetraterpenoids owing a 14/6/14 membered tricyclic scaffold that have been mainly discovered in the soft corals, especially the genera Sarcophyton, Lobophytum and Sinularia. Recent findings have demonstrated the great anti-inflammatory potential of biscembranoid analogues in human neutrophils, motivating more chemical and biological explorations targeting these marine-derived natural products. In the current study, the chemical diversity of biscembranoids derived from the cultured-type Sarcophyton trocheliophorum von Marenzeller was illustrated through MS/MS molecular networking (MN) profiling approach. Based on the MN patterns, the prioritization of unknown biscembranoid derivatives was putatively analyzed. As a result, the biscembrane targeting isolation afforded two new metabolites, sarcotrochelides A (1) and B (2), along with six known analogues (3-8). Their structures and relative configurations were determined by spectroscopic methods. In vitro neutrophil inflammatory inhibition was further investigated for all isolates based on reduced superoxide anion (O2•-) generation detections. Compounds 5-8 showed significant dose-dependently inhibitory effects, suggesting the cruciality of 6,7-dihydrooxepin-2(5H)-one moiety and saturated γ-lactone ring in their reactive oxygen species (ROS)-dependent anti-inflammatory properties.

Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas.

Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway.

The serial changes of Neutrophile-Lymphocyte Ratio and correlation to weight loss after Laparoscopic Sleeve Gastrectomy.

Purpose: This study aims to identify the pre- and postoperative changes in the neutrophil-lymphocyte ratio (NLR) and its correlations to clinical characteristics in obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Method: Retrospectively, we included patients who has undergone LSG in our institution between January 2019 and April 2021. A total of 100 patients whose body mass index over 32.5 and received primary laparoscopic sleeve gastrectomy without infectious condition were included. Results: There was a significant decline in NLR (T0 vs. POM3 2.21 vs. 1.78, p = 0.005), neutrophil (T0 vs. POM3 5369 vs. 4050, p < 0.001) and lymphocyte count (T0 vs. POM3 2440: 2100, p < 0.001, respectively) at postoperative 3 months (POM3) compared to preoperative (T0) levels, but similar between POM3 and POM6. The declined counts (Neutrophile vs. Lymphocyte 1445.5/µl vs. 323.5/µl, p < 0.001) and percentage (Neutrophile vs. Lymphocyte 25.11% vs. 13.07%, p < 0.001) of neutrophile are higher than lymphocyte from T0 to POM3, but similar in POM3 and POM6. Preoperative NLR has a significant correlation with the preoperative body weight, preoperative insulin level, and excessive body weight loss (EBWL) at POM3. Preoperative NLR <2.36 had a sensitivity of 67.6% and a specificity of 62.5% in predicting successful weight loss (EBWL > 37.7%) at POM3 (AUC = 0.635, p = 0.032). Conclusion: There was a significant decline in NLR, neutrophil, and lymphocyte count from T0 to POM3, but similar between POM3 and POM6. The declined counts and percentage of neutrophile are higher than lymphocyte. Preoperative NLR shows the potential to be used as a prognostic biomarker for predicting successful weight loss at POM3 after LSG. Further studies could be designed to evaluate the value of prediction in successful outcome after LSG and figure out the relationship between the changes of neutrophil function and oncogenesis.

Lonicerae Japonicae Flos Attenuates Neutrophilic Inflammation by Inhibiting Oxidative Stress.

Lonicerae japonicae flos (LJ) is an Asian traditional herb that is used as a dietary supplement, tea, and beverage to clear heat and quench thirst. However, no studies investigated its effect on activated human neutrophils, which played a crucial role in the bad prognosis of coronavirus disease of 2019 (COVID-19) patients by aggravating lung inflammation and respiratory failure. Herein, we evaluated the anti-inflammatory effect of LJ ethanol extract (LJEE) on human neutrophils activated by N-formyl-methionyl-leucyl-phenylalanine (fMLF). Our experimental results indicated that LJEE suppressed fMLF-activated superoxide anion (O2•-) generation, the expression of CD11b, and cell adhesion and migration, as well as the formation of neutrophil extracellular traps in human neutrophils. Further in-depth mechanical investigation revealed that pretreatment with LJEE accelerated the Ca2+ clearance, but did not affect the phosphorylation of mitogen-activated protein kinases (MAPKs) and protein kinase B (Akt) in activated human neutrophils. In addition, LJEE displayed a dose-dependent reactive oxygen species (ROS) scavenger activity, which assisted its anti-inflammatory activity. From the bioassay-coupled chromatographic profile, chlorogenic acids were found to dominate the anti-inflammatory effects of LJEE. Moreover, LJ water extract (LJWE) demonstrated an interrupting effect on the severe acute respiratory syndrome coronavirus-2 spike protein (SARS-CoV-2-Spike)/angiotensin-converting enzyme 2 (ACE2) binding. In conclusion, the obtained results not only supported the traditional use of LJ for heat-clearance, but also suggested its potential application in daily health care during the COVID-19 pandemic.

5-Methoxytryptophan Sensitizing Head and Neck Squamous Carcinoma Cell to Cisplatitn Through Inhibiting Signal Transducer and Activator of Transcription 3 (STAT3).

Head and neck squamous cell carcinoma (HNSCC) is a common cancer of the oral cavity. Cisplatin (CDDP) is the ideal chemo-radiotherapy used for several tumor types, but resistance to the drug has become a major obstacle in treating patients with HNSCC. 5-methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of tryptophan metabolism, reduces inflammation-mediated proliferation and metastasis. This study aimed to assess the anti-oral cancer activity of 5-MTP when used alone or in combination with CDDP. Results showed that CDDP dose dependently reduced the growth of SSC25 cells but not 5-MTP. The combination of CDDP and 5-MTP exerted additional inhibitory effect on the growth of SSC25 cells by attenuating the phosphorylation of STAT3. In the 4-nitroquinoline-1-oxide-induced oral cancer mouse model, 5-MTP sensitized the reduction effect of CDDP on tumorigenesis, which restricted the tongue tissue in hyperkeratotic lesion rather than squamous cell carcinoma. The combination of CDDP and 5-MTP may be a potent therapeutic strategy for HNSCC patients with radiotherapy.

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors.

For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-κB in macrophage-like THP-1 cells while showing low general cytotoxicity. One of the best compounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 µM) and, less potently, of TNFα (IC50 = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC50s of 1.1 and 11.4 µM, respectively. Interestingly, 19 was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-κB activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP-1 cells, they might be particularly effective in various inflammatory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases.

From EGFR kinase inhibitors to anti-inflammatory drugs: Optimization and biological evaluation of (4-(phenylamino)quinazolinyl)-phenylthiourea derivatives as novel NF-κB inhibitors.

The transcription factor NF-κB is a pivotal mediator of chronic inflammatory and autoimmune diseases. Based on our previously published dual EGFR/NF-κB inhibitors, we designed and synthesized new thiourea quinazoline derivatives that retained only the NF-κB inhibitory activity. Several congeners displayed a strong suppression of NF-κB activity in a reporter gene assay, yet low cytotoxicity, and were further evaluated in differentiated macrophage-like THP-1 cells. The compounds exhibited a strong inhibition of IL-6 and, less potently, of TNFα release, which was accompanied by a selective induction of macrophage cell death. The mode of action was investigated with a selected inhibitor, 18, revealing that the translocation of p65/RelA to the nucleus but not its release from the IκB complex was inhibited. Eventually, 18 was identified as the first small molecule inhibitor affecting only the phosphorylation of p65-Ser468 but not of Ser536, which may be causally related to the retention of NF-κB in the cytoplasm. Altogether, our novel NF-κB inhibitors seem applicable for the suppression of cytokine release and the additional selective depletion of activated macrophages in various inflammatory diseases.

Development of novel conformationally restricted selective Clk1/4 inhibitors through creating an intramolecular hydrogen bond involving an imide linker.

As prime regulators of pre-mRNA alternative splicing, different Clk isoforms were found to be overexpressed in various tumour types and have received much attention recently as potential targets for cancer therapy. Several studies have reported potent small-molecule Clk1/4 inhibitors with promising cellular anti-cancer activities; however, their clinical use was generally hampered by their compromised selectivity against off-targets, mainly Clk2 and Dyrk1A. In this study, we present a novel series of N-aroylated 5-methoxybenzothiophene-2-carboxamides (imides) as potent and selective Clk1/4 inhibitors. Potency of this series was found to be mainly dependent on the presence of an intramolecular H-bond between an ortho-methoxy group and the imide NH, that stabilizes a nearly coplanar conformation of high affinity to the ATP binding pocket(s) of Clk1/4. The two most potent hits in this series, compounds 20 (4-fluoro-2-methoxy) and 31 (5-chloro-2-methoxy) had cell free Clk1 IC50s of 4 and 9.7 nM, respectively, besides an unprecedented selectivity over Clk2 with 62- and 50-times higher affinities towards Clk1, respectively. 20 and 31 also exhibited remarkable selectivity over most common off-targets including Dyrk1A. Moreover, compounds 26 (2-ethoxy) and 31 showed growth inhibitory activities in T24 cancer cells with GI50s of <0.1 and 1.1 µM, respectively.