The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer.

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients. Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles. We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance. Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells. An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930. Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding. HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway. This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization. Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4. Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice. A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts. Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer. Further investigation is warranted to fully establish its therapeutic potential.

Development of a tetrahydroindazolone-based HDAC6 inhibitor with in-vivo anti-arthritic activity.

Histone deacetylase 6 (HDAC6) induces the expression of pro-inflammatory cytokines in macrophages; therefore, HDAC inhibitors may be beneficial for the treatment of macrophage-associated immune disorders and chronic inflammatory diseases, including atherosclerosis and rheumatoid arthritis. Structure-activity relationship studies were conducted on various phenyl hydroxamate HDAC6 inhibitors with indolone/indazolone-based bi- or tricyclic ring moieties as the cap group aiming to develop novel anti-arthritic drug candidates. Several compounds exhibited nanomolar activity and HDAC6 selectivity greater than 500-fold over HDAC1. Compound 21, a derivative with the tetrahydroindazolone cap group, is a potent HDAC6 inhibitor with an IC50 of 18 nM and 217-fold selectivity over HDAC1 and showed favorable oral bioavailability in animals. Compound 21 increases the acetylation level of tubulin without affecting histone acetylation in cutaneous T-cell lymphoma cells and inhibits TNF-α secretion in LPS-stimulated macrophage cells. The anti-arthritic effects of compound 21 were evaluated using a rat adjuvant-induced arthritis (AIA) model. Treatment with compound 21 significantly reduced the arthritis score, and combination treatment with methotrexate showed a synergistic effect in AIA models. We identified a novel HDAC6 inhibitor, compound 21, with excellent in vivo anti-arthritic efficacy, which can lead to the development of oral anti-arthritic drugs.

Beet pulp as soluble fiber source and dietary energy levels for growing pigs under heat stress.

The study evaluated the effects of dietary fiber and energy levels administered during two growing periods (d 0-28 and d 29-56) for pigs exposed to a high temperature. A total of 96 growing pigs were used in six treatments as: Two treatments in thermoneutral temperature (21°C-24°C) with dietary energy of 3,300 and the inclusion of high or low fiber, two treatments in heat stress (30°C-34°C) with dietary energy of 3,300 and the inclusion of high or low fiber, and two treatments in heat stress with dietary energy of 3,450 and the inclusion of high or low fiber. Among standard energy level treatments, heat-stressed pigs showed lower average daily gain (ADG), feed intake, digestibility of dry matter, gross energy, crude protein, and crude fiber in phases 1 and 2. Moreover, higher concentrations of acetate, propionate, butyrate, and total short-chain fatty acid (SCFA) in feces were shown in pigs fed high fiber diets. There was a negative interaction between dietary fiber and energy for the fecal concentration of isobutyrate in phase 1 and valerate in phase 2. Pigs in heat stress treatments showed a higher rectal temperature, respiratory rate, hair cortisol, plasma zonulin, and fecal lipocalin-2. Among heat stress treatments, the overall ADG was increased in pigs fed high fiber. Pigs fed high dietary fiber showed a greater concentration of acetate, propionate, butyrate, and total SCFA. High fiber treatments decreased plasma zonulin. In conclusion, the inclusion of beet pulp, soluble fiber, at the level of 4% looks necessary in pigs diet during heat stress.

Effects of Recycled Polymer on Melt Viscosity and Crystallization Temperature of Polyester Elastomer Blends.

As the world is paying attention to the seriousness of environmental pollution, the need for a resource circulation economy is emerging due to the development of eco-friendly industrial groups. In particular, the recycling of thermoplastic elastomers without cross-link has been highlighted in the plastics field, which has rapidly developed the industry. Growing interests have been directed towards the advancement of thermoplastic polyether-ester elastomer (TPEE) as a material suitable for the circular economy owing to its remarkable recyclability, both in terms of mechanical and chemical processes. Due to its excellent processability, simple mechanical recycling is easy, which is a driving force towards achieving price competitiveness in the process. In molding TPEE resin, it is essential to check the thermal properties of the resin itself because the thermal properties, including the melting and crystallization temperatures of the resin, depend on the design of the polymer. In this study, the thermal and mechanical performances of TPEE blends were evaluated by manufacturing compounds by changing the amount of recycled resin and additives. When the recycled resin was added, the melt flow index (MFI) changed rapidly as the temperature of the melt flow index measurement increased. Rapid changes in MFI make the fiber spinning process uncontrollable and must be controlled by optimizing the addition of compatibilizers. Based on the thermal property results, compatibilizers such as Lotader and Elvaloy series exhibited minimal change in glass transition temperature, even with greater amounts added. This makes them well-suited as compatibilizers for fiber spinning.

Cellular heterogeneity and plasticity during NAFLD progression.

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease that can progress to nonalcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma (HCC). NAFLD ranges from simple steatosis (or nonalcoholic fatty liver [NAFL]) to NASH as a progressive form of NAFL, which is characterized by steatosis, lobular inflammation, and hepatocellular ballooning with or without fibrosis. Because of the complex pathophysiological mechanism and the heterogeneity of NAFLD, including its wide spectrum of clinical and histological characteristics, no specific therapeutic drugs have been approved for NAFLD. The heterogeneity of NAFLD is closely associated with cellular plasticity, which describes the ability of cells to acquire new identities or change their phenotypes in response to environmental stimuli. The liver consists of parenchymal cells including hepatocytes and cholangiocytes and nonparenchymal cells including Kupffer cells, hepatic stellate cells, and endothelial cells, all of which have specialized functions. This heterogeneous cell population has cellular plasticity to adapt to environmental changes. During NAFLD progression, these cells can exert diverse and complex responses at multiple levels following exposure to a variety of stimuli, including fatty acids, inflammation, and oxidative stress. Therefore, this review provides insights into NAFLD heterogeneity by addressing the cellular plasticity and metabolic adaptation of hepatocytes, cholangiocytes, hepatic stellate cells, and Kupffer cells during NAFLD progression.

An intelligent method for pregnancy diagnosis in breeding sows according to ultrasonography algorithms.

Pig breeding management directly contributes to the profitability of pig farms, and pregnancy diagnosis is an important factor in breeding management. Therefore, the need to diagnose pregnancy in sows is emphasized, and various studies have been conducted in this area. We propose a computer-aided diagnosis system to assist livestock farmers to diagnose sow pregnancy through ultrasound. Methods for diagnosing pregnancy in sows through ultrasound include the Doppler method, which measures the heart rate and pulse status, and the echo method, which diagnoses by amplitude depth technique. We propose a method that uses deep learning algorithms on ultrasonography, which is part of the echo method. As deep learning-based classification algorithms, Inception-v4, Xception, and EfficientNetV2 were used and compared to find the optimal algorithm for pregnancy diagnosis in sows. Gaussian and speckle noises were added to the ultrasound images according to the characteristics of the ultrasonography, which is easily affected by noise from the surrounding environments. Both the original and noise added ultrasound images of sows were tested together to determine the suitability of the proposed method on farms. The pregnancy diagnosis performance on the original ultrasound images achieved 0.99 in accuracy in the highest case and on the ultrasound images with noises, the performance achieved 0.98 in accuracy. The diagnosis performance achieved 0.96 in accuracy even when the intensity of noise was strong, proving its robustness against noise.

Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer.

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance. In particular, tumor-associated macrophages (TAMs), as the predominant infiltrated immune cells in a tumor, play a pivotal role in regulating the immunosuppressive tumor microenvironment. As a potential therapeutic strategy to counteract TAMs, here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages. Exosomes derived from M1-type macrophages (M1-Exo) promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency. Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability, potentiating antitumor immunity surrounding the tumor. Strikingly, these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II, offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.

Synthesis and biological evaluation of novel N-benzyltriazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Histone deacetylases (HDAC) regulate post-translational acetylation and the inhibition of these enzymes has emerged as an intriguing disease therapeutic. Among them, class IIb HDAC6 has the unique characteristic of mainly deacetylating cytoplasmic proteins, suggesting clinical applications for neurodegenerative diseases, inflammation, and cancer. In this study, we designed a novel N-benzyltriazolyl-hydroxamate scaffold based on the known HDAC6 inhibitors nexturastat A and tubastatin A. Among the 27 derivatives, 3-fluoro-4-((3-(2-fluorophenyl)-1H-1,2,4-triazol-1-yl)methyl)-N-hydroxybenzamide 4u (HDAC6 IC50 = 7.08 nM) showed nanomolar HDAC6 inhibitory activity with 42-fold selectivity over HDAC1. Structure-activity relationship (SAR) and computational docking studies were conducted to optimize the triazole capping group. Docking analysis revealed that the capping group aligned with the conserved L1 pocket of HDAC6 and was associated with subtype selectivity. Overall, our study explored the triazole-based biaryl capping group and its substitution and orientation, suggesting a rationale for the design of HDAC6-selective inhibitors.

Reshaping tumor immune microenvironment by Epstein-Barr virus activation in the stroma of colorectal cancer.

The formation of tumor immune microenvironment (TIM) is complicated and poorly understood. Little is known about the effect of a viral infection potentially inducing an additional immune response in the TIM. Here, we identify Epstein-Barr virus (EBV) expression in the TIM in colorectal cancer (CRC) tissue through EBV-encoded RNA in-situ hybridization and RNA sequencing data and investigate the effects of EBV on TIM composition and clinical outcomes. EBV was detected in tumor-infiltrating lymphocytes, but not in cancer cells. EBV positivity was associated with older age, male sex, and SMAD4 mutations. EBV-positive tumors were characterized by enrichment in chemokine/cytokine signaling pathways and altered immune cell composition, including plasma and CD4 T cells, as well as cancer cells intrinsically enriched pathways related to immune tolerance, leading to poor prognosis. In conclusion, we identified EBV expression in TIM and suggested its association with poor prognosis by altering the TIM in CRC.

Rapid discovery and classification of inhibitors of coronavirus infection by pseudovirus screen and amplified luminescence proximity homogeneous assay.

To identify potent antiviral compounds, we introduced a high-throughput screen platform that can rapidly classify hit compounds according to their target. In our platform, we performed a compound screen using a lentivirus-based pseudovirus presenting a spike protein of coronavirus, and we evaluated the hit compounds using an amplified luminescence proximity homogeneous assay (alpha) test with purified host receptor protein and the receptor binding domain of the viral spike. With our screen platform, we were able to identify both spike-specific compounds (class I) and broad-spectrum antiviral compounds (class II). Among the hit compounds, thiosemicarbazide was identified to be selective to the interaction between the viral spike and its host cell receptor, and we further optimized the binding potency of thiosemicarbazide through modification of the pyridine group. Among the class II compounds, we found raloxifene and amiodarone to be highly potent against human coronaviruses including Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and SARS-CoV-2. In particular, using analogs of the benzothiophene moiety, which is also present in raloxifene, we have identified benzothiophene as a novel structural scaffold for broad-spectrum antivirals. This work highlights the strong utility of our screen platform using a pseudovirus assay and an alpha test for rapid identification of potential antiviral compounds and their mechanism of action, which can lead to the accelerated development of therapeutics against newly emerging viral infections.

Chemical screen uncovers novel structural classes of inhibitors of the papain-like protease of coronaviruses.

The papain-like protease (PLpro) of coronaviruses is an attractive antiviral target to inhibit both viral replication and interference of the host immune response. We have identified and characterized three novel classes of small molecules, thiophene, cyanofuran, and triazoloquinazoline, as PLpro inhibitors. Thiophene inhibited the PLpro of two major coronaviruses, Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) including SARS-CoV-2, while cyanofuran and triazoloquinazoline more selectively inhibited MERS-CoV PLpro. Unlike GRL0617, a known PLpro inhibitor, all three compounds contain no naphthyl group but like GRL0617 were predicted to fit on the cleft near the BL2 loop. Docking studies further revealed that the location and direction of the binding determined their specificity to different coronaviruses. Together, our work demonstrates that the BL2 loop and nearby regions are outstanding druggable targets, and our three inhibitors can be applicable to the development of therapeutics for coronavirus infection.

A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response.

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.

Relationship between aging-related pulmonary function, cognition, motor function, and activities of daily living in older adults with dementia.

BACKGROUND: The aging process is related to cerebrovascular dysfunction and physiological changes, such as reduced pulmonary function. This ultimately induces cognitive impairment or dementia. OBJECTIVE: This study aimed to determine the relationship between aging-related pulmonary function, cognition, motor function, and activities of daily living (ADLs) in older adults with dementia. METHODS: This cross-sectional study included 69 older adults diagnosed with dementia. Aging-related pulmonary function and cognition were measured using a hand-held spirometer and the Korean version of the Mini-Mental State Examination (MMSE-K), respectively. To assess motor function and ADLs, the Berg Balance Scale (BBS), 10-meter walk test (10-MWT), 6-minute walk test (6-MWT), and modified Barthel index (MBI) were used to measure balance, walking speed, physical functional capacity (or walking tolerance), and ADLs, respectively. All data were analyzed using the Pearson's product correlation coefficient (r). RESULTS: Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) as measures of aging-related pulmonary function correlated only with the 6-MWT (FVC: r = 0.483, p = 0.002; FEV1: r = 0.512, p = 0.001). In cognitive function, MMSE-K was associated with BBS (r = 0.283, p = 0.022) and MBI (r = 0.454, p = 0.000). Additionally, there were significant correlations (r = 0.425-0.671, p = 0.000) between all motor function and ADLs measures in older adults with dementia. CONCLUSIONS: Our findings demonstrated that aging-pulmonary function was related to a lower physical functional capacity, and hence, suggested that the reduced pulmonary function were unable to walk for longer distance in older adults with dementia.

Cooperative Friendly Jamming Techniques for Drone-Based Mobile Secure Zone.

Threats of eavesdropping and information leakages have increased sharply owing to advancements in wireless communication technology. In particular, the Internet of Things (IoT) has become vulnerable to sniffing or jamming attacks because broadcast communication is usually conducted in open-network environments. Although improved security protocols have been proposed to overcome the limitations of wireless-communication technology and to secure safe communication channels, they are difficult to apply to mobile communication networks and IoT because complex hardware is required. Hence, a novel security model with a lighter weight and greater mobility is needed. In this paper, we propose a security model applying cooperative friendly jamming using artificial noise and drone mobility, which are autonomous moving objects, and we demonstrate the prevention of eavesdropping and improved security through simulations and field tests. The Cooperative Friendly Jamming Techniques for Drone-based Mobile Secure Zone (CFJ-DMZ) can set a secure zone in a target area to support a safe wireless mobile communication network through friendly jamming, which can effectively reduce eavesdropping threats. According to the experimental results, the average information leakage rate of the eavesdroppers in CFJ-DMZ-applied scenarios was less than or equal to 3%, an average improvement of 92% over conventional methods.

A novel C-terminal heat shock protein 90 inhibitor that overcomes STAT3-Wnt-ß-catenin signaling-mediated drug resistance and adverse effects.

Rationale: The heat shock protein (Hsp) system plays important roles in cancer stem cell (CSC) and non-CSC populations. However, limited efficacy due to drug resistance and toxicity are obstacles to clinical use of Hsp90 inhibitors, suggesting the necessity to develop novel Hsp90 inhibitors overcoming these limitations. Methods: The underlying mechanism of resistance to Hsp90 inhibitors was investigated by colony formation assay, sphere formation assay, western blot analysis, and real-time PCR. To develop anticancer Hsp90 inhibitors that overcome the signal transducer and activator of transcription 3 (STAT3)-mediated resistance, we synthesized and screened a series of synthetic deguelin-based compounds in terms of inhibition of colony formation, migration, and viability of non-small cell lung cancer (NSCLC) cells and toxicity to normal cells. Regulation of Hsp90 by the selected compound NCT-80 [5-methoxy-N-(3-methoxy-4-(2-(pyridin-3-yl)ethoxy)phenyl)-2,2-dimethyl-2H-chromene-6-carboxamide] was investigated by immunoprecipitation, drug affinity responsive target stability assay, binding experiments using ATP-agarose beads and biotinylated drug, and docking analysis. The antitumor, antimetastatic, and anti-CSC effects of NCT-80 were examined in vitro and in vivo using various assays such as MTT, colony formation, and migration assays and flow cytometric analysis and tumor xenograft models. Results: We demonstrated a distinct mechanism in which Hsp90 inhibitors that block N-terminal ATP-binding pocket causes transcriptional upregulation of Wnt ligands through Akt- and ERK-mediated activation of STAT3, resulting in NSCLC cell survival in an autocrine or paracrine manner. In addition, NCT-80 effectively reduced viability, colony formation, migration, and CSC-like phenotypes of NSCLC cells and their sublines with acquired resistance to anticancer drugs by inducing apoptosis and inhibiting epithelial-mesenchymal transition and the growth of NSCLC patient-derived xenograft tumors without overt toxicity. With regards to mechanism, NCT-80 directly bound to the C-terminal ATP-binding pocket of Hsp90, disrupting the interaction between Hsp90 and STAT3 and degrading STAT3 protein. Moreover, NCT-80 inhibited chemotherapy- and EGFR TKI-induced programmed cell death ligand 1 expression and potentiated the antitumor effect of chemotherapy in the LLC-Luc allograft model. Conclusions: These data indicate the potential of STAT3/Wnt signaling pathway as a target to overcome resistance to Hsp90 inhibitors and NCT-80 as a novel Hsp90 inhibitor that targets both CSCs and non-CSCs in NSCLC.

Applicability of ferric(III) hydroxide as a phosphate-selective adsorbent for sewage treatment.

This research was undertaken to evaluate the usability of ferric(III) hydroxide for phosphate removal from sewage. Batch adsorption experiments, partly fixed bed column experiments, were conducted to study the influence of various factors, competing anions and contact time on the adsorption of phosphate on ferric(III) hydroxide. Processing ferric iron in the form of akaganeite (ß-FeOOH) greatly increased the adsorption capacity for phosphate. The optimum phosphate removal was observed in the pHeq ≤ 6.0. All results from this study demonstrate the potential usability of ß-FeOOH as a good phosphate-selective adsorbent for the phosphate removal system for a sewage treatment plant.

Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer.

A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90α C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the C-terminal domain, forming key interactions.

A novel CMAQ-CNN hybrid model to forecast hourly surface-ozone concentrations 14 days in advance.

Issues regarding air quality and related health concerns have prompted this study, which develops an accurate and computationally fast, efficient hybrid modeling system that combines numerical modeling and machine learning for forecasting concentrations of surface ozone. Currently available numerical modeling systems for air quality predictions (e.g., CMAQ) can forecast 24 to 48 h in advance. In this study, we develop a modeling system based on a convolutional neural network (CNN) model that is not only fast but covers a temporal period of two weeks with a resolution as small as a single hour for 255 stations. The CNN model uses meteorology from the Weather Research and Forecasting model (processed by the Meteorology-Chemistry Interface Processor), forecasted air quality from the Community Multi-scale Air Quality Model (CMAQ), and previous 24-h concentrations of various measurable air quality parameters as inputs and predicts the following 14-day hourly surface ozone concentrations. The model achieves an average accuracy of 0.91 in terms of the index of agreement for the first day and 0.78 for the fourteenth day, while the average index of agreement for one day ahead prediction from the CMAQ is 0.77. Through this study, we intend to amalgamate the best features of numerical modeling (i.e., fine spatial resolution) and a deep neural network (i.e., computation speed and accuracy) to achieve more accurate spatio-temporal predictions of hourly ozone concentrations. Although the primary purpose of this study is the prediction of hourly ozone concentrations, the system can be extended to various other pollutants.

Metabolic Spectrum of Liver Failure in Type 2 Diabetes and Obesity: From NAFLD to NASH to HCC.

Liver disease is the spectrum of liver damage ranging from simple steatosis called as nonalcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC). Clinically, NAFLD and type 2 diabetes coexist. Type 2 diabetes contributes to biological processes driving the severity of NAFLD, the primary cause for development of chronic liver diseases. In the last 20 years, the rate of non-viral NAFLD/NASH-derived HCC has been increasing rapidly. As there are currently no suitable drugs for treatment of NAFLD and NASH, a class of thiazolidinediones (TZDs) drugs for the treatment of type 2 diabetes is sometimes used to improve liver failure despite the risk of side effects. Therefore, diagnosis, prevention, and treatment of the development and progression of NAFLD and NASH are important issues. In this review, we will discuss the pathogenesis of NAFLD/NASH and NAFLD/NASH-derived HCC and the current promising pharmacological therapies of NAFLD/NASH. Further, we will provide insights into "adipose-derived adipokines" and "liver-derived hepatokines" as diagnostic and therapeutic targets from NAFLD to HCC.

Structure-Activity Relationship Study and Biological Evaluation of 2-(Disubstituted phenyl)-indole-5-propanoic Acid Derivatives as GPR40 Full Agonists.

G-protein-coupled receptor 40 (GPR40) is considered as an attractive drug target for treating type 2 diabetes, owing to its role in the free fatty acid-mediated increase in glucose-stimulated insulin secretion (GSIS) from pancreatic ß-cells. To identify a new chemotype of GPR40 agonist, a series of 2-aryl-substituted indole-5-propanoic acid derivatives were designed and synthesized. We identified two GPR40 agonist lead compounds-4k (3-[2-(4-fluoro-2-methylphenyl)-1H-indol-5-yl]propanoic acid) and 4o (3-[2-(2,5-dimethylphenyl)-1H-indol-5-yl]propanoic acid), having GSIS and glucagon-like peptide 1 secretory effects. Unlike previously reported GPR40 partial agonists that only activate the Gq pathway, 4k and 4o activated both the Gq and Gs signaling pathways and were characterized as GPR40 full agonists. In in vivo efficacy studies, 4o significantly improved glycemic control in both C57BL/6J and db/db mice and increased plasma-active GLP-1 in C57BL/6J mice. Thus, 4o represents a promising lead for further development as a novel GPR40 full agonist against type 2 diabetes.