Efficacy and Safety of Botulinum Toxin Type A in the Treatment of Trigeminal Neuralgia: An Update on Systematic Review With Meta-analyses.

OBJECTIVE: Pain management in patients with TN is challenging, as facial pain often does not respond well to conventional therapies. Botulinum toxin type A (BTX-A) has been suggested as a potential treatment option, but there is limited evidence regarding its long-term efficacy. This review aimed to analyze the current data for the use of in the treatment of trigeminal neuralgia (TN) and highlight the evidence for its efficacy and safety. METHODS: A comprehensive search was conducted in various databases (PubMed, Scopus, Embase, ClinicalTrials, and Cochrane Library) to identify clinical studies evaluating the use of BTX-A in TN until October 2023. Randomized controlled trials (RCTs), single-arm studies, and stratified studies were included in the analysis. The mean difference (MD), effect size (ES), and 95% confidence interval (CI) were estimated for visual analogue scale (VAS) scores, pain episode frequency, and the proportion of responders. RESULTS: The analysis included 23 studies, including 4 RCTs, 14 single-arm studies, and 5 stratified studies. In the RCTs, BTX-A was found to significantly reduce mean VAS scores compared with baseline (ES: -4.05; 95% CI: -6.13, -1.97; P =0.002). In 19 non-RCTs, the pooled single-arm analysis revealed that BTX-A decreased VAS scores (ES: -5.19, 95% CI: -6.05, -4.33, P <0.001) and pain attack frequency (ES: -17.85, 95% CI: -23.36, -12.34, P <0.001) from baseline to the end of follow-up. The overall proportion of responders to BTX-A treatment was also significant (95% CI: 0.653, 0.761, P =0.003). DISCUSSION: Current evidence indicates that BTX-A injection is an effective and safe option for patients with refractory TN or not responding to medical or surgical management. However, more high-quality studies are needed to further confirm its efficacy.

LncRNA SNHG14 Served as a Biomarker of Depression Disorder Patients and Regulated Depression-Like Behaviors via MiR-200a-3p.

Depression disorder has become a major mental disease and has attracted special attention globally. Identifying specific biomarkers for the diagnosis and severity of depression disorder would benefit its clinical management. This study focused on the significance of lncRNA SNHG14 in depression disorder and investigated its effect on depression-like behaviors, aiming to explore a potential biomarker for depression disorder occurrence and development. This study included 147 patients with depression disorder and 98 healthy individuals. The serum SNHG14 in all participants was analyzed by PCR, and its diagnostic value was evaluated by receiver operatorating characteristic curve (ROC) analysis. The depression-like behaviors were induced via chronic social defeat stress (CSDS) and evaluated by sucrose preference, forced swimming, and open field tests. SNHG14 was significantly upregulated in depression disorder patients relative to healthy individuals, which discriminated depression disorder patients with a relatively high efficiency. Depression disorder patients with severe conditions showed higher serum SNHG14 levels, and a significantly positive correlation of SNHG14 with PHQ9 score was demonstrated. In CSDS mice, increasing SNHG14 and decreasing miR-200a-3p were observed. Silencing SNHG14 and overexpressing miR-200a-3p could alleviate reduced sucrose preference, increased swimming immobility time, decreased standing times, and decreased traveling distance induced by CSDS. The knockdown of SNHG14 promoted the expression of miR-200a-3p, and silencing miR-200a-3p could reverse the protective effect of SNHG14 silencing on depression-like behaviors. SNHG14 served as a biomarker for the occurrence and severity of depression disorder. Silencing SNHG14could alleviate depression-like behaviors via modulating miR-200a-3p.

A degradation feature extraction technique based on static divided symbol sequence entropy.

Due to the doping of considerable noise and impact components in vibration signals of quay crane gearboxes, some traditional methods have difficulty uncovering degradation patterns. To accurately extract degradation features from vibration monitoring signals, a degradation feature extraction technique based on static divided symbol sequence entropy is proposed. Based on the basic scale entropy technique, considering the uniformity of the symbolization standard, the technique takes the root mean square of the health condition signal as the basis and incorporates the scale coefficient to establish a uniform basic scale. Simultaneously, the symbol set is expanded to enhance the information content and the ability of the approach to characterize the complexity levels of signals in large-value regions. Therefore, the proposed static divided symbol sequence entropy technique can accurately and flexibly characterize performance degradations. The logistic chaotic sequence and the lifetime signal of hoisting mechanism gearbox are separately used for analysis. It shows that the proposed technique can characterize the complexity of the nonlinear time series and sensitively describe the performance degradation exhibited by hoisting mechanism gearbox. This technique is computationally fast, and it can be implemented as a foundation for developing new methods for evaluating the health conditions of quay crane gearboxes.

Anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: To identify anatomic prognostic factors and their potential roles in refining M1 classification for de novo metastatic nasopharyngeal carcinoma (M1-NPC). MATERIALS AND METHODS: All M1-NPC treated with chemotherapy and/or radiotherapy between 2010 and 2019 from two centers (training and validation cohort) were included. The prognostic value of metastatic disease extent and involved organs for overall survival (OS) were assessed by several multivariable analyses (MVA) models. A new M1 classification was proposed and validated in a separate cohort who received immuno-chemotherapy. RESULTS: A total of 197 M1-NPC in the training and 307 in the validation cohorts were included for M1 subdivision study with median follow-up of 46 and 57 months. MVA model with "≤2 organs/≤5 lesions" as the definition of oligometastasis had the highest C-index (0.623) versus others (0.606-0.621). Patients with oligometastasis had better OS versus polymetastasis (hazard ratio [HR] 0.47/0.63) while liver metastases carried worse OS (HR 1.57/1.45) in MVA in the training/validation cohorts, respectively. We proposed to divide M1-NPC into M1a (oligometastasis without liver metastases) and M1b (liver metastases or polymetastasis) with 3-year OS of 66.5%/31.7% and 64.9%/35.0% in the training/validation cohorts, respectively. M1a subset had a better median progress-free survival (not reach vs. 17 months, p < 0.001) in the immuno-chemotherapy cohort (n = 163). CONCLUSION: Oligometastasis (≤2 organs/≤5 lesions) and liver metastasis are prognostic for M1-NPC. Subdivision of M1-NPC into M1a (oligometastasis without liver metastasis) and M1b (liver metastasis or polymetastasis) depicts the prognosis well in M1-NPC patients who received immuno-chemotherapy.

Artesunate, as an Hsp90 inhibitor, inhibits the proliferation of Burkitt's lymphoma cells by inhibiting AKT and ERK.

Introduction: Artesunate, a derivative of artemisinin, has anti-malarial effects, and in recent years has also been reported to have anti-tumor activity. However, its anti-tumor mechanisms are not well understood. Methods: In this study, we focused on the targeting of Hsp90 by artesunate to inhibit tumor cell proliferation, which we examined using immunoprecipitation, a proliferation assay, flow cytometry, western blotting, a tumor xenograft animal model, and immunohistochemistry. Furthermore, to examine the tumor-suppressive effects of artesunatein nude mice, we used artesunate-loaded PLGA-PEG nanoparticles. Results: The binding of artesunate to Hsp90 was found to reduce the expression of its client proteins AKT, ERK, p-AKT, p-ERK, and EGFR, thereby blocking the cell cycle at the G0/G1 → S stage in lymphoma cells and inducing apoptosis. In addition, the results of tumor xenograft experiments revealed that artesunate reduced the expression of AKT and ERK proteins in tumor tissues, inhibited tumor proliferation, and reduced tumor size and weight. Furthermore, nanoparticle encapsulation was demonstrated to enhance the anti-cancer activity of artesunate. Discussion: We thus established that artesunate inhibits the proliferation of lymphoma cells by targeting the Hsp90 protein, and we accordingly believe that this compound has potential for development as a novelanti-tumor drug.

Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells.

BACKGROUND: Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa. PURPOSE: We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells. METHODS: Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling. RESULTS: CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts. CONCLUSIONS: Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.

Gastric Mucosa Pathology in Rats with Precancerous Lesions of Gastric Cancer with Spleen Deficiency and Blood Stasis.

Objective: This research aimed at better understanding the histopathological development of precancerous lesions of gastric cancer (PLGC) and organelle ultrastructure changes. Methods: Sprague-Dawley rats were randomly assigned to the model and control groups. Model rats drank N-methyl-N'-nitro-N-nitrosoguanidine solution, while control rats drank pure water ad libitum. At 1, 3, 5, 6, and 8 months after the start of feeding, eight rats were randomly chosen from each group, and gastric mucosa tissues were removed for histopathological analysis. H&E staining was applied to analyze the pathological histological structure of the rat gastric mucosa via a light microscope, and the ultrastructural changes were observed via a transmission electron microscope. Results: Gastric mucosal pathologies of model rats such as mucosal atrophy, intestinal metaplasia, inflammatory lesions, and even intraepithelial neoplasia deteriorated over time. The endoplasmic reticulum gap widened, the mitochondrial endothelial cristae were disrupted, the nuclear membrane thickened, and chromatin condensed with heterotypic alterations in the main and parietal cells. Additionally, endothelial cell enlargement and thickening of the microvascular intima were seen. Conclusion: Our research showed that the PLGC progression of rats is correlated with the pathological alteration axis of "normal gastric mucosa-gastric mucosa inflammatory changes-intestinal metaplasia with mild dysplasia-moderate to severe dysplasia." Ultrastructure analysis of model rats is compatible with the structural changes in the gastric mucosa with spleen deficiency and blood stasis. The pathological evolutionary axis and ultrastructural analysis are helpful for evaluating potential novel herbal therapies for PLGC.

Thymol Disrupts Cell Homeostasis and Inhibits the Growth of Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is a typical kind of symbiotic bacteria, which can cause human pneumonia, food poisoning, and other health problems. Nowadays, the corresponding prevention and treatment have been a hot issue of general concern in related research areas. However, the mechanism of action against S. aureus is not well understood. In order to tackle such problem, we used broth microdilution to discuss the antibacterial effect of 5-methyl-2-isopropylphenol and determine inhibitory concentration. In addition, membrane potential and lipid peroxidation levels were also measured under experimental conditions. The experimental results suggested that 300 µg/mL thymol might cause cell membrane damage and decrease of NADPH concentration and increase of NADP+ and lipid peroxidation level. In such condition, thymol has the potential to result in membrane rupture and disruption of cellular homeostasis. Furthermore, we also found that NOX2 is involved in maintaining the balance of NADPH/NADP+ in cells. Finally, our work confirms that NOX2 is a potential downstream target for thymol in the cell. Such target can provide specific guidance and recommendations for its application in antifungal activity. Meanwhile, our study also provides a new inspiration for the molecular mechanism of thymol's bacteriostatic action.

Aspalathus linearis suppresses cell survival and proliferation of enzalutamide-resistant prostate cancer cells via inhibition of c-Myc and stability of androgen receptor.

Enzalutamide, a nonsteroidal antiandrogen, significantly prolonged the survival of patients with metastatic castration-resistant prostate cancer (CRPC). However, patients receiving enzalutamide frequently develop drug resistance. Rooibos (Aspalathus linearis) is a shrub-like leguminous fynbos plant endemic to the Cedarberg Mountains area in South Africa. We evaluated the possibility of using a pharmaceutical-grade green rooibos extract (GRT, containing 12.78% aspalathin) to suppress the proliferation and survival of enzalutamide-resistant prostate cancer (PCa) cells. Treatment with GRT dose-dependently suppressed the proliferation, survival, and colony formation of enzalutamide-resistant C4-2 MDV3100r cells and PC-3 cells. Non-cancerous human cells were more resistant to GRT treatment. GRT suppressed the expression of proteins involved in phosphoinositide 3-kinase (PI3K)-Akt signaling, androgen receptor (AR), phospho-AR (Ser81), cyclin-dependent kinase 1 (Cdk1), c-Myc and Bcl-2 but increased the expression of apoptotic proteins. Overexpression of c-Myc antagonized the suppressive effects of GRT, while knockdown of c-Myc increased the sensitivity of PCa cells to GRT treatment. Expression level of c-Myc correlated to resistance of PCa cells to GRT treatment. Additionally, immunofluorescence microscopy demonstrated that GRT reduced the abundance of AR proteins both in nucleus and cytoplasm. Treatment with cycloheximide revealed that GRT reduced the stability of AR. GRT suppressed protein expression of AR and AR's downstream target prostate specific antigen (PSA) in C4-2 MDV3100r cells. Interestingly, we observed that AR proteins accumulate in nucleus and PSA expression is activated in the AR-positive enzalutamide-resistant PCa cells even in the absence of androgen. Our results suggested that GRT treatment suppressed the cell proliferation and survival of enzalutamide-resistant PCa cells via inhibition of c-Myc, induction of apoptosis, as well as the suppression of expression, signaling and stability of AR. GRT is a potential adjuvant therapeutic agent for enzalutamide-resistant PCa.

Differential Gene Analysis of Trastuzumab in Breast Cancer Based on Network Pharmacology and Medical Images.

The purpose of this study was to use network pharmacology, biomedical images and molecular docking technology in the treatment of breast cancer to investigate the feasible therapeutic targets and mechanisms of trastuzumab. In the first place, we applied pubchem swisstarget (http://www.swisstargetprediction.ch/), (https://pubchem.ncbi.nlm.nih.gov/) pharmmapper (http://lilab-ecust.cn/pharmmapper/), and the batman-tcm (http://bionet.ncpsb.org.cn/batman-tcm/) database to collect the trastuzumab targets. Then, in NCBI-GEO, breast cancer target genes were chosen (https://www.ncbi.nlm.nih.gov/geo/). The intersection regions of drug and disease target genes were used to draw a Venn diagram. Through Cytoscape 3.7.2 software, and the STRING database, we then formed a protein-protein interaction (PPI) network. Besides, we concluded KEGG pathway analysis and Geen Ontology analysis by using ClueGO in Cytospace. Finally, the top 5 target proteins in the PPI network to dock with trastuzumab were selected. After screening trastuzumab and breast cancer in databases separately, we got 521 target genes of the drug and 1,464 target genes of breast cancer. The number of overlapping genes was 54. PPI network core genes include GAPDH, MMP9, CCNA2, RRM2, CHEK1, etc. GO analysis indicated that trastuzumab treats breast cancer through abundant biological processes, especially positive regulation of phospholipase activity, linoleic acid metabolic process, and negative regulation of endothelial cell proliferation. The molecular function is NADP binding and the cellular component is tertiary granule lumen. The results of KEGG enrichment analysis exhibited four pathways related to the formation and cure of breast cancer, containing Drug metabolism, Glutathione metabolism, Pyrimidine metabolism and PPAR signaling pathway. Molecular docking showed that trastuzumab has good binding abilities with five core target proteins (GAPDH, MMP9, CCNA2, RRM2, CHEK1). This study, through network pharmacology and molecular docking, provides new pieces of evidence and ideas to understand how trastuzumab treats breast cancer at the gene level.

Relationship between Prognosis, Immune Infiltration Level, and Differential Expression of PARVG Gene in Uterine Corpus Endometrial Carcinoma.

Endometrial cancer (UCEC) is very common in gynecological diseases and ranks second in the death cause of gynecological cancer in developed countries. The connection between the overall survival of UCEC patients and immune invasion of the tumor microenvironment is positive. The PARVG gene has not been given notice in cancer, and its mechanism is unknown. The research utilized TCGA data to test the function of PARVG in UCEC. The manifestation of PARVG in UCEC was studied by GEPIA. By assessing the survival module, the authors learned the impact of PARVG on the survival of people with UCEC and then obtained UCEC information from TCGA. This study uses logistic regression to prove the possible relationship between PARVG expression and clinical information. From the research of Cox regression, clinicopathological characteristics of people with TCGA were connected with overall survival. Furthermore, the "correlation" module of GEPIA and CIBERSORT was used to study the association between cancer immune invasion and PARVG. Using univariate logistic regression analysis with PARVG expression as a categorical variable (median expression value of 2.5), the result suggested that raised PARVG expression was considerably connected with tumor status, pathological stage, and lymph nodes. Multiple factor studies have shown that upregulation of PARVG, distant metastasis, and negative pathological stage are absolute elements of excellent prognosis. In addition, CIBERSORT analysis was utilized to determine that raised PARVG expression has a positive connection with immune infiltration by T cells, mast cells, neutrophils, and B cells. This is recognized in GEPIA's "correlation" module. The above outcomes show us that the raised expression of PARVG is associated with a good prognosis and it raises the proportion of immune cells (such as T cells, mast cells, neutrophils, and B cells) in UCEC. These outcomes tell us that PARVG can be utilized as a possible biomarker to evaluate UCEC's immune infiltration levels and prognosis.

Efficacy of Whole-Blood Exchange Transfusion in Refractory Severe Autoimmune Haemolytic Anaemia Secondary to Systemic Lupus Erythematosus: A Real-World Observational Retrospective Study.

Background: Severe autoimmune haemolytic anaemia (AIHA) in systemic lupus erythematosus (SLE) patients could be life-threatening and formidable, especially in those nonresponsive to glucocorticoids (GCs) and immunosuppressants (ISAs). Whole-blood exchange transfusion (WBE), with plasma exchange and pathogenic cell removal as well as healthy red blood cell transfusion, could be beneficial. The objective of this study was to investigate the efficacy and safety of WBE in combination with GCs/ISAs. Methods: In this retrospective study, the clinical data of 22 refractory severe SLE-AIHA inpatients between February 2016 and February 2021 were collected and analysed, among whom 14 patients had received WBE and were compared with those treated with typical second-line therapy of intravenous immunoglobulin and/or rituximab (IVIG/RTX). Results: Among the 22 severe refractory SLE-AIHA patients, eight patients received IVIG and/or RTX without WBE (group 1, IVIG/RTX, n = 8), seven patients were given WBE without IVIG/RTX (group 2, WBE alone, n = 7), and seven patients who failed initial IVIG/RTX therapy were given sequential WBE therapy (group 3 IVIG/RTX→WBE, n = 7). Fourteen patients had accepted WBE treatment regardless of prior IVIG/RTX usage (group 2 + 3, WBE ± IVIG/RTX, n = 14). On days 1, 3, 5, and 7 after corresponding therapies, patients of groups 2, 3, and 2 + 3 showed significantly higher levels of haemoglobin (Hb) than patients of group 1. Compared with patients of group 1, patients of groups 2, 3, and 2 + 3 took less time to reach and maintain Hb ≥60 g/L from baseline. Groups 2 and 2 + 3 consumed a lower dose of GCs than group 1 to reach and maintain Hb ≥60 g/L from baseline. Group 1 experienced longer hospital stays than group 2, and group 3's cost of hospitalisation is more than groups 1 and 2. Hbmin <40 g/L may be a key indicative factor for initiating WBE remedy therapy as IVIG/RTX may not be effective enough in 48-72 h in those patients with refractory severe SLE-AIHA. No severe adverse effects were observed in the WBE group. Conclusions: WBE could be a safe and beneficial alternative therapy for refractory severe SLE-AIHA.

Combination treatment of docetaxel with caffeic acid phenethyl ester suppresses the survival and the proliferation of docetaxel-resistant prostate cancer cells via induction of apoptosis and metabolism interference.

BACKGROUND: Docetaxel has been approved by USFDA as a first-line treatment for castration-resistant prostate cancer (CRPC) patients. Patients receiving androgen deprivation therapy along with docetaxel result in superior survival, lower serum prostate specific antigen (PSA) level, and better quality of life. However, a significant proportion of these patients ultimately develop resistance to docetaxel within months. Caffeic acid phenethyl ester (CAPE), one of the main bioactive components extracted from the propolis, has been reported to be effective for repressing the tumor growth, the migration and invasion of prostate cancer (PCa) cells, as well as the downstream signaling and stability of androgen receptor (AR). We hence determined if combination treatment of docetaxel with CAPE can suppress the proliferation and the survival of docetaxel-resistant PCa cells. METHODS: We established docetaxel-resistant PC/DX25 and DU/DX50 CRPC cell lines from PC-3 and DU-145 human PCa cells, respectively. Proliferation assay, MTT assay, flow cytometry with Annexin V staining, Comet Assay, and nude mice xenograft model were applied to determine the effects of combination treatment on cell proliferation and survival of the docetaxel-resistant PCa cells. Micro-Western Array (MWA) and qRT-PCR were used to investigate the molecular mechanism lying underneath. RESULTS: Combination treatment effectively suppressed the proliferation, survival and tumor growth of docetaxel-resistant PCa cells both in vitro and in nude mice. Comet assay and flow cytometry indicated that combination treatment induced apoptosis in docetaxel-resistant PCa cells. MWA and Western blotting assay revealed that combination treatment suppressed protein expression of Bcl-2, AKT2, c-Myc, apoptosis and caspase activation inhibitor (AVEN), pyruvate kinase M2 (PKM2) but increased protein expression of Bax, caspase 3, cytochrome c, glucose-6-phosphate dehydrogenase (G6PD) and acylglycerol kinase (AGK). Overexpression of Bcl-2 in the docetaxel-resistant PCa cells enhanced cell proliferation of docetaxel-resistant PCa cells under combination treatment. Analysis with qRT-PCR suggested that combination treatment decreased cholesterol biosynthesis genes DHCR24 (24-dehydrocholesterol reductase) and LSS (lanosterol synthase) but increased genes involved in glycolysis and TCA cycle. CONCLUSIONS: Combination treatment of docetaxel with CAPE effectively suppressed the proliferation and survival of docetaxel-resistant PCa cells via inhibition of Bcl-2 and c-Myc as well as induction of metabolism interference. Combination treatment can be beneficial for patients with docetaxel-resistant PCa.

Study on the Mechanism of Fentanyl in Pain Treatment Based on Network Pharmacology.

This is a study that is based on network pharmacology, focusing on the pharmacological mechanism of fentanyl in easing pain. Through PPI, GO, and KEGG network pharmacology, the potential pharmacological mechanism of fentanyl was studied. This study compared and analyzed the overlap between the target genes of the active ingredient of fentanyl and the pain treatment target genes. After constructing PPI based on fentanyl, the GO and KEDD pathways were analyzed for enrichment. On the basis of overlapping genes, we constructed the PPI, GO, and KEGG, and analysis showed that the mechanism was likely to be related to some biological process. This study preliminarily identified the important proteins and metabolic pathways related to fentanyl in pain treatment and expected to provide new evidence and research ideas for the use of fentanyl, enhancing effects and alleviating adverse drug reactions.

Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new anti-vitiligo compounds.

Humans have been suffering from vitiligo for a long time. Target vitiligo drugs have yet been approved. Activation of Wnt/ß-catenin signalling has potential in the therapeutic use of vitiligo, so exploring new drugs that specifically directly activate Wnt is worthwhile to obtain new anti-vitiligo agents. In this work, two portions design and synthesis were put into effect. firstly, 17 phenanthridine derivatives with C-4 substitutes were designed and synthesized, which compounds 4, 6, 12, 13 served as H-acceptor with protein showed enhance melanogenesis activity; Secondly, 7 hybrid new scaffolds of compounds were designed and synthesized, scaffold hopping compound 36 that aromatic benzene was replaced pyrazole on ring C showed enhance melanogenesis and tyrosinase activity; The last and most important, a comprehensive optimization and SARs of compound 36 were carried out, compounds 41 and 43 shared phenolic hydroxyl or 3-methyl-pyridine substitutes at C-7 position remarkably improved the capacity of melanogenesis and tyrosinase activity. Compound 43 were identified as new anti-vitiligo agents that specifically activate the Wnt/ß-catenin signalling pathway by targeting Axin. Structure-activity relationship analysis implied that H-acceptor substitutions at the C-4 position and phenolic hydroxyl or pyridine substitutions at the C-7 position would improve the activities of the compounds. These findings reveal a new therapeutic strategy for vitiligo, and compounds 41 and 43 may represent potential compounds for vitiligo treatment.

Two new cytotoxic cycloartane triterpenoids from Aphanamixis polystachya (Wall.) R. N. Parker.

Two new cycloartane triterpenoids, (24 R)-cycloartane-3ß,24,25,30-tetrol (1) and (24 R)-24,25,30-trihydroxy-9,19-cycloartane-3-one (2), along with three known compounds (3-5) were isolated from leaves and twigs of Aphanamixis polystachya. The new compounds were elucidated based on comprehensive spectroscopic analysis, including 1 D, 2 D NMR and HREIMS. The in vitro cytotoxic activities evaluation of five human cancer cell lines revealed that compound 1 exhibited cytotoxic activity on all of tested human cancer cell lines, while compound 2 only had specific activity on SMMC-7721 cell line.

Novel nucleocapsid protein-targeting phenanthridine inhibitors of SARS-CoV-2.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unprecedented in human history. As a major structural protein, nucleocapsid protein (NPro) is critical to the replication of SARS-CoV-2. In this work, 17 NPro-targeting phenanthridine derivatives were rationally designed and synthesized, based on the crystal structure of NPro. Most of these compounds can interact with SARS-CoV-2 NPro tightly and inhibit the replication of SARS-CoV-2 in vitro. Compounds 12 and 16 exhibited the most potent anti-viral activities with 50% effective concentration values of 3.69 and 2.18 µM, respectively. Furthermore, site-directed mutagenesis of NPro and Surface Plasmon Resonance (SPR) assays revealed that 12 and 16 target N-terminal domain (NTD) of NPro by binding to Tyr109. This work found two potent anti-SARS-CoV-2 bioactive compounds and also indicated that SARS-CoV-2 NPro-NTD can be a target for new anti-virus agents.

Combined diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 1 diabetes mellitus induced by immune checkpoint inhibitors: Underrecognized and underreported emergency in ICIs-DM.

Background: Combined diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) secondary to immune checkpoint inhibitors (ICIs) is extremely rarely reported among ICIs- diabetes mellitus (DM) cases and is always ignored by physicians. This study aimed to conduct a systematic review to recognize better the rare adverse event of combined DKA-HHS associated with immune checkpoints. Methods: A electronic search in Pubmed/Cochrane/Web of Science, complemented by manual searches in article references, was conducted to identify clinical features of ICIs-combined DKA-HHS. Results: we identified 106 patients with ICIs- type 1 diabetes mellitus (T1DM) from 82 publications: 9 patients presented a coexistence of metabolic acidosis, severe hyperglycemia, and/or DKA; All patients were not diagnosed as combined DKA-HHS. Compared with ICIs-DKA patients, combined DKA-HHS cases were prone to higher hyperglycemia (1020 ± 102.5 vs 686.7 ± 252.6mg/dL). Moreover, acute kidney injury (87.5% vs 28.6%) and prior chemotherapy (66.7% vs 31.6%) showed higher occurrences with the onset of ICIs-HHS or combined DKA-HHS.B. Conclusions: Combined DKA-HHS portends a poor diagnosis in patients with coexistence features of DKA and HHS, which healthcare professionals and patients should be aware of due to differences in treatment. Our observational retrospective case series shows that patients with more risk factors were more likely to develop combined DKA-HHS. We are the first to report this group of patients' clinical characteristics and outcomes.

Comparison of radiotherapy combined with nimotuzumab vs. chemoradiotherapy for locally recurrent nasopharyngeal carcinoma.

BACKGROUND: The present study compared the effectiveness and toxicity of two treatment modalities, namely radiotherapy combined with nimotuzumab (N) and chemoradiotherapy (CRT) in patients with locally recurrent nasopharyngeal carcinoma (LR-NPC). METHODS: Patients with LR-NPC who were treated with radiotherapy were retrospectively enrolled from January 2015 to December 2018. The treatment included radiotherapy combined with N or platinum-based induction chemotherapy and/or concurrent chemotherapy. The comparison of survival and toxicity between the two treatment modalities was evaluated using the log-rank and chi-squared tests. Overall survival (OS) was the primary endpoint. RESULTS: A total of 87 patients were included, of whom 32 and 55 were divided into the N group and the CRT group, respectively. No significant differences were noted in the survival rate between the N and the CRT groups (4-year OS rates, 37.1% vs. 40.7%, respectively; P = 0.735). Mild to moderate acute complications were common during the radiation period and mainly included mucositis and xerostomia. The majority of the acute toxic reactions were tolerated well. A total of 48 patients (55.2%) demonstrated late radiation injuries of grade ≥ 3, including 12 patients (37.5%) in the N group and 36 patients (66.5%) in the CRT group. The CRT group exhibited significantly higher incidence of severe late radiation injuries compared with that of the N group (P = 0.011). CONCLUSION: Radiotherapy combined with N did not appear to enhance treatment efficacy compared with CRT in patients with LR-NPC. However, radiotherapy combined with N may be superior to CRT due to its lower incidence of acute and late toxicities. Further studies are required to confirm the current findings.