Talaesthanes A-C, three new meroterpenoids from the endophytic fungus Talaromyces primulinus H21.

Three new meroterpenoids (1-3) and ten known ones (4-13) were obtained from the endophytic fungus Talaromyces primulinus H21 isolated from the plant of Euphorbia sikkimensis. Their structures including their absolute configurations were elucidated by extensive analysis of spectroscopic data such as HR-ESI-MS, 1D/2D NMR, and X-ray diffraction of single crystal together with comparison of experimental ECD with calculated ECD. All compounds were examined for their inhibitory effects on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW264.7 cells, and compounds 3, 9, 12, and 13 exhibited certain inhibition on NO production, with IC50 values of 27.19, 41.55, 25.23, and 24.71 µM, respectively.

Comprehensive genomic analysis of adrenocortical carcinoma reveals genetic profiles associated with patient survival.

BACKGROUND: Adrenocortical carcinoma (ACC) is one of the most lethal endocrine malignancies and there is a lack of clinically useful markers for prognosis and patient stratification. Therefore our aim was to identify clinical and genetic markers that predict outcome in patients with ACC. METHODS: Clinical and genetic data from a total of 162 patients with ACC were analyzed by combining an independent cohort consisting of tumors from Yale School of Medicine, Karolinska Institutet, and Düsseldorf University (YKD) with two public databases [The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO)]. We used a novel bioinformatical pipeline combining differential expression and messenger RNA (mRNA)- and DNA-dependent survival. Data included reanalysis of previously conducted whole-exome sequencing (WES) for the YKD cohort, WES and RNA data for the TCGA cohort, and RNA data for the GEO cohort. RESULTS: We identified 3903 significant differentially expressed genes when comparing ACC and adrenocortical adenoma, and the mRNA expression levels of 461/3903 genes significantly impacted survival. Subsequent analysis revealed 45 of these genes to be mutated in patients with significantly worse survival. The relationship was significant even after adjusting for stage and age. Protein-protein interaction showed previously unexplored interactions among many of the 45 proteins, including the cancer-related proteins DNA polymerase delta 1 (POLD1), aurora kinase A (AURKA), and kinesin family member 23 (KIF23). Furthermore 14 of the proteins had significant interactions with TP53 which is the most frequently mutated gene in the germline of patients with ACC. CONCLUSIONS: Using a multiparameter approach, we identified 45 genes that significantly influenced survival. Notably, many of these genes have protein interactions not previously implicated in ACC. These findings may lay the foundation for improved prognostication and future targeted therapies.

Understanding the molecular mechanism responsible for developing therapeutic radiation-induced radioresistance of rectal cancer and improving the clinical outcomes of radiotherapy - A review.

Rectal cancer accounts for the second highest cancer-related mortality, which is predominant in Western civilizations. The treatment for rectal cancers includes surgery, radiotherapy, chemotherapy, and immunotherapy. Radiotherapy, specifically external beam radiation therapy, is the most common way to treat rectal cancer because radiation not only limits cancer progression but also significantly reduces the risk of local recurrence. However, therapeutic radiation-induced radioresistance to rectal cancer cells and toxicity to normal tissues are major drawbacks. Therefore, understanding the mechanistic basis of developing radioresistance during and after radiation therapy would provide crucial insight to improve clinical outcomes of radiation therapy for rectal cancer patients. Studies by various groups have shown that radiotherapy-mediated changes in the tumor microenvironment play a crucial role in developing radioresistance. Therapeutic radiation-induced hypoxia and functional alterations in the stromal cells, specifically tumor-associated macrophage (TAM) and cancer-associated fibroblasts (CAF), play a crucial role in developing radioresistance. In addition, signaling pathways, such as - the PI3K/AKT pathway, Wnt/ß-catenin signaling, and the hippo pathway, modulate the radiation responsiveness of cancer cells. Different radiosensitizers, such as small molecules, microRNA, nanomaterials, and natural and chemical sensitizers, are being used to increase the effectiveness of radiotherapy. This review highlights the mechanism responsible for developing radioresistance of rectal cancer following radiotherapy and potential strategies to enhance the effectiveness of radiotherapy for better management of rectal cancer.

A Review on Emerging Techniques for Diagnosis of Colorectal Cancer.

Common detection methods in practice for diagnosing colorectal cancer (CRC) are painful and invasive leading to less participation of individuals for CRC diagnosis. Whereas, improved or enhanced imaging systems and other minimally invasive techniques with shorter detection times deliver greater detail and less discomfort in individuals. Thus, this review is a summary of the diagnostic tests, ranging from the simple potential use in developing a flexible CRC treatment to the patient's potential benefits in receiving less invasive procedures and the advanced treatments that might provide a better assessment for the diagnosis of CRC and reduce the mortality related to CRC.

A concise review on miRNAs as regulators of colon cancer stem cells and associated signalling pathways

Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes (AU)

An Updated Review on Molecular Biomarkers in Diagnosis and Therapy of Colorectal Cancer.

Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of numerous new colorectal cancer biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer.

Experimental Study of Dynamic Tensile Strength of Steel-Fiber-Reinforced Self-Compacting Concrete Using Modified Hopkinson Bar.

As a typical brittle material, the tensile strength of concrete is much lower than its compressive strength. The main failure mode of concrete buildings under explosive and impact loading is spalling, so it is crucial to understand the dynamic tensile performance of concrete. This paper presents an experimental study on the dynamic tensile strength of steel-fiber-reinforced self-compacting concrete (SFRSCC). Specimens of two different self-compacting concrete (SCC) mixes (C40 and C60) and four different fiber volume fractions (0.5%, 1.0%, 1.5%, and 2.0%) are fabricated. Dynamic tensile strengths of SFRSCC are obtained using a modified Hopkinson bar system. The relationships between the dynamic tensile strength of the corresponding SCC mix, the quasi-static compressive strength, and the fiber volume fraction are discussed. An empirical equation is proposed. It is shown that SFRSCC with high compressive strength has higher dynamic tensile strength than low-strength SFRSCC for the same fiber content, and the dynamic tensile strength of SFRSCC possesses an approximately linear relation with the fiber volume fraction. The mechanism underlying this fiber-reinforcement effect is investigated.

Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN.

The TP53 and PTEN tumour suppressor genes are inactivated by nonsense mutations in a significant fraction of human tumours. TP53 nonsense mutatant tumours account for approximately one million new cancer cases per year worldwide. We have screened chemical libraries with the aim of identifying compounds that induce translational readthrough and expression of full-length p53 protein in cells with nonsense mutation in this gene. Here we describe two novel compounds with readthrough activity, either alone or in combination with other known readthrough-promoting substances. Both compounds induced levels of full-length p53 in cells carrying R213X nonsense mutant TP53. Compound C47 showed synergy with the aminoglycoside antibiotic and known readthrough inducer G418, whereas compound C61 synergized with eukaryotic release factor 3 (eRF3) degraders CC-885 and CC-90009. C47 alone showed potent induction of full-length PTEN protein in cells with different PTEN nonsense mutations. These results may facilitate further development of novel targeted cancer therapy by pharmacological induction of translational readthrough.

Research on Performance Degradation Estimation of Key Components of High-Speed Train Bogie Based on Multi-Task Learning.

The safe and comfortable operation of high-speed trains has attracted extensive attention. With the operation of the train, the performance of high-speed train bogie components inevitably degrades and eventually leads to failures. At present, it is a common method to achieve performance degradation estimation of bogie components by processing high-speed train vibration signals and analyzing the information contained in the signals. In the face of complex signals, the usage of information theory, such as information entropy, to achieve performance degradation estimations is not satisfactory, and recent studies have more often used deep learning methods instead of traditional methods, such as information theory or signal processing, to obtain higher estimation accuracy. However, current research is more focused on the estimation for a certain component of the bogie and does not consider the bogie as a whole system to accomplish the performance degradation estimation task for several key components at the same time. In this paper, based on soft parameter sharing multi-task deep learning, a multi-task and multi-scale convolutional neural network is proposed to realize performance degradation state estimations of key components of a high-speed train bogie. Firstly, the structure takes into account the multi-scale characteristics of high-speed train vibration signals and uses a multi-scale convolution structure to better extract the key features of the signal. Secondly, considering that the vibration signal of high-speed trains contains the information of all components, the soft parameter sharing method is adopted to realize feature sharing in the depth structure and improve the utilization of information. The effectiveness and superiority of the structure proposed by the experiment is a feasible scheme for improving the performance degradation estimation of a high-speed train bogie.

A concise review on miRNAs as regulators of colon cancer stem cells and associated signalling pathways.

Despite recent therapy advances and a better understanding of colon cancer biology, it remains one of the major causes of death. The cancer stem cells, associated with the progression, metastasis, and recurrence of colon cancer, play a major role in promoting the development of tumour and are found to be chemo resistant. The stroma of the tumour, which makes up the bulk of the tumour mass, is composed of the tumour microenvironment. With the advent of theranostic and the development of personalised medicine, miRNAs are becoming increasingly important in the context of colon malignancies. A holistic understanding of the regulatory roles of miRNAs in cancer cells and cancer stem cells will allow us to design effective strategies to regulate miRNAs, which could lead to improved clinical translation and creating a potent colon cancer treatment strategy. In this review paper, we briefly discuss the history of miRNA as well as the mechanisms of miRNA and cancer stem cells that contribute to the tumour growth, apoptosis, and advancement of colon cancer. The usefulness of miRNA in colorectal cancer theranostic is further concisely reviewed. We conclude by holding a stance in addressing the prospects and possibilities for miRNA by the disclosure of recent theranostic approaches aimed at eradicating cancer stem cells and enhancing overall cancer treatment outcomes.

Association of MicroRNA-652 Expression with Radiation Response of Colorectal Cancer: A Study from Rectal Cancer Patients in a Swedish Trial of Preoperative Radiotherapy.

BACKGROUND: Radiotherapy is a standard adjuvant therapy in patients with progressive rectal cancer, but many patients are resistant to radiotherapy, leading to poor prognosis. Our study identified microRNA-652 (miR-652) value on radiotherapy response and outcome in rectal cancer patients. METHODS: miR-652 expression was determined by qPCR in primary rectal cancer from 48 patients with and 53 patients without radiotherapy. The association of miR-652 with biological factors and the prognosis was examined. The biological function of miR-652 was identified through TCGA and GEPIA database searches. Two human colon cancer cell lines (HCT116 p53+/+ and p53-/-) were used for in vitro study. The molecular interactions of miR-652 and tumor suppressor genes were studied through a computational approach. RESULTS: In RT patients, miR-652 expression was significantly decreased in cancers when compared to non-radiotherapy cases (P = 0.002). High miR-652 expression in non-RT patients was with increased apoptosis marker (P = 0.036), ATM (P = 0.010), and DNp73 expression (P = 0.009). High miR-652 expression was related to worse disease-free survival of non-radiotherapy patients, independent of gender, age, tumor stage, and differentiation (P = 0.028; HR = 7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with apoptosis in rectal cancer. miR-652 expression in cancers was negatively related to WRAP53 expression (P = 0.022). After miR-652 inhibition, the estimation of reactive oxygen species, caspase activity, and apoptosis in HCT116 p53+/+ cells was significantly increased compared with HCT116 p53-/- cells after radiation. The results of the molecular docking analysis show that the miR652-CTNNBL1 and miR652-TP53 were highly stable. CONCLUSION: Our findings suggest the potential value of miR-652 expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.

CD163 as a Potential Biomarker in Colorectal Cancer for Tumor Microenvironment and Cancer Prognosis: A Swedish Study from Tissue Microarrays to Big Data Analyses.

(1) Background: CD163, a specific macrophage receptor, affects the progression of malignant tumors. Unfortunately, the regulation and expression of CD163 are poorly understood. In this study, we determined the expressions of CD163 in TMA samples from CRC patients and combined them with patient data from several Swedish hospitals. (2) Methods: The expressions of CD163 in tissue samples from CRC patients were examined. After combining 472 CRC patients' gene expression and 438 CRC patients' clinical data with the TCGA database, 964 cases from the GEO database, and experimental expression data from 1247 Swedish CRC patients, we selected four genes (PCNA, LOX, BCL2, and CD163) and analyzed the tumor-infiltrating immune cells (TICs) and CRC prognosis. (3) Results: Based on histopathological TMA analysis, CD163 was strongly expressed in the stroma of both normal and cancer tissues, and the expressions in normal and cancer cells varied from negative to strong. The results from public databases show decreased expression of CD163 in cancer tissue compared to normal mucosa (|log FC| > 1 and FDR < 0.01), and it is a negative prognostic factor for CRC patients (p-value < 0.05). Through tumor microenvironment (TME) analysis, we found a potential influence of CD163 on immune cell infiltration. Furthermore, the enrichment analysis indicated the possible interaction with other proteins and biological pathways. (4) Conclusions: CD163 is expressed differently in CRC tissue and is a negative prognostic factor. Its expression is associated with the TME and tumor purity of CRC. Considering all results, CD163 has the potential to be a predictive biomarker in the investigation of CRC.

MicroRNA34a is associated with chemotherapy resistance, metastasis, recurrence, survival, and prognosis in patient with osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the primary malignant bone tumor that most commonly affects children, adolescents, and young adults. MicroRNA-34a (miR-34a) is involved in tumor metastasis and may be a prognostic marker for patients with cancer. The aim of the present study was to explore the role of miR-34a in patients with OS. The underlying associations between miR-34a expressions and metastasis, recurrence as well as and prognosis were comprehensively analyzed in OS patients. METHODS: Reverse transcriptase quantitative PCR (RT-qPCR) was used to investigate serum level of miR-34a between clinical OS patients (n = 162) and age-matched healthy controls (n = 162). Expression of miR-34a in OS tissues and adjacent tissues was analyzed using RT-qPCR. RT-qPCR was used to compare the serum level of miR-34a in patients with OS before and after chemotherapy. Multivariate Cox-regression analysis was used to analyze the association between serum level of miR-34a and chemotherapy resistance, overall survival, as well as recurrence and prognosis of OS patients. Five-year recurrence and survival were estimated using Kaplan-Meier curves. RESULTS: Serum level of miR-34a was downregulated in OS patients (n = 86) compared to age-matched healthy controls (n = 86). Expression of miR-34a was downregulated in OS tissue compared to adjacent tissues in clinical patients. The expression of serum miR-34a before and after chemotherapy was positively correlated with the expression of miR-34a in the corresponding tissues. Expression of miR-34a was higher in the group where chemotherapy was effective than that patient where chemotherapy was ineffective. Expression of miR-34a was negatively associated with chemotherapy resistance of OS patients. High serum levels of miR-34a were associated with longer overall survival in OS patients and lower metastasis. Multivariate Cox-regression analysis identified miR-34a serum level with potential prognostic significance. CONCLUSION: The expression level of serum miR-34a in patients with OS is closely related to the chemotherapy resistance, metastasis, recurrence, and survival of osteosarcoma, which can be used as one of the potential biomarkers and prognosis for the treatment of OS patients. Therefore, miR-34a may be a potential molecular for prediction of the efficacy of chemotherapy and prognosis in OS patients.

Performance Degradation Estimation of High-Speed Train Bogie Based on 1D-ConvLSTM Time-Distributed Convolutional Neural Network.

High-speed train bogies are essential for the safety and comfort of train operation. The performance of the bogie usually degrades before it fails, so it is necessary to detect the performance degradation of a high-speed train bogie in advance. In this paper, with two key dampers on the bogie taken as experimental objects (lateral damper and yaw damper), a novel 1D-ConvLSTM time-distributed convolutional neural network (CLTD-CNN) is proposed to estimate the performance degradation of a high-speed train bogie. The proposed CLTD-CNN is an encoder-decoder structure. Specifically, the encoder part of the proposed structure consists of a time-distributed 1D-CNN module and a 1D-ConvLSTM. The decoder part consists of a 1D-ConvLSTM and a simple time-CNN with residual connections. In addition, an auxiliary training part is introduced into the structure to support CLTD-CNN in learning the performance degradation trend characteristic, and a special input format is designed for this structure. The whole structure is end-to-end and does not require expert knowledge or engineering experience. The effectiveness of the proposed CLTD-CNN is tested by the high-speed train CRH380A under different performance states. The experimental results demonstrate the superiority of CLTD-CNN. Compared to other methods, the estimation error of CLTD-CNN is the smallest.

Rare cytochalasans isolated from the mangrove endophytic fungus Xylaria arbuscula.

Four new cytochalasans, arbuschalasins A-D (1-4), along with thirteen known analogues (5-17), were isolated from the solid rice medium of endophytic fungus Xylaria arbuscula. Arbuschalasins A-B feature a rare 5/6/6/6 fused ring system while arbuschalasin D was characterized as the first example of natural cytochalasans that possesses a 5/5/11 fused scaffold. The structures of 1-4 were assigned by spectroscopic data, with their absolute structures being determined by electronic circular dichroism (ECD) calculations. All of the isolates were evaluated against the human colorectal adenocarcinoma cell lines (HCT15). Compounds 6 and 7 showed significant inhibitory effects (IC50 values were 13.5 and 13.4 µM, respectively), being more active than those of the positive control, fluorouracil (103.1 µM).

Asymmetric Total Synthesis of the Highly Strained 4ß-Acetoxyprobotryane-9ß,15α-diol.

The first and asymmetric total synthesis of 4ß-acetoxyprobotryane-9ß,15α-diol, containing a rare and highly strained trans-fused bicyclo[3.3.0]octane ring system, has been achieved. The synthetically challenging [6-5-5] tricyclic ring system in the final product was efficiently and diastereoselectively synthesized via an asymmetric rhodium-catalyzed [4 + 2] cycloaddition reaction, followed by a unique benzilic acid type rearrangement under very mild conditions. The seven contiguous stereocenters were installed efficiently and diastereoselectively.

Puerarin improves graft bone defect through microRNA­155­3p­mediated p53/TNF­α/STAT1 signaling pathway.

Bone graft defects may lead to dysfunction of bone regeneration and metabolic disorders of bone mesenchymal stem cells (BMSCs). Puerarin has demonstrated pharmacological activities in the treatment of human metabolic diseases. The purpose of the present study was to investigate the role of puerarin and to explore its possible protective mechanism of action in rats with bone grafts. A bone graft rat model was established using bone grafting surgery and the rats received puerarin or PBS. Reverse transcription­quantitative PCR, western blot, TUNEL, immunofluorescence and immunohistochemistry assays were used to analyze the beneficial effects of puerarin on bone repair. The results demonstrated that puerarin effectively ameliorated pathological graft bone defects, decreased bone loss and apoptosis of BMSCs, promoted BMSC proliferation and differentiation, and increased bone mass and the parameters of bone formation in rats with bone grafts. Puerarin decreased the levels of pro­inflammatory cytokines [tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­17A, IL­6 and transforming growth factor (TGF)­ß1] and increased the levels of anti­inflammatory cytokines (IL­2 and IL­10) in the serum compared with the PBS group. Puerarin treatment was associated with lower serum alanine transaminase, glutamic oxaloacetic transaminase, γ­glutamyl transferase, alkaline phosphatase, direct bilirubin and total bilirubin levels compared with those in the PBS group in experimental rats. The expression of microRNA­155­3p (miR­155­3p) was upregulated, whereas that of p53, TNF­α and signal transducer and activator of transcription (STAT)1 was downregulated in BMSC cultures of puerarin­treated rats. In vitro assay demonstrated that knockdown of miR­155­3p increased p53, TNF­α and STAT1 expression in BMSCs, and blocked puerarin­regulated p53/TNF­α/STAT1 signaling. Most importantly, miR­155­3p knockdown inhibited puerarin­regulated apoptosis, proliferation and differentiation of BMSCs. Moreover, the results demonstrated that puerarin regulated vascular endothelial growth factor expression via the miR­155­3p signaling pathway. In conclusion, the results of the present study demonstrated that the upregulation of miR­155­3p induced by puerarin promoted BMSC differentiation and bone formation and increased bone mass in rats with bone grafts, thereby supporting the potential application of puerarin in the prevention of bone graft defects.

Tigliane Diterpenoids as a New Type of Antiadipogenic Agents Inhibit GRα-Dexras1 Axis in Adipocytes.

The phytochemical study of Euphorbia prolifera led to the isolation of two tiglianes (1 and 2) and 23 mysrinanes (3-25). Most of these isolates showed significant antiadipogenic activity in 3T3-L1 adipocyte without apparent cytotoxicity. Subsequent structural modification yielded 10 derivatives, among which 1a, the 5- O-acetyl derivative of 1, turned out to be the most active compound with improved triglyceride-lowering activity (EC50 for 1 and 1a: 0.61 and 0.32 µM, respectively) and reduced cytotoxicity (selectivity index for 1 and 1a: 28 and 312, respectively). The structure-activity relationship study revealed that the trans-fused 5/7/6 ring system in an angular shape was important to the activity. A mechanistic study indicated that 1 and 1a could inhibit the glucocorticoid receptor α-Dexras1 axis in adipocyte, leading to the retardation of cell differentiation at the early stage. These findings may provide a new type of lipid-lowering agents for future antiobesity drug development.

Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway.

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

Geospallins A⁻C: New Thiodiketopiperazines with Inhibitory Activity against Angiotensin-Converting Enzyme from a Deep-Sea-Derived Fungus Geosmithia pallida FS140.

Three new thiodiketopiperazines, geospallins A⁻C (1⁻3), together with nine known analogues (4⁻12), were isolated from the culture of the deep-sea sediment-derived fungus Geosmithia pallida FS140. Among them, geospallins A and B (1 and 2) represent rare examples of thiodiketopiperazines featuring an S-methyl group at C-10 and a tertiary hydroxyl group at C-11. Their structures were determined by high-resolution electrospray mass spectrometry (HRESIMS), spectroscopic analyses, and electronic circular dichroism (ECD) calculations. Their angiotensin-converting enzyme (ACE) inhibitory activity was reported, and geospallins A⁻C (1⁻3) showed inhibitory activity with IC50 values of 29⁻35 µM.