Protective effects of Jing-Si-herbal-tea in inflammatory cytokines-induced cell injury on normal human lung fibroblast via multiomic platform analysis.

Objectives: The protective effects and related mechanisms of Jing-Si herbal tea (JSHT) were investigated in cellular damage mediated by pro-inflammatory cytokines, including interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α, on normal human lung fibroblast by multiomic platform analysis. Materials and Methods: The in silico high-throughput target was analyzed using pharmacophore models by BIOVIA Discovery Studio 2022 with ingenuity pathway analysis software. To assess cell viability, the study utilized the MTT assay technique. In addition, the IncuCyte S3 ZOOM System was implemented for the continuous monitoring of cell confluence of JSHT-treated cytokine-injured HEL 299 cells. Cytokine concentrations were determined using a Quantibody Human Inflammation Array. Gene expression and signaling pathways were determined using next-generation sequencing. Results: In silico high-throughput target analysis of JSHT revealed ingenuity in canonical pathways and their networks. Glucocorticoid receptor signaling is a potential signaling of JSHT. The results revealed protective effects against the inflammatory cytokines on JSHT-treated HEL 299 cells. Transcriptome and network analyses revealed that induction of helper T lymphocytes, TNFSF12, NFKB1-mediated relaxin signaling, and G-protein coupled receptor signaling play important roles in immune regulatory on JSHT-treated cytokine-injured HEL 299 cells. Conclusion: The findings from our research indicate that JSHT holds promise as a therapeutic agent, potentially offering advantageous outcomes in treating virus infections through various mechanisms. Furthermore, the primary bioactive components in JSHT justify extended research in antiviral drug development, especially in the context of addressing coronavirus.

The diameter of cutaneous melanoma serves as a prognostic indicator for survival among acral-melanoma predominant East Asian patients.

BACKGROUND: Tumor staging plays a pivotal role in melanoma management, where the depth of tumor invasion has been traditionally used as the cornerstone of staging. Paradoxically, the tumor diameter has not been integrated into the staging system. The aim of this study is to elucidate the clinical implications and prognostic value of tumor diameter in cutaneous melanoma, with a particular emphasis on the acral-melanoma predominant East Asian population, thus potentially enriching the clinical evaluation and treatment strategies for cutaneous melanoma. METHODS: From January 1st, 2006 to December 31st, 2022, a total of 352 patients were diagnosed with melanoma in our center. Among them, there were 135 patients diagnosed as cutaneous melanoma who received complete surgical wide excision and regional lymph nodes assessment. The diameter of the tumor, the depth of tumor invasion, lymph node status and patient survival were all collected and analyzed. RESULTS: The diameter of cutaneous melanoma had a weak positive correlation with tumor thickness (r = 0.26), however, it still had a significant predictive value for patients' overall survival (p = 0.005) and disease free survival (p = 0.023). As for lymph node metastasis prediction, the Breslow thickness had a better predictive value than tumor diameter (p = 0.002 vs. p = 0.565). CONCLUSIONS: In this study, though with only weak positive correlation to tumor thickness, the tumor diameter of melanoma showed a statistically significant correlation with the patients' overall survival and disease free survival. However, the larger tumor diameter cannot be used as an indicator of high risk of lymph node metastasis.

Comparative transcriptomic analysis reveals differences in gene expression and regulatory pathways between nonacral and acral melanoma in Asian individuals.

Melanoma predominantly occurs in White individuals, which is associated with factors such as exposure to UV radiation and skin pigmentation. Despite its low incidence, melanoma is the primary cause of skin cancer-related death in Asia, typically in areas with low sun exposure. In our previous whole-exome sequencing study, we identified mutational signature 12 as the most prevalent variant in Asian patients, differing from the common UV-associated mutational signature 7 observed in White individuals. We also observed major differences between acral melanoma (AM) and nonacral melanoma (NAM) in terms of signatures 7, 21, and 22. Notably, few studies have investigated the genomic differences between AM and NAM in Asian individuals. Therefore, in this study, we conducted transcriptomic sequencing to examine the disparities in RNA expression between AM and NAM. Ribosomal RNA depletion was performed to enhance the detection of functionally relevant coding and noncoding transcripts. Ingenuity pathway analysis revealed significant differences in gene expression and regulatory pathways between AM and NAM. The results also indicate that the genes involved in cell cycle signaling or immune modulation and programmed cell death protein 1/programmed cell death 1 ligand 1 signaling were differentially expressed in NAM and AM. In addition, high CDK4 expression and cell cycle variability were observed in AM, with high immunogenicity in NAM. Overall, these findings provide further insights into the pathogenesis of melanoma and serve as a reference for future research on this major malignant disease.

Genome-Wide Association Study of Alopecia Areata in Taiwan: The Conflict Between Individuals and Hair Follicles.

Purpose: Alopecia areata (AA) is one of the most prevalent autoimmune diseases affecting humans. Given that hair follicles are immune-privileged, autoimmunity can result in disfiguring hair loss. However, the genetic basis for AA in the Taiwanese population remains unknown. Materials and Methods: A genome-wide association study was conducted using a cohort of 408 AA cases and 8167 controls. To link variants to gene relationships, we used 882 SNPs (P<1E-05) within 74 genes that were associated with AA group to build the biological networks by IPA software. HLA diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)-R package and chi-square analysis. Results: Seven single nucleotide polymorphisms (SNPs) including LINC02006 (rs531166736, rs187306735), APC (rs112800832_C_CAT), SRP19 (rs139948960, rs144784670), EGFLAM (rs16903975) and LDLRAD3 (rs79874564) were closely associated with the AA phenotype (P<5E-08). Examination of biological networks revealed that these genomic areas are associated with antigen presentation signaling, B cell and T cell development, Th1 and Th2 activation pathways, Notch signaling, crosstalk signaling between dendritic cells and natural killer cells, and phagosome maturation. Based on human leukocyte antigen (HLA) genotype analysis, four HLA genotypes (HLA-B*15:01-*40:01, HLA-DQA1*01:02-*03:03, HLA-DQA1*01:02, and HLA-DQB1*02:01) were found to be associated with AA (adjusted p-value<0.05). HLA-DQA1*01:02 is the most significantly related gene in the Taiwanese population (adjusted p-value = 2.09E-05). Conclusion: This study successfully identified susceptibility loci associated with AA in the Taiwanese population. These findings not only shed light on the origins of AA within the Taiwanese context but also contribute to a comprehensive understanding of the genetic factors influencing AA susceptibility.

Diagnostic value of 18 F-fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in acral melanoma-predominant Asian patients.

BACKGROUND: Tumor staging is crucial for melanoma, of which acral melanoma is the predominant subtype in Asians. 18 F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) and 18 F-FDG-PET/computed tomography ( 18 F-FDG-PET/CT) serve as noninvasive imaging tools for tumor staging. However, the literature is scarce on the diagnostic value of PET for acral melanoma. METHODS: From January 1, 2006 to November 30, 2022, a total of 352 patients were diagnosed with melanoma at our hospital. Of them, 90 were diagnosed with cutaneous melanoma and underwent preoperative PET/CT for staging and sentinel lymph node biopsy or complete lymph node dissection. Staging of PET/CT was confirmed by histopathology or following imaging. The lymph node biopsy, distant metastasis status, and PET/CT imaging results were analyzed. RESULTS: Of all the 90 patients with cutaneous melanoma, 72 of them were diagnosed as acral melanoma (80.0%). Compared with the histopathologic results, the lymph nodes were true-positive, true-negative, false-positive, and false-negative in 12, 54, 7, and 17 cases, respectively. The sensitivity of PET/CT for local lymph nodes was 41.4% (95% CI, 23.5%-61.1%), whereas its specificity was 88.5% (95% CI, 77.8%-95.3%). As for the detection of distal metastasis, the PET results were true-positive, true-negative, false-positive, and false-negative in 6, 65, 15, and 4 cases, respectively. The sensitivity of PET for distal metastasis detection was 60.0% (95% CI, 26.2%-87.8%), whereas its specificity was 81.3% (95% CI, 71.0%-89.1%). CONCLUSION: Although noninvasive, PET/CT has relatively low sensitivity in regional lymph node evaluations, and fair sensitivity in distal metastasis detection in Asian patients with acral melanoma. Thus, PET/CT may be more useful in patients with clinically palpable nodes or more advanced disease stages.

Outcome analysis of free flap reconstruction for head and neck cancer with intraoperative indocyanine green angiography.

BACKGROUND: Intraoperative indocyanine green (ICG) angiography is used in free flap surgery to evaluate the patency of vessel anastomosis. This study evaluated the outcomes of intraoperative ICG angiography in free flap surgery for head and neck cancer. MATERIALS AND METHODS: This was a retrospective study of free flap reconstruction for head and neck cancer performed between 2015 and 2021. The outcomes analyzed were the total flap failure rate, re-exploration rate, and flap salvage rate. Differences in outcomes were compared in patients treated using intraoperative ICG angiography and those treated without. RESULTS: Of the 520 free flap surgeries in the 486 enrolled patients, 259 cases underwent intraoperative ICG angiography. In this group, there were 10 (3.9%) cases of total flap failure. In the non-ICG group, there were 22 cases (8.4%). There were 35 (13.5%) cases requiring re-exploration in the ICG group and 40 (15.3%) in the non-ICG group. The difference was not statistically significant. The flap salvage rate was 75.8% (25/33) in the ICG group and 51.4% (18/35) in the non-ICG group, which was a significant difference. CONCLUSION: We found that free flap surgery with intraoperative ICG angiography significantly decreased total flap failure rate and significantly increased salvage rate but did not significantly affect the re-exploration rate.

Phase coexistence implications of violating Newton's third law.

Newton's third law, action = reaction, is a foundational statement of classical mechanics. However, in natural and living systems, this law appears to be routinely violated for constituents interacting in a nonequilibrium environment. Here, we use computer simulations to explore the macroscopic phase behavior implications of breaking microscopic interaction reciprocity for a simple model system. We consider a binary mixture of attractive particles and introduce a parameter that is a continuous measure of the degree to which interaction reciprocity is broken. In the reciprocal limit, the species are indistinguishable, and the system phase separates into domains with distinct densities and identical compositions. Increasing nonreciprocity is found to drive the system to explore a rich assortment of phases, including phases with strong composition asymmetries and three-phase coexistence. Many of the states induced by these forces, including traveling crystals and liquids, have no equilibrium analogs. By mapping the complete phase diagram for this model system and characterizing these unique phases, our findings offer a concrete path forward toward understanding how nonreciprocity shapes the structures found in living systems and how this might be leveraged in the design of synthetic materials.

Liraglutide With Metformin Therapy Ameliorates Hepatic Steatosis and Liver Injury in a Mouse Model of Non-alcoholic Steatohepatitis.

BACKGROUND/AIM: Non-alcoholic fatty liver disease is a major cause of liver-related morbidity and mortality. Metformin is a widely used medication and may have additional benefits beyond glycemic control. Liraglutide, a novel treatment for diabetes and obesity, also has beneficial effects on non-alcoholic steatohepatitis (NASH). Metformin and liraglutide have both benefited NASH treatment. However, no study has reported the effects of combination therapy with liraglutide and metformin on NASH. MATERIALS AND METHODS: We investigated the in vivo effects of metformin and liraglutide on NASH in a methionine/choline-deficient (MCD) diet-fed C57BL/6JNarl mouse model. Serum triglyceride, alanine aminotransferase and alanine aminotransferase levels were documented. Histological analysis was performed according to the NASH activity grade. RESULTS: After treatment with liraglutide and metformin, body weight loss improved, and the liver/body weight ratio decreased. The metabolic effects and liver injury improved. Liraglutide and metformin alleviated MCD-induced hepatic steatosis and injury. Histological analysis revealed that NASH activity was reduced. CONCLUSION: Our results provide evidence for the anti-NASH activity of liraglutide in combination with metformin. Liraglutide with metformin may offer the potential for a disease-modifying intervention for NASH.

Ant Waist Surgery: Aesthetic Removal of Floating Ribs to Decrease the Waist-hip Ratio.

Decreasing waist circumference has become an essential feature in modern body contouring surgery owing to the attractiveness of hourglass body shapes. Traditionally, this can be achieved through lipomodeling and abdominal musculature strengthening techniques. An adjunctive procedure for ideal shaping of the waistline is resection of the 11th and 12th ribs, referred to as floating ribs. This study aimed to report and analyze clinical outcomes and self-reported patient satisfaction after "ant waist" surgery (floating rib removal) for aesthetic reasons. We retrospectively reviewed the medical records of five patients who had undergone bilateral 11th and 12th rib resections at a single institute in Taiwan in an outpatient setting. The mean lengths of the resected left and right 11th ribs were 9.1 and 9.5 cm, respectively. The mean lengths of the resected left and right 12th ribs were 6.3 and 6.4 cm, respectively. The mean waist-to-hip ratio decreased from 0.78 preoperatively to 0.72 postoperatively, with a mean decrease of 7.7%. No adverse events were reported. Generally, all patients reported being satisfied with the operation. Floating rib resection proved useful and effective in decreasing the waist-to-hip ratio using a safe, simple, and reproducible technique without significant complications. Although preliminarily, the authors' comprehensive demonstration of this ant waist surgery supports further studies focusing on waistline contouring.

Influencing factors associated with lymph node status in patients with cutaneous melanoma: An Asian population study.

BACKGROUND: Sentinel lymph node (SLN) status is the predominant prognostic factor in patients diagnosed with clinically localized melanoma. The significance of completion lymph node dissection in patients with SLN metastasis is debatable. Not many studies have been conducted on acrallentiginous melanoma (ALM). This study aimed to characterize the prognostic factors of nodal positive ALM and confirm whether ALM patients can undergo the same treatment strategy as non-ALM patients in the Asian population. METHODS: This is a retrospective review of patients who underwent surgery for cutaneous melanoma (CM) at Taipei Veterans General Hospital between January 1993 and December 2019. We investigated the risk factors for lymph node status. The association between clinicopathological factors and lymph node status of ALM and non-ALM patients was analyzed. Outcomes of completion lymph node dissection (CLND) performed following sentinel lymph node biopsy (SLNB) in the CM and ALM groups were compared. RESULTS: A total of 197 patients were included in this study. ALM was the most common histological subtype, accounting for 66.5% of all the cases. Patients in the CM and ALM subgroups with metastatic SLN ( p = 0.012) or lymph nodes ( p < 0.001 and p = 0.001) exhibited higher mortality rate. Multivariate analysis showed that patients with clinical presentation of T4 category tumor ( p = 0.012) and lymphovascular invasion ( p = 0.012) had a significantly higher risk of positive lymph nodes. The overall survival of patients with lymph nodes metastasis was not associated with the performance of CLND. CONCLUSION: Patients in the CM or ALM subgroups with metastatic SLNs or lymph nodes exhibited significantly poorer overall survival. Advanced Breslow thickness and lymphovascular invasion were independent predictive factors for CM and ALM patients with positive lymph node status. There was no significant difference in survival between CM and ALM patients following SLNB, regardless of CLND being performed.

Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells.

Gemcitabine is frequently utilized to treat pancreatic cancer. The purpose of our study was to create a gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cell line (MIA-GR100) and to evaluate the anti-pancreatic cancer efficacy of HMJ-38, a new quinazolinone analogue. Compared to their parental counterparts, MIA-PaCa-2, established MIA-GR100 cells were less sensitive to gemcitabine. MIA-GR100 cell viability was not affected by 10, 50 and 100 nM gemcitabine concentrations. HMJ-38 reduced MIA-GR100 cell growth and induced autophagy and apoptosis. When stained with monodansylcadaverine (MDC), acridine orange (AO), and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), MIA-GR100 cells shrunk, punctured their membranes, and produced autophagy vacuoles and apoptotic bodies. Combining chloroquine (CQ) and 3-methyladenine (3-MA) with HMJ-38 dramatically reduced cell viability, indicating that autophagy function as a cytoprotective mechanism. MIA-GR100 cells treated with both z-VAD-FMK and HMJ-38 were much more viable than those treated with HMJ-38 alone. HMJ-38 promotes apoptosis in MIA-GR100 cells by activating caspases. Epidermal growth factor receptor (EGFR) is one of HMJ-38's principal targets, as determined via in silico target screening with network prediction. HMJ-38 also inhibited EGFR kinase activity and EGFR-associated signaling in MIA-GR100 cells. HMJ-38 may be an effective chemotherapeutic adjuvant for gemcitabine-resistant pancreatic cancer cells, in which it induces an antitumor response.

In Silico and In Vitro studies of taiwan chingguan yihau (NRICM101) on TNF-α/IL-1ß-induced human lung cells.

COVID-19 pandemic has been a global outbreak of coronavirus (SARS-CoV-2 virus) since 2019. Taiwan Chingguan Yihau (NRICM101) is the first traditional Chinese medicine (TCM) classic herbal formula and is widely used for COVID-19 patients in Taiwan and more than 50 nations. This study is to investigate in silico target fishing for the components of NRICM101 and to explore whether NRICM101 inhibits cytokines-induced normal human lung cell injury in vitro. Our results showed that network prediction of NRICM101 by a high throughput target screening platform showed that NRICM101 has multiple functions that may affect cytokine regulation to prevent human lung cell injury. In addition, NRICM101 revealed protective effects against TNF-α/IL-1ß-induced normal human lung HEL 299 cell injury through JNK and p38MAPK kinase signaling. Next-generation sequencing (NGS) analysis of NRICM101 on TNF-α/IL-1ß-injured HEL 299 cells indicated that inflammatory pathway, cell movement of macrophages, cellular infiltration by macrophages, and Th1/Th2 immuno-regulation pathways were included. Thus, NRICM101 is a therapeutic agent, and it can improve COVID-19 syndrome to confer beneficial effects through multiple targeting and multiple mechanisms.

Genomic profiling with whole-exome sequencing revealed distinct mutations and novel pathways in Asian melanoma.

The clinical characteristics of malignant melanoma are highly variable between patient populations of different ethnicities. To explore the underlining genetic variations, we reviewed the clinical data of 242 malignant melanoma cases from Taiwan and among them submitted formalin-fixed paraffin-embedded tissue samples from 37 patients for whole-exome sequencing to identify the mutational signatures, tumor mutation burden and specific gene mutations. The genomic profiles and clinical outcomes were compared with the information derived from the publicly available TCGA and TGEN databases. Mutation signature 12 was the dominant signature in Taiwanese patients and represented approximately 45% of the mutation signatures observed. In contrast, mutation signature 7 was the most prominent among cases available in the TCGA database. Common gene mutations found in the TCGA melanoma dataset were not frequently found in melanomas from Taiwanese patients. There were a significant number of specific gene mutations that exclusively occurred in acral subtype but not in non-acral subtype melanomas, and vice versa. While certain common mutations form a shared core of genetic features, there appear to be specific genetic pathways that are involved in the occurrence of melanomas that grow in non-UV-exposed areas. Our findings have shed light on the tumorigenesis pathways involved in malignant melanoma.

MTH-3 sensitizes oral cancer cells to cisplatin via regulating TFEB.

OBJECTIVES: MTH-3, a curcumin derivative, exhibits improved water solubility. This study aims to elucidate the mechanisms underlying the anticancer effects of MTH-3 on human oral squamous cell carcinoma CAL27 cisplatin-resistant (CAR) cells. METHODS: To evaluate the biological functions of MTH-3 in CAR cells, flow cytometry, staining, and western blot analyses were used. KEY FINDINGS: MTH-3 reduced CAR cell viability and significantly induced autophagy in the presence of 10 and 20 µM MTH-3. Transcription factor EB was identified as the potential target of MTH-3. Autophagy-related proteins were upregulated after 24 h of MTH-3 incubation. MTH-3 treatment increased caspase-3 and caspase-9 enzyme activities. Mitochondrial membrane potential was decreased after MTH-3 treatment. MTH-3 triggered the intrinsic apoptotic pathway. CONCLUSIONS: MTH-3 induces autophagy and apoptosis of CAR cells via TFEB. MTH-3 might be an effective pharmacological agent for treating oral cancer cells.

A Systematic Review and Meta-Analysis of Extracorporeal Membrane Oxygenation in Patients with Burns.

BACKGROUND: Severely burned patients are at high risk for cardiopulmonary failure. Promising studies have stimulated interest in using extracorporeal membrane oxygenation as a potential therapy for burn patients with refractory cardiac and/or respiratory failure. However, the findings from previous studies vary. METHODS: In this study, the authors conducted a systematic review and meta-analysis using standardized mortality ratios to elucidate the benefits associated with the use of extracorporeal membrane oxygenation in patients with burn and/or inhalation injuries. A literature search was performed, and clinical outcomes in the selected studies were compared. RESULTS: The meta-analysis found that the observed mortality was significantly higher than the predicted mortality in patients receiving extracorporeal membrane oxygenation (standardized mortality ratio, 2.07; 95 percent CI, 1.04 to 4.14). However, the subgroup of burn patients with inhalation injuries had lower mortality rates compared to their predicted mortality rates (standardized mortality ratio, 0.95; 95 percent CI, 0.52 to 1.73). Other subgroup analyses reported no benefits from extracorporeal membrane oxygenation; however, these results were not statistically significant. Interestingly, the pooled standardized mortality ratio values decreased as the selected patients' revised Baux scores increased (R = -0.92), indicating that the potential benefits from the treatment increased as the severity of patients with burns increased. CONCLUSIONS: The authors' meta-analysis revealed that burn patients receiving extracorporeal membrane oxygenation treatment were at a higher risk of death. However, select patients, including those with inhalation injuries and those with revised Baux scores over 90, would benefit from the treatment. The authors suggest that burn patients with inhalation injuries or with revised Baux scores exceeding 90 should be considered for the treatment and early transfer to an extracorporeal membrane oxygenation center.

Gadodiamide Induced Autophagy and Apoptosis in Human Keratinocytes.

BACKGROUND/AIM: Gadolinium has been reported to cause liver lobular necrosis and nephrogenic systemic fibrosis. However, its toxicity to the skin remains unknown. This study aimed to investigate the effect of a high dose of gadolinium-based contrast agent gadodiamide on the human keratinocyte HaCaT cell line. MATERIALS AND METHODS: Cell viability was assessed using MTT assay, and autophagy was assessed using acridine orange and LysoTracker Red staining. Western blotting was performed to verify the changes in Bcl2 and Bax levels. RESULTS: The viability of HaCaT cells was significantly suppressed after gadodiamide treatment. Interestingly, gadodiamide caused autophagic vacuoles, whereas the autophagy inhibitors 3-methyladenine and chloroquine significantly alleviated autophagic cell death. Simultaneously, gadodiamide induced apoptosis, which was reduced by caspase inhibitors. Gadodiamide also inhibited Bcl-2 expression and promoted Bax expression. CONCLUSION: Gadodiamide induced both autophagy and apoptosis in HaCaT cells. Physicians should carefully assess the gadodiamide dosage used clinically.

Tremella fuciformis Inhibits Melanogenesis in B16F10 Cells and Promotes Migration of Human Fibroblasts and Keratinocytes.

BACKGROUND/AIM: Natural skin whiteners have been investigated for centuries. The development of preparations that safely achieve whitening of hyper-pigmented skin lesions is a challenge for the cosmetics industry. Furthermore, promoting rapid wound healing and minimizing inflammation in injured skin are key to prevent from abnormal pigmentation in scar tissue. Natural products, including the fungus Tremella fuciformis (TF), are attracting attention as potential sources of lead compounds for these applications. MATERIALS AND METHODS: We investigated the in vitro effects of TF on melanogenesis in murine B16F10 cells. Melanin and tyrosinase levels were measured after treatment with TF. Wound healing in human keratinocytes (HaCaT) and fibroblasts (Detroit 551) was also determined via cell migration assay prior to TF exposure. RESULTS: TF significantly decreased melanin content and tyrosinase expression in a concentration-dependent manner in B16F10 cells. Furthermore, TF promoted wound healing in human HaCaT keratinocytes and Detroit 551 fibroblasts. CONCLUSION: TF proved effectively on inhibiting melanogenesis and promoting wound healing in vitro, demonstrating its potential as a novel skin-whitening agent. However, further clinical studies of safety and efficacy are required.

Curcumin suppresses cell proliferation and triggers apoptosis in vemurafenib-resistant melanoma cells by downregulating the EGFR signaling pathway.

Melanoma is a malignant tumor with aggressive behavior. Vemurafenib, a BRAF inhibitor, is clinically used in melanoma, but resistance to melanoma cytotoxic therapies is associated with BRAF mutations. Curcumin can effectively inhibit numerous types of cancers. However, there are no reports regarding the correlation between curcumin and vemurafenib-resistant melanoma cells. In this study, vemurafenib-resistant A375.S2 (A375.S2/VR) cells were established, and the functional mechanism of the epidermal growth factor receptor (EGFR), serine-threonine kinase (AKT), and the extracellular signal-regulated kinase (ERK) signaling induced by curcumin was investigated in A375.S2/VR cells in vitro. Our results indicated that A375.S2/VR cells had a higher IC50 concentration of vemurafenib than the parental A375.S2 cells. Moreover, curcumin reduced the viability and confluence of A375.S2/VR cells. Curcumin triggered apoptosis via reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential (ΔΨm), and intrinsic signaling (caspase-9/-3-dependent) pathways in A375.S2/VR cells. Curcumin-induced apoptosis was also mediated by the EGFR signaling pathway. Combination treatment with curcumin and gefitinib (an EGFR inhibitor) synergistically potentiated the inhibitory effect of cell viability in A375.S2/VR cells. The present study provides new insights into the therapy of vemurafenib-resistant melanoma and suggests that curcumin might be an encouraging therapeutic candidate for its drug-resistant treatment.

Helicobacter pylori Targets in AGS Human Gastric Adenocarcinoma: In Situ Proteomic Profiling and Systematic Analysis.

BACKGROUND/AIM: Helicobacter pylori, a gram-negative bacterium, causes chronic stomach diseases in humans. Heat shock proteins (HSPs) are involved in cell integrity, cell growth, and gastric mucosa colonization by H. pylori. This study aimed to investigate HSP expression levels in H. pylori-infected gastric adenocarcinoma AGS cells. MATERIALS AND METHODS: We determined protein expression levels using iTRAQ proteomics analysis. We analyzed the possible network interactions for H. pylori targets in AGS cells using the Ingenuity Pathway Analysis (IPA) software. RESULTS: H. pylori-infected AGS cells potentially targeted EIF2 and BAG2 signaling pathways to regulate cell physiology. In addition, after 3, 6, and 12 h of infection, western blotting revealed significantly decreased HSP70 and HSP105 expression. CONCLUSION: H. pylori decreases HSPs in AGS gastric adenocarcinoma cells, and this is associated with the regulation of EIF2 and BAG2 signaling pathways.

Study of Baicalin toward COVID-19 Treatment: In silico Target Analysis and in vitro Inhibitory Effects on SARS-CoV-2 Proteases.

Negative impacts of COVID-19 on human health and economic and social activities urge scientists to develop effective treatments. Baicalin is a natural flavonoid, extracted from a traditional medicinal plant, previously reported with anti-inflammatory activity. In this study, we used pharmacophore fitting and molecular docking to screen and determine docking patterns and the binding affinity of baicalin on 3 major targets of SARS-CoV-2 (3-chymotrypsin-like cysteine protease [3CLpro], papain-like protease [PLpro], and RNA-dependent RNA polymerase). The obtained data revealed that baicalin has high pharmacophore fitting on 3CLpro and predicted good binding affinity on PLpro. Moreover, using the enzymatic assay, we examined the inhibitory effect of baicalin in vitro on the screened enzymes. Baicalin also exhibits inhibitory effect on these proteases in vitro. Additionally, we performed pharmacophore-based screening of baicalin on human targets and conducted pathway analysis to explore the potential cytoprotective effects of baicalin in the host cell that may be beneficial for COVID-19 treatment. The result suggested that baicalin has multiple targets in human cell that may induce multiple pharmacological effects. The result of pathway analysis implied that these targets may be associated with baicalin-induced bioactivities that are involved with signals of pro-inflammation factors, such as cytokine and chemokine. Taken together with supportive data from the literature, the bioactivities of bailalin may be beneficial for COVID-19 treatment by reducing cytokine-induced acute inflammation. In conclusion, baicalin is potentially a good candidate for developing new therapeutic to treat COVID-19.