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.

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.

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.

Effect of Quercetin on Dexamethasone-Induced C2C12 Skeletal Muscle Cell Injury.

Glucocorticoids are widely used anti-inflammatory drugs in clinical settings. However, they can induce skeletal muscle atrophy by reducing fiber cross-sectional area and myofibrillar protein content. Studies have proven that antioxidants can improve glucocorticoid-induced skeletal muscle atrophy. Quercetin is a potent antioxidant flavonoid widely distributed in fruits and vegetables and has shown protective effects against dexamethasone-induced skeletal muscle atrophy. In this study, we demonstrated that dexamethasone significantly inhibited cell growth and induced cell apoptosis by stimulating hydroxyl free radical production in C2C12 skeletal muscle cells. Our results evidenced that quercetin increased C2C12 skeletal cell viability and exerted antiapoptotic effects on dexamethasone-treated C2C12 cells by regulating mitochondrial membrane potential (ΔΨm) and reducing oxidative species. Quercetin can protect against dexamethasone-induced muscle atrophy by regulating the Bax/Bcl-2 ratio at the protein level and abnormal ΔΨm, which leads to the suppression of apoptosis.

Detection of free flap pedicle thrombosis by infrared surface temperature imaging.

BACKGROUND: Reliable detection of any circulatory issue threatening flap viability after free flap surgery is essential for prompt flap salvage. Currently, the gold standard of flap monitoring is clinical monitoring. However, this method presents logistical challenges to insufficient trained personnel. Auxiliary methods are becoming increasingly vital. MATERIALS AND METHODS: Twelve swine pedicle myocutaneous flaps were harvested and monitored using infrared cameras to investigate the developed monitoring parameters and vascular thrombosis in the free flap model. RESULTS: The mean flap surface temperature after vein or artery occlusion decreased significantly, but the differences were relatively small. As a result, the difference between recorded (flap surface temperature [Ts]) and predicted (estimated surface temperature [Tes]) flap surface temperature (ΔT = Ts- Tes) was used as the parameter for pedicle thrombosis. A ΔT of <0.86°C was used as a vascular occlusion criterion; the sensitivity and specificity of this parameter were 90% and 81%, respectively. The standard deviation of the surface temperature (SDT) was another indicator of vascular occlusion; the estimated sensitivity and specificity for vessel occlusion of SDT < 0.48°C were 84% and 73%, respectively. CONCLUSIONS: Infrared thermal imaging has the advantages of being noninvasive, contact-free, continuous, and able to detect the whole flap surface area. Two indicators, ΔT and SDT, can be used with high sensitivity and specificity for early prediction of flap pedicle thrombosis. Further human studies are necessary to validate clinical application of infrared thermal imaging.

Fractional CO2 laser contributes to the treatment of non-segmental vitiligo as an adjunct therapy: a systemic review and meta-analysis.

The treatment of stable non-segmental vitiligo is often challenging, which new therapies are being searched. Multiple clinical trials have proposed the benefits and safety of using fractional carbon dioxide (CO2) laser as an adjunct therapy to conventional treatments. This study aimed to evaluate the safety and efficacy of fractional carbon dioxide laser as a combination therapy to conventional treatments in patients with stable non-segmental vitiligo. A literature search using PubMed, EMBASE, and the Cochrane Library was performed for comparative studies among vitiligo patients treated with additional fractional CO2 laser. Clinical outcomes in the selected studies were compared, and a meta-analysis was performed via Review Manager version 5.3, according to the PRISMA guidelines. Six studies with a total of 184 patches/patients were included in the present meta-analysis. The combination therapy group had significantly superior results than that of the control group (≥ 75% re-pigmentation, risk ratio [RR] 2.80, 95% confidence interval [CI] 1.29-6.07; ≥ 50% re-pigmentation, RR 2.26, 95% CI 1.23-5.9; < 25% re-pigmentation, RR 0.57, 95% CI 0.43-0.75). Limitations of the study included the small number of studies and sample size, inadequate blinding of participants, and variation between therapy protocols. Meta-analysis revealed that using fractional CO2 laser in combination with conventional treatments is efficient and safe, and may be considered as an adjunct therapeutic option for patients with refractive non-segmental vitiligo.

Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells.

Arsenic trioxide is an old drug and has been used for a long time in traditional Chinese and Western medicines. However, the cancer treatment of arsenic trioxide has heart and vascular toxicity. The cytotoxic effects of arsenic trioxide and its molecular mechanism in human umbilical mesenchymal stem cells (HUMSC) and human bone marrow-derived mesenchymal stem cells (HMSC-bm) were investigated in this study. Our results showed that arsenic trioxide significantly reduced the viability of HUMSC and HMSC-bm in a concentration- and time-dependent manner. Arsenic trioxide is able to induce apoptotic cell death in HUMSC and HMSC-bm, as shown from the results of morphological examination, flow cytometric analyses, DAPI staining and comet assay. The appearance of arsenic trioxide also led to an increase of intracellular free calcium (Ca(2+) ) concentration and the disruption of mitochondrial membrane potential (ΔΨm). The caspase-9 and caspase-3 activities were time-dependently increased in arsenic trioxide-treated HUMSC and HMSC-bm. In addition, the proteomic analysis and DNA microarray were carried out to investigate the expression level changes of genes and proteins affected by arsenic trioxide treatment in HUMSC. Our results suggest that arsenic trioxide induces a prompt induction of ER stress and mitochondria-modulated apoptosis in HUMSC and HMSC-bm. A framework was proposed for the effect of arsenic trioxide cytotoxicity by targeting ER stress.

Integrating dermal substitutes in soft tissue repair: Insights from a case series and comprehensive literature review.

The use of dermal substitutes with subsequent skin graft application constitutes an alternative treatment option in situations that limit the use of other conventional approaches.

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.

Genome­wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan.

Psoriasis is a chronic inflammatory dermatological disease, and there is a lack of understanding of the genetic factors involved in psoriasis in Taiwan. To establish associations between genetic variations and psoriasis, a genome­wide association study was performed in a cohort of 2,248 individuals with psoriasis and 67,440 individuals without psoriasis. Using the ingenuity pathway analysis software, biological networks were constructed. Human leukocyte antigen (HLA) diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)­R software and chi­square analysis. The present study aimed to assess the potential risks associated with psoriasis using a polygenic risk score (PRS) analysis. The genetic association between single nucleotide polymorphisms (SNPs) in psoriasis and various human diseases was assessed by phenome­wide association study. METAL software was used to analyze datasets from China Medical University Hospital (CMUH) and BioBank Japan (BBJ). The results of the present study revealed 8,585 SNPs with a significance threshold of P<5x10­8, located within 153 genes strongly associated with the psoriasis phenotype, particularly on chromosomes 5 and 6. This specific genomic region has been identified by analyzing the biological networks associated with numerous pathways, including immune responses and inflammatory signaling. HLA genotype analysis indicated a strong association between HLA­A*02:07 and HLA­C*06:02 in a Taiwanese population. Based on our PRS analysis, the risk of psoriasis associated with the SNPs identified in the present study was quantified. These SNPs are associated with various dermatological, circulatory, endocrine, metabolic, musculoskeletal, hematopoietic and infectious diseases. The meta­analysis results indicated successful replication of a study conducted on psoriasis in the BBJ. Several genetic loci are significantly associated with susceptibility to psoriasis in Taiwanese individuals. The present study contributes to our understanding of the genetic determinants that play a role in susceptibility to psoriasis. Furthermore, it provides valuable insights into the underlying etiology of psoriasis in the Taiwanese community.

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.

[Corrigendum] Next­generation sequencing analysis reveals that MTH­3, a novel curcuminoid derivative, suppresses the invasion of MDA­MB­231 triple­negative breast adenocarcinoma cells.

Subsequently to the publication of the article, an interested reader drew to the authors' attention that, in Fig. 2A on p. 5, the 'Control  (24 h)' and 'MTH­3 (1 µM; 24 h)' data panels contained partially overlapping data, such that they appeared to have been derived from the same original source. The authors have examined their original data, and realized that this error arose inadvertently as a consequence of having compiled this figure incorrectly. The revised version of Fig. 2, featuring the data from one of the repeated experiments in Fig. 2A, is shown below. The revised data shown for this figure do not affect the overall conclusions reported in the paper. The authors apologize to the Editor of Oncology Reports and to the readership for any inconvenience caused. [Oncology Reports 46: 133, 2021; DOI: 10.3892/or.2021.8084].

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.

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.

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.

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.

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.

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.

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.

Activations of Both Extrinsic and Intrinsic Pathways in HCT 116 Human Colorectal Cancer Cells Contribute to Apoptosis through p53-Mediated ATM/Fas Signaling by Emilia sonchifolia Extract, a Folklore Medicinal Plant.

Emilia sonchifolia (L.) DC (Compositae), an herbaceous plant found in Taiwan and India, is used as folk medicine. The clinical applications include inflammation, rheumatism, cough, cuts fever, dysentery, analgesic, and antibacteria. The activities of Emilia sonchifolia extract (ESE) on colorectal cancer cell death have not been fully investigated. The purpose of this study explored the induction of apoptosis and its molecular mechanisms in ESE-treated HCT 116 human colorectal cancer cells in vitro. The methanolic ESE was characterized, and γ-humulene was formed as the major constituent (63.86%). ESE induced cell growth inhibition in a concentration- and time-dependent response by MTT assay. Apoptotic cells (DNA fragmentation, an apoptotic catachrestic) were found after ESE treatment by TUNEL assay and DNA gel electrophoresis. Alternatively, ESE stimulated the activities of caspase-3, -8, and -9 and their specific caspase inhibitors protected against ESE-induced cytotoxicity. ESE promoted the mitochondria-dependent and death-receptor-associated protein levels. Also, ESE increased ROS production and upregulated the levels of ATM, p53, and Fas in HCT 116 cells. Strikingly, p53 siRNA reversed ESE-reduced viability involved in p53-mediated ATM/Fas signaling in HCT 116 cells. In summary, our result is the first report suggesting that ESE may be potentially efficacious in the treatment of colorectal cancer.