Recurrence pattern of glioblastoma treated with intensity-modulated radiation therapy versus three-dimensional conformal radiation therapy.

PURPOSE: To evaluate recurrence patterns of and survival outcomes in glioblastoma treated with intensity-modulated radiation therapy (IMRT) versus three-dimensional conformal radiation therapy (3D-CRT). MATERIALS AND METHODS: We retrospectively examined 91 patients with glioblastoma treated with either IMRT (n = 60) or 3D-CRT (n = 31) between January 2013 and December 2019. Magnetic resonance imaging showing tumor recurrence and planning computed tomography scans were fused for analyzing recurrence patterns categorized as in-field, marginal, and out-of-field based on their relation to the initial radiation field. RESULTS: The median overall survival (OS) was 18.9 months, with no significant difference between the groups. The median progression-free survival (PFS) was 9.4 months, with no significant difference between the groups. Patients who underwent gross total resection (GTR) had higher OS and PFS than those who underwent less extensive surgery. Among 78 relapse cases, 67 were of in-field; 5, marginal; and 19, out-of-field recurrence. Among 3D-CRT-treated cases, 24 were of in-field; 1, marginal; and 9, out-of-field recurrence. Among IMRT-treated cases, 43 were of in-field; 4, marginal; and 10, out-of-field recurrence. In partial tumor removal or biopsy cases, out-of-field recurrence was less frequent in the IMRT (16.2%) than in the 3D-CRT (36.3%) group, with marginal significance (p = 0.079). CONCLUSION: IMRT and 3D-CRT effectively managed glioblastoma with no significant differences in OS and PFS. The survival benefit with GTR underscored the importance of maximal surgical resection. The reduced rate of out-of-field recurrence in IMRT-treated patients with partial resection highlights its potential utility in cases with unfeasible complete tumor removal.

Uvaol ameliorates lipid deposition in hyperlipidemic hepatocytes by suppressing protein-tyrosine phosphatase 1B/ER stress signaling.

Uvaol (UV), a pentacyclic triterpene found in olives and virgin olive oil, is known for its anti-inflammatory and antioxidant effects in various disease models. While olive oil is reported to reduce obesity and insulin resistance, the specific impact of UV on liver lipid metabolism and its molecular mechanisms are not fully understood. In this study, hepatic lipid accumulation was measured using oil red O staining, and protein expression levels in liver cells were assessed via Western blot analysis. Apoptosis was evaluated through cell viability and caspase 3 activity assays. UV treatment reduced lipid accumulation, fatty acid uptake, apoptosis, and ER stress in palmitate-treated liver cells. Additionally, UV enhanced fatty acid oxidation. Mechanistically, increased SIRT6 expression and autophagy were observed in UV-treated cells. SIRT6-targeted siRNA or 3-methyladenine blocked the effects of UV in hyperlipidemic cells. In conclusion, UV improves SIRT6/autophagy signaling, reducing lipid deposition and apoptosis in liver cells under high lipid conditions. This in vitro study provides strong evidence for potential therapeutic strategies for hepatic steatosis.

Glucose transporters and sodium glucose co-transporters cooperatively import glucose into energy-demanding organs in carcinogenic liver fluke Clonorchis sinensis.

BACKGROUND: The liver fluke Clonorchis sinensis imports large amounts of glucose to generate energy and metabolic intermediates through glycolysis. We hypothesized that C. sinensis absorbs glucose through glucose transporters and identified four subtypes of glucose transporter (CsGTP) and one sodium glucose co-transporter (CsSGLT) in C. sinensis. METHODOLOGY/PRINCIPAL FINDINGS: Expressed sequence tags encoding CsGTPs were retrieved from the C. sinensis transcriptome database, and their full-length cDNA sequences were obtained by rapid amplification of cDNA ends (RACE). The tissue distribution of glucose transporters in C. sinensis adults was determined using immunohistochemical staining. Developmental expression was measured using RT-qPCR. The transport and distribution of glucose into living C. sinensis were monitored using confocal microscopy. Membrane topology and key functional residues of CsGTPs were homologous to their counterparts in animals and humans. CsGTP1, 2, and 4 were transcribed 2.4-5.5 times higher in the adults than metacercariae, while CsGTP3 was transcribed 2.1 times higher in the metacercariae than adults. CsSGLT transcription was 163.6 times higher in adults than in metacercariae. In adults, CsSGLT was most abundant in the tegument; CsGTP3 and CsSGLT were localized in the vitelline gland, uterine wall, eggs, mesenchymal tissue, and testes; CsGTP4 was found in sperm and mesenchymal tissue; and CsGTP1 was mainly in the sperm and testes. In C. sinensis adults, exogenous glucose is imported in a short time and is present mainly in the middle and posterior body, in which the somatic and reproductive organs are located. Of the exogenous glucose, 53.6% was imported through CsSGLT and 46.4% through CsGTPs. Exogenous glucose import was effectively inhibited by cytochalasin B and phlorizin. CONCLUSIONS/SIGNIFICANCE: We propose that CsSGLT cooperates with CsGTPs to import exogenous glucose from the environmental bile, transport glucose across mesenchymal tissue cells, and finally supply energy-demanding organs in C. sinensis adults. Studies on glucose transporters may pave the way for the development of new anthelmintic drugs.

Risk of radionecrosis in HER2-positive breast cancer with brain metastasis receiving trastuzumab emtansine (T-DM1) and brain stereotactic radiosurgery.

OBJECTIVES: To investigate the potential relationship between trastuzumab emtansine (T-DM1) treatment and radionecrosis induced by brain stereotactic radiosurgery (SRS) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. MATERIALS AND METHODS: Patients with HER2-positive breast cancer who were diagnosed with brain metastasis and received both SRS and HER2-targeted agents between 2012 and 2022 were retrospectively analyzed. Patients who received T-DM1 within 1 year (either before or after) of SRS were considered as 'T-DM1 exposure (+)'. T-DM1 exposure (-) group had other HER2-targeted agents or received T-DM1 more than 1 year before or after SRS. Symptomatic radionecrosis was defined as Common Terminology Criteria for Adverse Events grade 2 or greater. RESULTS: A total of 103 patients with 535 treatment sessions were included from seven tertiary medical centers in Korea and Italy. The median follow-up duration was 15.5 months (range 1.1-101.9). By per-patient analysis, T-DM1 exposure (+) group had an increased risk of overall radionecrosis after multivariate analysis (HR 2.71, p = 0.020). Additionally, T-DM1 exposure (+) group was associated with a higher risk of symptomatic radionecrosis compared to T-DM1 exposure (-) patients (HR 4.34, p = 0.030). In per-treatment analysis, T-DM1 exposure (+) was linked to higher incidences of overall (HR 3.13, p = 0.036) and symptomatic radionecrosis (HR 10.4, p = 0.013) after multivariate analysis. A higher prevalence of radionecrosis was observed with T-DM1 exposure (+) and a previous history of whole brain radiotherapy. CONCLUSION: An increased risk of radionecrosis was observed in patients receiving T-DM1 with brain SRS. Further research is needed to better understand the optimal sequence and interval for administering T-DM1 and SRS.

Prostate-Specific Antigen (PSA) Bounces Following Stereotactic Body Radiotherapy for Prostate Cancer: Importance of PSA Test Frequency.

PURPOSE: Prostate-specific antigen (PSA) bounce is a common phenomenon that can be observed in patients of prostate cancer treated by radiotherapy. However, the clinical, pathological, or dosimetric predictors and clinical significance of PSA bounce in stereotactic body radiotherapy (SBRT) patients is still unknown. METHODS: Between August 2006 to December 2015, 74 prostate cancer patients were treated by SBRT with Cyberknife at two medical centers. The prescription dose was 35-37.5 Gy in 5 fractions. Follow-up PSA tests were more frequently performed in one hospital than the other (median 4 vs. 10 times for initial one year). PSA bounce was defined as a rise of 0.2 ng/mL followed by a decline to or below previous nadir. RESULTS: A total of 74 patients, PSA bounce was observed in 41 patients (55.4%). On univariate analysis, the treated medical center (p = 0.02), PSA follow-up frequency (p = 0.01), patient age (p < 0.01), and total prescription dose (p = 0.03) were significant clinical factors to predict the incidence of PSA bounce, while in multivariable analysis only the PSA follow-up frequency, and patient age remains significant. CONCLUSION: PSA bounce was seen in a significant proportion of patients after Cyberknife SBRT. The PSA follow-up test frequency, and patient age were significant factors that were correlated with the incidence of PSA bounces in this study.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

PURPOSE: Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. METHODS: A total of 66 patients were divided into two groups: those treated with 30 Gy (2 Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30 Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6 Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50 Gy (range, 36.0-55.8 Gy). RESULTS: The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. CONCLUSION: Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

CTRP4 attenuates apoptosis and epithelial-mesenchymal transition markers in podocytes through an AMPK/autophagy-dependent pathway.

Hyperglycemia, characterized by high blood glucose levels resulting from pancreatic beta cell dysfunction or impaired insulin signaling, is a contributing factor in the development of diabetic nephropathy. This study aimed to investigate the effects of C1q/TNF-related protein 4 (CTRP4), known for its anti-obesity and anti-inflammatory properties in various disease models, on podocyte apoptosis and endoplasmic reticulum (ER) stress in the presence of elevated glucose levels. The expression levels of various proteins in podocytes and adipocytes were evaluated by Western blotting. Autophagosomes in podocytes were stained by MDC. Chromatin condensation in podocytes was examined by Hoechst staining. The research revealed increased expression of CTRP4 in 3T3-L1 adipocytes and CIHP-1 podocytes exposed to high glucose (HG) conditions. Treatment with CTRP4 effectively mitigated HG-induced apoptosis and ER stress and normalized epithelial-to-mesenchymal transition (EMT) markers in CIHP-1 cells. Furthermore, elevated levels of AMPK phosphorylation and autophagy were observed in CIHP-1 cells treated with CTRP4. Silencing of AMPK or the use of 3-methyl adenine (3 MA) reduced the impacts of CTRP4 on apoptosis, EMT markers and ER stress in CIHP-1 cells. In conclusion, these findings suggest that CTRP4 alleviates ER stress in podocytes under hyperglycemic conditions, leading to the suppression of apoptosis and the restoration of EMT through AMPK/autophagy-mediated signaling. These insights provide valuable information for the development of therapeutic strategies for diabetic nephropathy.

Consolidative Radiotherapy after Complete Remission following R-CHOP Immunochemotherapy in Stage III-IV Diffuse Large B-Cell Lymphoma Patients: A Systematic Review and Meta-Analysis.

Patients with diffuse large B-cell lymphoma (DLBCL) are treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) remains unclear among patients with advanced DLBCL who achieved complete remission (CR) after R-CHOP immunochemotherapy. The current systematic review and meta-analysis aimed to clarify the role of consolidative RT among these patients. The MEDLINE, Embase, and Cochrane Library databases were searched for studies comparing RT to no RT following CR after R-CHOP immunochemotherapy in Ann Arbor stage III-IV DLBCL patients. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS) was the secondary endpoint. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to assess the primary and secondary outcomes. Review Manager (version 5.4) was used to analyze the data. Six retrospective studies involving 813 patients who received R-CHOP ± consolidative RT were identified. OS was higher in the consolidative RT group, with an HR of 2.01 and a 95% CI of 1.30 to 3.12 (p = 0.002). DFS was also higher in the RT group, with an HR of 2.18 and a 95% CI of 1.47 to 3.24 (p < 0.0001). The results suggested that consolidative RT improved OS and DFS compared to no RT among advanced-stage DLBCL patients. Further research is needed to determine the optimal radiation fields and the appropriate indications for consolidative RT for advanced-stage DLBCL patients in the rituximab era.

Musclin attenuates lipid deposition in hepatocytes through SIRT7/autophagy-mediated suppression of ER stress.

Musclin, an exercise-responsive myokine, has the ability to attenuate inflammation, oxidative stress, and apoptosis in cardiomyocytes under pathogenic conditions. While the potential benefits of musclin in the cardiovascular system have been well documented, its effects on hepatic endoplasmic reticulum (ER) stress and lipid metabolism are not fully understood. The present study showed that musclin treatment reduced lipid accumulation and lipogenic protein expression in primary hepatocytes exposed to palmitate. Palmitate treatment led to an increase in markers of ER stress, which was reversed by musclin treatment. Musclin treatment increased SIRT7 expression and markers of autophagy in a dose-dependent manner. Small interfering (si) RNA of SIRT7 or 3-methyladenine (3 MA) reduced the effects of musclin on lipogenic lipid deposition in hepatocytes under hyperlipidemic conditions. These findings suggest that musclin can suppress palmitate-induced ER stress by upregulating SIRT7 and autophagy signaling, thereby alleviating lipid accumulation in primary hepatocytes. The current study provides a potential therapeutic strategy for the treatment of liver diseases characterized by lipid accumulation and ER stress, such as nonalcoholic fatty liver disease (NAFLD).

Oroxylin-A alleviates hepatic lipid accumulation and apoptosis under hyperlipidemic conditions via AMPK/FGF21 signaling.

Oroxylin-A (OA) is an O-methylated flavone that has been demonstrated to have anti-inflammatory properties in various disease models. However, the roles of OA in hepatic lipid metabolism and the specific molecular mechanisms by which it exerts these effects are not yet fully understood. In the current study, we aimed to investigate the effects of OA on hepatic lipid deposition and apoptosis, which play a pivotal role in the development of nonalcoholic fatty liver disease (NAFLD) in obesity in vitro models. We found that treatment with OA attenuated lipid accumulation, the expression of lipogenesis-associated proteins and apoptosis in palmitate-treated primary mouse hepatocytes. OA treatment suppressed phosphorylated NFκB and IκB expression in as well as TNFα and MCP-1 release from hepatocytes treated with palmitate. Treatment of hepatocytes with OA augmented AMPK phosphorylation and FGF21 expression. siRNA of AMPK or FGF21 abolished the effects of OA on inflammation as well as lipid accumulation and apoptosis in hepatocytes under palmitate treatment conditions. In conclusion, OA improves inflammation through the AMPK/FGF21 pathway, thereby attenuating lipid accumulation and apoptosis in hepatocytes. This study may help identify new targets for developing treatments for NAFLD.

Structure-based virtual screening and molecular dynamics of potential inhibitors targeting sodium-bile acid co-transporter of carcinogenic liver fluke Clonorchis sinensis.

BACKGROUND: Clonorchis sinensis requires bile acid transporters as this fluke inhabits bile juice-filled biliary ducts, which provide an extreme environment. Clonorchis sinensis sodium-bile acid co-transporter (CsSBAT) is indispensable for the fluke's survival in the final host, as it circulates taurocholate and prevents bile toxicity in the fluke; hence, it is recognized as a useful drug target. METHODOLOGY AND PRINCIPAL FINDINGS: In the present study, using structure-based virtual screening approach, we presented inhibitor candidates targeting a bile acid-binding pocket of CsSBAT. CsSBAT models were built using tertiary structure modeling based on a bile acid transporter template (PDB ID: 3zuy and 4n7x) and were applied into AutoDock Vina for competitive docking simulation. First, potential compounds were identified from PubChem (holding more than 100,000 compounds) by applying three criteria: i) interacting more favorably with CsSBAT than with a human homolog, ii) intimate interaction to the inward- and outward-facing conformational states, iii) binding with CsSBAT preferably to natural bile acids. Second, two compounds were identified following the Lipinski's rule of five. Third, other two compounds of molecular weight higher than 500 Da (Mr > 500 Da) were presumed to efficiently block the transporter via a feasible rational screening strategy. Of these candidates, compound 9806452 exhibited the least hepatotoxicity that may enhance drug-likeness properties. CONCLUSIONS: It is proposed that compound 9806452 act as a potential inhibitor toward CsSBAT and further studies are warranted for drug development process against clonorchiasis.

Accelerator mass spectrometry for quantification of micro- and therapeutic-dose diclofenac in microdialysis samples.

Background: Microdialysis sampling after drug microdosing may provide tissue pharmacokinetic data early in clinical drug development. However, low administered doses and small sample volumes pose an analytical challenge, particularly for highly protein-bound drugs. Materials & methods: Carbon-14 [14C]diclofenac was used as a model drug to assess the technical and analytical feasibility of in vivo microdialysis after microdose administration in an in vitro setup. Results: [14C]diclofenac dialysate concentrations were accurately quantified with accelerator MS. [14C]diclofenac dialysate recoveries were similar in the presence and absence of therapeutic diclofenac concentrations but were considerably decreased when albumin was added to the immersion solution, suggesting high protein binding. Conclusion: These results demonstrate the feasibility of combining microdosing and microdialysis to assess tissue pharmacokinetics.

Multiple biochemical indices and metabolomics of Clonorchis sinensis provide a novel interpretation of biomarkers.

BACKGROUND: Clonorchiasis, an infectious disease caused by the liver fluke Clonorchis sinensis, may lead to the development of liver and gallbladder diseases, and even cholangiocarcinoma (CCA). However, the pathogenesis, host-pathogen interaction, and diagnostic markers for clonorchiasis remain unclear. METHODS: Eighteen rabbits were randomly divided into control group (n = 9) and C. sinensis-infected group (n = 9), and their plasma samples were collected at 7, 14, 28, and 63 days post-infection (dpi). Biochemical indices and metabolites in different infection periods were detected. A non-targeted ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach was employed to investigate the metabolic profiles of plasma in rabbits, and related metabolic pathways of differential metabolites and correlation between candidate biochemical indices and differential metabolites were analyzed. Finally, the candidate biomarkers were verified with human samples using a targeted metabolomics method. RESULTS: The result of biochemical indices indicated C. sinensis infection would affect the liver function biochemical indices, especially alanine aminotransferase, aspartate transaminase (AST), glutamyl transpeptidase (GGT), total bile acid, high-density lipoprotein, and cholinesterase. The metabonomic results showed that 58, 212, 23, and 21 differential metabolites were identified in different phases of the infection. Multivariate statistical analysis of differential metabolites revealed distinct metabolic signatures during different phases of infection, with most of these signatures being observed at 14 dpi, which mainly influences the amino acid metabolisms. For metabolites and biochemical indices, AST, GGT, hypoxanthine, L-pipecolic acid, and D-glucuronate represented potential noninvasive biomarkers for the diagnosis of C. sinensis (P < 0.05 and AUC > 0.8). Furthermore, GGT and D-glucuronate levels were positively correlated with the infection (r(28) = 0.98, P < 0.0001) and showed excellent diagnostic performance (AUC = 0.972; 95% confidence interval, 0.921 to 1.000). CONCLUSIONS: The present results provide new insights into plasma metabolic changes in rabbits during C. sinensis infection, and the potential biomarker may be used for developing an effective method to diagnose clonorchiasis in the future.

Dimethyl itaconate attenuates palmitate-induced insulin resistance in skeletal muscle cells through the AMPK/FGF21/PPARδ-mediated suppression of inflammation.

AIM: Itaconate (ITA), a derivative of the tricarboxylic acid cycle, has been documented to have a direct antimicrobial effect by inhibiting isocitrate lyase and suppressing proinflammatory cytokines in LPS-treated macrophages. However, the effects of dimethyl ITA (DITA), a membrane-permeable derivative of ITA, on insulin signaling and inflammation in skeletal muscle in an obese state remain to be elucidated. Thus, this study was designed to investigate the effects of DITA on the impairment of insulin signaling and inflammation in palmitate-treated C2C12 myocytes. MATERIALS AND METHODS: Western blotting was used to determine the expression of insulin signaling associated genes, inflammatory markers, fibroblast growth factor 21 (FGF21), and PPARδ expression, as well as AMPK phosphorylation in mouse skeletal muscle cells. Secreted proinflammatory cytokine levels were detected by enzyme-linked immunosorbent assay. Insulin signaling was assessed by glucose uptake assay. KEY FINDINGS: Treating C2C12 myocytes with DITA attenuated palmitate-induced aggravation of insulin signaling markers, such as insulin receptor substrate-1 (IRS-1) and Akt phosphorylation and inflammatory markers, such as NFκB and IκB phosphorylation. AMPK phosphorylation, as well as PPARδ and myokine FGF21 expression, were enhanced in C2C12 myocytes by DITA treatment. siRNA-mediated suppression of AMPK or FGF21 expression abolished the effects of DITA on insulin resistance and inflammation in palmitate-treated C2C12 myocytes. SIGNIFICANCE: In sum, DITA suppresses inflammation through the AMPK/FGF21/PPARδ signaling, thereby alleviating insulin resistance in palmitate-treated C2C12 myocytes. The current study appears to be an essential basis for performing animal experiments to develop insulin resistance therapeutics.

Capmatinib improves insulin sensitivity and inflammation in palmitate-treated C2C12 myocytes through the PPARδ/p38-dependent pathway.

Capmatinib (CAP) has been used to treat metastatic non-small lung cancer (NSCL) and suppress inflammation. It causes hypoglycemia in NSCL patients. Therefore, it is expected that CAP improves inflammation-mediated insulin resistance due to its anti-inflammatory effect. However, the impacts of CAP on insulin signaling in skeletal muscle cells have not yet been fully elucidated. Herein, we investigated the effect of CAP on insulin resistance in palmitate-treated C2C12 myocytes and explored the related molecular mechanisms. We found that treatment of C2C12 myocytes with CAP reversed palmitate-induced impairment of insulin signaling and glucose uptake. CAP treatment ameliorated phosphorylation of inflammatory markers, including NFκB and IκB, in palmitate-treated C2C12 myocytes. Further, it augmented PPARδ expression and suppressed palmitate-induced p38 phosphorylation in a dose-dependent manner. siRNA-mediated suppression of PPARδ abolished the effects of CAP on palmitate-induced insulin resistance and inflammation as well as p38 phosphorylation. Therefore, it has been shown that CAP treatment ameliorates insulin resistance in palmitate-treated C2C12 myocytes via PPARδ/p38 signaling-mediated suppression of inflammation. These results may represent a novel therapeutic approach that could halt insulin resistance and type 2 diabetes.

Patchouli alcohol improves wound healing in high fat diet-fed mice through AMPK-mediated suppression of inflammation and TGFb1 signaling.

Obesity impairs wound healing with substantial alterations in skin inflammation. Patchouli alcohol (PA), extracted from patchouli, has been reported to ameliorate inflammation in various cell types. However, the effects of PA on inflammation and wound healing have not been reported to date. In the present study, we examined whether PA affects cutaneous wound healing in high fat diet (HFD)-fed mice and explored PA-mediated molecular mechanisms through in vitro experiments. We found that PA administration accelerated wound healing as well as ameliorates inflammation in skin of HFD-fed mice. PA treatment augmented AMP-activated protein kinase (AMPK) phosphorylation and TGFb1 expression. PA enhanced cell migration and suppressed inflammation in LPS-treated HaCaT cells. Further, PA increased dose-dependently AMPK phosphorylation as along with TGFb1 and cell migration markers expression. siRNA for AMPK or TGFb1 abrogated the effects of PA on cell migration and inflammation. TGFb1 siRNA mitigated PA-induced expression of cell migration markers. These results suggest that PA ameliorates wound healing via AMPK and TGFb1-mediated suppression of inflammation. In sum, PA can be used as a novel treatment strategy for wound healing in obesity or insulin resistance.

Pharmacokinetics of 2-phenoxyethanol and its major metabolite, phenoxyacetic acid, after dermal and inhaled routes of exposure: application to development PBPK model in rats.

2-Phenoxyethanol (PE), ethylene glycol monophenyl ether, is widely used as a preservative in cosmetic products as well as in non-cosmetics. Since PE has been used in many types of products, it can be absorbed via dermal or inhaled route for systemic exposures. In this study, the pharmacokinetic (PK) studies of PE and its major metabolite, phenoxyacetic acid (PAA), after dermal (30 mg and 100 mg) and inhaled administration (77 mg) of PE in rats were performed. PE was administered daily for 4 days and blood samples were collected at day 1 and day 4 for PK analysis. PE was rapidly absorbed and extensively metabolized to form PAA. After multiple dosing, the exposures of PE and PAA were decreased presumably due to the induction of metabolizing enzymes of PE and PAA. In dermal mass balance study using [14C]-phenoxyethanol ([14C]PE) as a microtracer, most of the PE and its derivatives were excreted in urine (73.03%) and rarely found in feces (0.66%). Based on these PK results, a whole-body physiologically-based pharmacokinetic (PBPK) model of PE and PAA after dermal application and inhalation in rats was successfully developed. Most of parameters were obtained from the literatures and experiments, and intrinsic clearance at steady-state (CLint,ss) were optimized based on the observed multiple PK data. With the developed model, systemic exposures of PE and PAA after dermal application and inhalation were simulated following no-observed-adverse-effect level (NOAEL) of 500 mg/kg/day for dermal application and that of 12.7 mg/kg/day for inhalation provided by the Environmental Protection Agency. The area under the concentration-time curve at steady state (AUCss) in kidney and liver (and lung for inhalations), which are known target organs of exhibiting toxicity of PE, as well as AUCss in plasma of PE and PAA were obtained from the model.

Capmatinib attenuates lipogenesis in 3T3-L1 adipocytes through an adenosine monophosphate-activated protein kinase-dependent pathway.

Recently, there is a rapid increase in the incidence of obesity, a condition for which there are no effective therapeutic agents. Capmatinib (CAP), a novel mesenchymal-to-epithelial transition inhibitor, is reported to attenuate pro-inflammatory mediators and oxidative stress. In this study, the effects of CAP on lipogenesis in the adipocytes were examined. Treatment with CAP dose-dependently suppressed lipid accumulation in, and differentiation of, and increased lipolysis in, 3T3-L1 adipocytes. Additionally, CAP treatment augmented adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and FNDC5 expression in the adipocytes. Transfection with si-AMPK or si-FNDC5 mitigated the CAP-induced suppression of lipogenesis and enhanced lipolysis. Furthermore, transfection with si-FNDC5 mitigated the CAP-induced phosphorylation of AMPK. These results suggest that the anti-obesity effect of CAP is mediated through the irisin/AMPK pathway and that CAP is a novel therapeutic agent for obesity.

Serodiagnostic antigens of Clonorchis sinensis identified and evaluated by high-throughput proteogenomics.

Clonorchiasis caused by Clonorchis sinensis is endemic in East Asia; approximately 15 million people have been infected thus far. To diagnose the infection, serodiagnostic tests with excellent functionality should be performed. First, 607 expressed sequence tags encoding polypeptides with a secretory signal were expressed into recombinant proteins using an in vitro translation system. By protein array-based screening using C. sinensis-infected sera, 18 antigen candidate proteins were selected and assayed for cross-reactivity against Opisthorchis viverrini-infected sera. Of the six antigenic proteins selected, four were synthesized on large scale in vitro and evaluated for antigenicity against the flukes-infected human sera using ELISA. CsAg17 antigen showed the highest sensitivity (77.1%) and specificity (71.2%). The sensitivity and specificity of the bacterially produced CsAg17-28GST fusion antigen was similar to those of CsAg17 antigen. CsAg17 antigen can be used to develop point-of-care serodiagnostic tests for clonorchiasis.