Curcuma xanthorrhiza extract and xanthorrhizol ameliorate cancer-induced adipose wasting in CT26-bearing mice by regulating lipid metabolism and adipose tissue browning.

Background: Cancer cachexia-characterized by anorexia, body weight loss, skeletal muscle atrophy, and fat loss-affects nearly 80% of cancer patients and accounts for 20% of cancer deaths. Curcuma xanthorrhiza, known as Java turmeric, and its active compound xanthorrhizol (XAN) exhibit anticancer, anti-inflammatory, and antioxidant properties. However, the ameliorative effects of C. xanthorrhiza extract (CXE) and XAN on cancer-associated adipose atrophy remain unexplored. This study aimed to evaluate the therapeutic effects of CXE and XAN on cancer cachexia-induced adipose tissue wasting in CT26 tumor-bearing mice. Methods: CT26 cells were injected subcutaneously into the right flank of BALB/c mice to establish a cancer cachexia model. To evaluate the inhibitory effects of CXE and XAN on cancer cachexia, 50 and 100 mg/kg CXE and 15 mg/kg XAN were administered orally every day for 1 week. Results: CXE and XAN administration significantly attenuated the loss of body weight and epidydimal fat mass by cancer cachexia. In epididymal adipose tissues, administration of CXE or XAN inhibited white adipose tissue browning by repressing expression of the thermogenic genes. Simultaneously, CXE or XAN attenuated fat catabolism through the downregulation of lipolytic genes. The administration of CXE or XAN induced the expression of genes associated with adipogenesis and lipogenesis-related genes. Moreover, CXE or XAN treatment was associated with maintaining metabolic homeostasis; regulating the expression of adipokines and AMP-activated protein kinase (AMPK). Conclusions: CXE and XAN mitigate cancer-induced adipose tissue atrophy, primarily by modulating lipid metabolism and WAT browning, indicating their therapeutic potential for cachectic cancer patients.

Aquaporin-4-IgG positive neuromyelitis optica spectrum disorder in a paraneoplastic context.

OBJECTIVE: The association between aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and cancer via a plausible immunological response has been reported. Here, we investigated the frequency of cancer in a large cohort of patients with AQP4-IgG-NMOSD. METHODS: Between May 2005 and January 2023, patients with AQP4-IgG-NMOSD and a history of cancer were included by searching for diagnostic codes of both NMOSD and cancer in the electronic medical records and/or reviewing the database of the National Cancer Center registry of inflammatory diseases of the central nervous system. Probable paraneoplastic AQP4-IgG-NMOSD was defined according to the 2021 Criteria for Paraneoplastic Neurological Syndrome. RESULTS: Of 371 patients with AQP4-IgG-NMOSD, 23 (6.2%) had a history of cancer and four (1.1%) experienced NMOSD in a paraneoplastic context. Among the four patients with probable paraneoplastic AQP4-IgG-NMOSD, the types of cancer were lung (1 adenocarcinoma, 1 squamous cell carcinoma) and colorectal (2 adenocarcinomas). In three patients, the first NMOSD symptoms developed after a cancer diagnosis (median, 8 months [range, 4-23]), and one patient's symptoms preceded the cancer diagnosis (6 months). Compared to the 367 non-paraneoplastic patients, those in the paraneoplastic context had an older age at onset (median: 59.5 vs. 37 years, p = 0.012) and a higher proportion of longitudinally extensive transverse myelitis (LETM) as an initial manifestation (4/4[100%] vs. 130/367[35.4%], p = 0.017). CONCLUSIONS: In a large cohort of patients with AQP4-IgG-NMOSD, the frequency of cancer was low. Older age, LETM features at onset, and adenocarcinoma as the histological type were usually observed in patients with AQP4-IgG-NMOSD in a paraneoplastic context.

The Phytophthora capsici RxLR effector CRISIS2 triggers cell death via suppressing plasma membrane H+-ATPase in the host plant.

Pathogen effectors can suppress various plant immune responses, suggesting that they have multiple targets in the host. To understand the mechanisms underlying plasma membrane-associated and effector-mediated immunity, we screened the Phytophthora capsici RxLR cell death-inducer suppressing immune system (CRISIS). We found that the cell death induced by the CRISIS2 effector in Nicotiana benthamiana was inhibited by the irreversible plasma membrane H+-ATPase (PMA) activator fusicoccin. Biochemical and gene-silencing analyses revealed that CRISIS2 physically and functionally associated with PMAs and induced host cell death independent of immune receptors. CRISIS2 induced apoplastic alkalization by suppressing PMA activity via its association with the C-terminal regulatory domain. In planta expression of CRISIS2 significantly enhanced the virulence of P. capsici, whereas host-induced gene-silencing of CRISIS2 compromised the disease symptoms and the biomass of the pathogen. Thus, our study has identified a novel RxLR effector that plays multiple roles in the suppression of plant defense and in the induction of cell death to support the pathogen hemibiotrophic life cycle in the host plant.

Mannosylated poly(acrylic acid)-coated mesoporous silica nanoparticles for anticancer therapy.

Although mesoporous silica nanoparticles (MSNs) are widely used as anticancer drug carriers, unmodified MSNs induce off-target effects and at high doses, there are adverse effects of hemolysis because of the interaction with the silanol group on the surface and cells. In this study, we developed doxorubicin (DOX)-loaded MSNs coated with mannose grafted poly (acrylic acid) copolymer (DOX@MSNs-man-g-PAA) to enhance the hemocompatibility and target efficacy to cancer cells. This uniform nanosized DOX@MSNs-man-g-PAA showed sustained and pH-dependent drug release with improved hemocompatibility over the bare MSNs. The uptake of the DOX@MSN-man-g-PAA in breast cancer cells was significantly improved by mannose receptor-mediated endocytosis, which showed significant increasing intracellular ROS and changes in mitochondrial membrane potential. This formulation exhibited superior tumor-suppressing activity in the MDA-MB-231 cells inoculated mice. Overall, the present study suggested the possibility of the copolymer-coated MSNs as drug carriers for cancer therapy.

Plasma membrane-localized plant immune receptor targets H+ -ATPase for membrane depolarization to regulate cell death.

The hypersensitive response (HR) is a robust immune response mediated by nucleotide-binding, leucine-rich repeat receptors (NLRs). However, the early molecular event that links activated NLRs to cell death is unclear. Here, we demonstrate that NLRs target plasma membrane H+ -ATPases (PMAs) that generate electrochemical potential, an essential component of living cells, across the plasma membrane. CCA 309, an autoactive N-terminal domain of a coiled-coil NLR (CNL) in pepper, is associated with PMAs. Silencing or overexpression of PMAs reversibly affects cell death induced by CCA 309 in Nicotiana benthamiana. CCA 309-induced extracellular alkalization causes plasma membrane depolarization, followed by cell death. Coimmunoprecipitation analyses suggest that CCA 309 inhibits PMA activation by preoccupying the dephosphorylated penultimate threonine residue of PMA. Moreover, pharmacological experiments using fusicoccin, an irreversible PMA activator, showed that inhibition of PMAs contributes to CNL-type (but not Toll interleukin-1 receptor NLR-type) resistance protein-induced cell death. We suggest PMAs as primary targets of plasma membrane-associated CNLs leading to HR-associated cell death by disturbing the electrochemical gradient across the membrane. These results provide new insight into NLR-mediated cell death in plants, as well as innate immunity in higher eukaryotes.

Anti-Angiogenic Property of Free Human Oligosaccharides.

Angiogenesis, a fundamental process in human physiology and pathology, has attracted considerable attention owing to its potential as a therapeutic strategy. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are deemed major mediators of angiogenesis. To date, inhibition of the VEGF-A/VEGFR-2 axis has been an effective strategy employed in the development of anticancer drugs. However, some limitations, such as low efficacy and side effects, need to be addressed. Several drug candidates have been discovered, including small molecule compounds, recombinant proteins, and oligosaccharides. In this review, we focus on human oligosaccharides as modulators of angiogenesis. In particular, sialylated human milk oligosaccharides (HMOs) play a significant role in the inhibition of VEGFR-2-mediated angiogenesis. We discuss the structural features concerning the interaction between sialylated HMOs and VEGFR-2 as a molecular mechanism of anti-angiogenesis modulation and its effectiveness in vivo experiments. In the current state, extensive clinical trials are required to develop a novel VEGFR-2 inhibitor from sialylated HMOs.

Evaluation of Antioxidant Activity of Cudrania tricuspidata (CT) Leaves, Fruit Powder and CT Fruit in Pork Patties during Storage.

The objective of this study was to assess antioxidant activities of leaves and fruit powder of Cudrania tricuspidata (CT) with different particle sizes (crude, 500 µm, 150 µm), and determine the physicochemical properties and microbial counts of pork patties with various levels of CT fruit powder (CTFP) during refrigerated storage. Total phenolic content of crude leaves had the highest value of 3.54 g/100 g (p<0.05). Overall, CT leaves (CTLP) had higher total phenolic content than CTFP (p<0.05). 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity of CTFP was higher than that of CTLP (p<0.05), which showed higher iron chelating ability and reducing power than CTFP (p<0.05). After pork patties were manufactured with 0.5% and 1.0% of CTFP at 500 µm, pH, color values, thiobarbituric acid reactive substance (TBARS), and peroxide values (POV) were then measured. The addition of CTFP into pork patties significantly (p<0.05) increased redness and yellowness values of patties. TBARS values of pork patties containing CTFP were lower (p<0.05) than those of CTFP-0 patties after 10 days of storage. Pork patties added with CTFP showed no significant (p>0.05) difference TBARS values among different storage periods. POV values of pork patties containing CTFP were lower than those of the control from 3 days up to the end of refrigerated storage (p<0.05). These results suggest that CTFP could be used as a natural antioxidant to retard lipid oxidation in meat products during refrigerated storage.

FAM188B Expression Is Critical for Cell Growth via FOXM1 Regulation in Lung Cancer.

Although family with sequence similarity 188 member B (FAM188B) is known to be a member of a novel putative deubiquitinase family, its biological role has not been fully elucidated. Here, we demonstrate the oncogenic function of FAM188B via regulation of forkhead box M1 (FOXM1), another oncogenic transcription factor, in lung cancer cells. FAM188B knockdown induced the inhibition of cell growth along with the downregulation of mRNA and protein levels of FOXM1. FAM188B knockdown also resulted in downregulation of Survivin and cell cycle-related proteins, which are direct targets of FOXM1. Interestingly, FOXM1 co-immunoprecipitated with FAM188B, and the levels of FOXM1 ubiquitination increased with FAM188B knockdown but decreased with FAM188B overexpression. In addition, in vivo xenograft of FAM188B siRNA (siFAM188B) RNA-treated cells resulted in the retardation of tumor growth compared with that in the control. Furthermore, protein levels of FAM188B and FOXM1 were elevated in the human lung cancer tissues, and FAM188B expression was negatively correlated with the overall survival of lung cancer patients. These results indicate that FAM188B exerts its oncogenic effects by regulating FOXM1 deubiquitination and thus its stability. Therefore, FAM188B might be a potential therapeutic target to control lung cancer progression.

EHMT2 Inhibition Induces Cell Death in Human Non-Small Cell Lung Cancer by Altering the Cholesterol Biosynthesis Pathway.

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Besides genetic and environmental factors, epigenetic alterations contribute to the tumorigenesis of NSCLC. Epigenetic changes are considered key drivers of cancer initiation and progression, and altered expression and activity of epigenetic modifiers reshape the epigenetic landscape in cancer cells. Euchromatic histone-lysine N-methyltransferase 2 (EHMT2) is a histone methyltransferase and catalyzes mono- and di-methylation at histone H3 lysine 9 (H3K9me1 and H3K9me2, respectively), leading to gene silencing. EHMT2 overexpression has been reported in various types of cancer, including ovarian cancer and neuroblastoma, in relation to cell proliferation and metastasis. However, its role in NSCLC is not fully understood. In this study, we showed that EHMT2 gene expression was higher in NSCLC than normal lung tissue based on publicly available data. Inhibition of EHMT2 by BIX01294 (BIX) reduced cell viability of NSCLC cell lines via induction of autophagy. Through RNA sequencing analysis, we found that EHMT2 inhibition significantly affected the cholesterol biosynthesis pathway. BIX treatment directly induced the expression of SREBF2, which is a master regulator of cholesterol biosynthesis, by lowering H3K9me1 and H3K9me2 at the promoter. Treatment of a cholesterol biosynthesis inhibitor, 25-hydroxycholesterol (25-HC), partially recovered BIX-induced cell death by attenuating autophagy. Our data demonstrated that EHMT2 inhibition effectively induced cell death in NSCLC cells through altering cholesterol metabolism-dependent autophagy.

Links between Serine Biosynthesis Pathway and Epigenetics in Cancer Metabolism.

Cancer metabolism is considered as one of major cancer hallmarks. It is important to understand cancer-specific metabolic changes and its impact on cancer biology to identify therapeutic potentials. Among cancer-specific metabolic changes, a role of serine metabolism has been discovered in various cancer types. Upregulation of serine synthesis pathway (SSP) supports cell proliferation and metastasis. The change of serine metabolism is, in part, mediated by epigenetic modifiers, such as Euchromatic histone-lysine N-methyltransferase 2 and Lysine Demethylase 4C. On the other hand, SSP also influences epigenetic landscape such as methylation status of nucleic acids and histone proteins via affecting S-adenosyl methionine production. In the review, we highlight recent evidences on interactions between SSP and epigenetic regulation in cancer. It may provide an insight on roles and regulation of SSP in cancer metabolism and the potential of serine metabolism for cancer therapy.

Red Pepper (Capsicum annuum L.) Seed Extract Decreased Hepatic Gluconeogenesis and Increased Muscle Glucose Uptake In Vitro.

Red pepper seed, a by-product of red pepper, has been reported to have antioxidant and antiobesity activities. However, its role in diabetes has not yet been highly investigated. Glucose homeostasis is mainly maintained by insulin, which suppresses glucose production in the liver and enhances glucose uptake in peripheral tissues. In this study, we investigated the underlying mechanisms through which red pepper seed extract (RPSE) affects glucose production in AML12 hepatocytes and glucose uptake in C2C12 myotubes. RPSE reduced glucose production in a dose-dependent manner in AML12 cells. The levels of glucose 6 phosphatase, phosphoenolpyruvate carboxykinase, and critical enzymes for hepatic gluconeogenesis were decreased by RPSE. Gluconeogenesis regulating proteins, Akt and forkhead box protein O1, were also activated by RPSE. In addition, RPSE increased glucose uptake in C2C12 via inducing translocation of glucose transporter type 4 from cytosol to plasma membrane. Analysis of the insulin-dependent pathway showed that the activities of insulin receptor substrate 1, phosphatidylinositol 3-kinase, and Akt were significantly stimulated by RPSE. In conclusion, RPSE might improve glucose homeostasis by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. Results obtained also suggest that RPSE can be a compelling antidiabetic nutraceutical.

Acute Type A Aortic Dissection Causing Collapse of Previous Stent Graft.

A 69-year-old man presented to the emergency department with back pain and paraplegia. Computed tomography showed acute type A aortic dissection with a primary tear right below the origin of the left subclavian artery. He had undergone endovascular aneurysm repair 13 months earlier, and the previously inserted endovascular graft had totally collapsed. Total arch replacement covering the primary entry tear was performed. Femoral pulse was undetected before the operation but was monitored postsurgically after cardiopulmonary bypass was weaned. The patient was discharged from the hospital on foot without an additional intervention.

Medium-Chain Enriched Diacylglycerol (MCE-DAG) Oil Decreases Body Fat Mass in Mice by Increasing Lipolysis and Thermogenesis in Adipose Tissue.

Medium chain fatty acid (MCFA) escapes the formation of chylomicrons in the small intestine, resulting in energy expenditure through beta-oxidation. Diacylglycerol (DAG) is susceptible to oxidation rather than being stored in the adipose tissue. This study was conducted to verify the effect of MCE-DAG oil on body fat mass in vivo. Male C57BL/6 mice were randomly assigned to four groups (n = 12) as follows: (1) normal diet (18% kcal from fat), (2) canola oil as a control (40% kcal from canola oil), (3) MCE-DAG10 (10% kcal from MCE-DAG + 30% kcal from canola oil), and (4) MCE-DAG20 (20% kcal from MCE-DAG + 20% kcal from canola oil). The body weight and fat mass of MCE-DAG20 group mice were decreased relative to those of control mice (P < 0.05 and P < 0.001, respectively). Serum triacylglycerol (TAG) was decreased in both MCE-DAG10 and MCE-DAG20 groups (P < 0.01 and P < 0.05, respectively). Hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) were increased in the MCE-DAG20 group relative to the control in white adipose tissue (WAT) (P < 0.05). Uncoupling protein 1 (UCP1) was also increased in the MCE-DAG20 group relative to the control in brown adipose tissue (BAT) (P < 0.05). In summary, MCE-DAG reduced body fat mass likely by stimulating lipolysis in WAT and thermogenesis in BAT.