First Report of Paramyrothecium breviseta Causing Target Spot on Amorphophallus muelleri in Yunnan, China.

Amorphophallus muelleri is an Araceae plant with perennial tuber, widely used in food, pharmaceutical and chemical industry due to its richness in glucomannan. In April 2022, an outbreak of a target spot on A. muelleri plantlets was observed in a nursery in Ruili, Yunnan, China. The leafstalks of the diseased plantlets in the nursery turned brown and decayed (Fig.1 A-B), then gradually some water-soaked spots on the true leaves developed along the veins (Fig.1 A). Subquencely, the spots on the true leaves turned dark green to white-grayish in the center, which formed light to dark brown concentric rings with a target-like appearance surrounded by a yellow halo (Fig.1 C). When the temperature was 20-34℃ and the relatively humidity was 25-80%, dark-green to black sporodochia with white hypha appeared on the lower and upper leaf surfaces. Finally, 5-8% of the plants surveyed on 800 m2 of one-year-old plantlets in the nursery showed the symptoms and some plants with infected leafstalks would be death. Similar symptoms were also observed on about 10% of the transplanted plants surveyed on 12000 m2 (1.2 ha) of two-year-old plantlets in the field. Five diseased leaves from five distinct plantlets in the nursery were collected for pathogen isolation. Leaf pieces(5 x 5 mm) were cut from the edge of necrotic lesions, and surface-sterilized with 2.5% sodium hypochlorite for 1 min, 75% ethanol for 30 s, then rinsed 5 times by sterilized distilled water, finally put the leaf pieces on sterilized filter paper for 3-5 minutes to dry them and transferred onto potato dextrose agar (PDA) in petri dishes at 25℃ for three days. Five pure cultures identical to colony and conidial characteristics were isolated from five individual plants. The representative pure culture (M1) was grayish-white and circular colonies were 7.50 cm in diamter after 15 days at 25℃, with dark green concentric rings of sporodochia, the dorsal view of the colonies were yellowish. Conidia were aseptate, smooth, cylindrical, 5.00-6.25 (5.71) x 1.25-1.67 (1.63) µm (n = 20) rounded at both ends. A spore suspension (1 x 106 spores/ml) was prepared by harvesting spores from 15-day-old cultures grown in the dark at 25℃, then a thirty-ml of spore suspension was sprayed on the healthy leaves of 10 two-year-old plantlets. Thirty-ml of sterile water was sprayed on the healthy leaves of another 10 seedlings and used as the control. All seedlings were placed in a nursery at 20 to 34℃ and a relative humidity of 25 to 80%. Similar symptoms (Fig.1 D-F) to those observed in the nursery and field developed on all the 10 seedlings inoculated with M1 after two days, but not on the control leaves. The pathogenicity tests were repeated for three times. Fungal cultures reisolated from the infected leaves were identical to the original colonies and conidia, completing Koch's postulates. The internal transcribed spacer (ITS, primers ITS1 and ITS4) region of ribosomal DNA (OQ553785), calmodulin (cmdA, primers CAL-228F and CAL2Rd)(OQ559103), RNA polymerase II second largest subunit (rpb2, primers RPB2-5F2 and RPB2-7cR) (OQ559104) and ß-tubulin (tub2, primers Bt2a and Bt2b) (OQ559105) of M1 had 100%, 98.52%, 98.98% and 98.98% identity with the sequences of Paramyrothecium breviseta CBS544.75 (KU846289 for ITS, KU846262 for cmdA, KU846351 for rpb2, and KU846406 for tub2), respectively. In the phylogenic tree based on ITS, cmdA, rpb2 and tub2 gene sequences, the pure culture M1 clustered with P. breviseta CBS544.75, SDBR-CMU387, DRL4 and DRL3, which has been reported as the pathogen of leaf spot of Coffea arabica in China, C. canephora in China and Thailand (Wu et al. 2021; Withee et al. 2022). Molecular and morphological observations showed the pure culture M1 were P. breviseta (Withee et al. 2022), in addition the disease was named as target spot dueing to the typical target symptom on the leaves. To our knowledge, this is the first report of P. breviseta on A. muelleri from Yunnan, China, as well as worldwide. This disease can caused serious economic losses of A. muelleri dueing to that it can result 5-8% death of the plants in the nursery.

Access Polyarylbipyrazoles via Palladium-Catalysis and Visible-Light-Driven C(sp3)-P(V) Cleavage Relay Strategy.

An unprecedented palladium-catalyzed and visible-light-driven relay reaction of allenylphosphine oxide with in situ generated nitrile imines is presented for the direct synthesis of highly valuable polyarylbipyrazole skeletons. This one-pot strategy involves double 1,3-dipolar cycloaddition and C(sp3)-P(V) bond cleavage under photocatalyst-free and mild reaction conditions. The approach features simple operation, a high step economy, and a broad substrate scope, affording the corresponding products in moderate to excellent yields.

ABHD7-mediated depalmitoylation of lamin A promotes myoblast differentiation.

LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/ß hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.

Subarctic winter warming promotes soil microbial resilience to freeze-thaw cycles and enhances the microbial carbon use efficiency.

Climate change is predicted to cause milder winters and thus exacerbate soil freeze-thaw perturbations in the subarctic, recasting the environmental challenges that soil microorganisms need to endure. Historical exposure to environmental stressors can facilitate the microbial resilience to new cycles of that same stress. However, whether and how such microbial memory or stress legacy can modulate microbial responses to cycles of frost remains untested. Here, we conducted an in situ field experiment in a subarctic birch forest, where winter warming resulted in a substantial increase in the number and intensity of freeze-thaw events. After one season of winter warming, which raised mean surface and soil (-8 cm) temperatures by 2.9 and 1.4°C, respectively, we investigated whether the in situ warming-induced increase in frost cycles improved soil microbial resilience to an experimental freeze-thaw perturbation. We found that the resilience of microbial growth was enhanced in the winter warmed soil, which was associated with community differences across treatments. We also found that winter warming enhanced the resilience of bacteria more than fungi. In contrast, the respiration response to freeze-thaw was not affected by a legacy of winter warming. This translated into an enhanced microbial carbon-use efficiency in the winter warming treatments, which could promote the stabilization of soil carbon during such perturbations. Together, these findings highlight the importance of climate history in shaping current and future dynamics of soil microbial functioning to perturbations associated with climate change, with important implications for understanding the potential consequences on microbial-mediated biogeochemical cycles.

Whether including exotic species alters conservation prioritization: a case study in the Min River in southeastern China.

Conservation practices from the perspective of functional diversity (FD) and conservation prioritization need to account for the impacts of exotic species in freshwater ecosystems. This work first simulated the influence of exotic species on the values of FD in a schemed mechanistic model, and then a practical case study of conservation prioritization was performed in the Min River, the largest river in southeastern China, to discuss whether including exotic species alters prioritization. The mechanistic model revealed that exotic species significantly altered the expected FD if the number of exotic species occupied 2% of the community. Joint species distribution modelling indicated that the highest FD occurred in the west, northwest and north upstreams of the Min River. Values of FD in 64.69% of the basin decreased after the exotic species were removed from calculation. Conservation prioritization with the Zonation software proved that if first the habitats of exotic species were removed during prioritization, 62.75% of the highest prioritized areas were shifted, average species representation of the endemic species was improved and mean conservation efficiency was increased by 7.53%. Existence of exotic species will significantly alter the metrics of biodiversity and the solution for conservation prioritization, and negatively weighting exotic species in the scope of conservation prioritization is suggested to better protect endemic species. This work advocates a thorough estimate of the impacts of exotic species on FD and conservation prioritization, providing complementary evidence for conservation biology and valuable implications for local freshwater fish conservation.

Comparison of Short-Term Outcomes After Robotic Versus Laparoscopic Radical Gastrectomy for Advanced Gastric Cancer in Elderly Individuals: A Propensity Score-Matching Study.

BACKGROUND: Robotic gastrectomy (RG) has been widely used to treat gastric cancer. However, whether the short-term outcomes of robotic gastrectomy are superior to those of laparoscopic gastrectomy (LG) for elderly patients with advanced gastric cancer has not been reported. METHODS: The study enrolled of 594 elderly patients with advanced gastric cancer who underwent robotic or laparoscopic radical gastrectomy. The RG cohort was matched 1:3 with the LG cohort using propensity score-matching (PSM). RESULTS: After PSM, 121 patients were included in the robot group and 363 patients in the laparoscopic group. Excluding the docking and undocking times, the operation time of the two groups was similar (P = 0.617). The RG group had less intraoperative blood loss than the LG group (P < 0.001). The time to ambulation and first liquid food intake was significantly shorter in the RG group than in the LG group (P < 0.05). The incidence of postoperative complications did not differ significantly between the two groups (P = 0.14). Significantly more lymph nodes were dissected in the RG group than in the LG group (P = 0.001). Postoperative adjuvant chemotherapy was started earlier in the RG group than in the LG group (P = 0.02). CONCLUSIONS: For elderly patients with advanced gastric cancer, RG is safe and feasible. Compared with LG, RG is associated with less intraoperative blood loss; a faster postoperative recovery time, allowing a greater number of lymph nodes to be dissected; and earlier adjuvant chemotherapy.

Icariin improves cardiac function and remodeling via the TGF-ß1/Smad signaling pathway in rats following myocardial infarction.

BACKGROUND: Postinfarction cardiac remodeling presents a compensatory mechanism aimed at mitigating congestive heart failure. It is distinguished by progressive dilatation and hypertrophy of the ventricular chambers, fibrotic alterations, and prolonged apoptosis of cardiomyocytes. The primary objective of this study was to assess the effects of icariin on myocardial fibrosis and ventricular remodeling in rats subjected to myocardial infarction (MI). METHODS: Male Sprague‒Dawley (SD) rats were subjected to randomization and subsequently divided into distinct groups: the control group, the sham group (undergoing sham operation), the MI group (experiencing ligation of the left anterior descending artery), and the icariin group. Within the icariin group, rats were further categorized into three different dose groups based on the administered icariin dosage: the MI30 group (30 mg/kg/day), the MI60 group (60 mg/kg/day), and the MI120 group (120 mg/kg/day). Cardiac function evaluation was carried out using echocardiography. Histological examinations, including hematoxylin and eosin (HE) staining, Masson staining, and immunohistochemistry studies, were conducted 90 days after the occurrence of MI. Additionally, Western blotting was employed to assess TGF-ß1, p-Smad2, and p-Smad3 levels. RESULTS: The administration of icariin revealed a noteworthy enhancement in cardiac function among rats afflicted with left anterior descending coronary artery (LAD) ligation. In comparison to the icariin groups, the MI group exhibited reduced EF and FS, along with elevated LVEDD and LVESD. Furthermore, the cardiac fibrosis levels in the MI group rats exhibited a considerable increase compared to those in the icariin group. Notably, the levels of Collagen I, Collagen III, MMP2, and MMP9 were significantly higher in the MI group than in the icariin group, with evident distinctions. Moreover, the expression levels of TGF-ß, IL-13, p-Smad2, and p-Smad3 were notably upregulated in the MI group compared to the icariin group. CONCLUSIONS: In an experimental rat model of MI, the administration of icariin resulted in the amelioration of both cardiac function and remodeling processes, operating through the intricate TGF-ß1/Smad signaling pathway.

Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9.

OBJECTIVE: To explore whether the ethanol extract of Herpetospermum caudigerum Wall (EHC), a Xizang medicinal plant traditionally used for treating liver diseases, can improve imiquimod-induced psoriasis-like skin inflammation. METHODS: Immunohistochemistry and immunofluorescence staining were used to determine the effects of topical EHC use in vivo on the skin pathology of imiquimod-induced psoriasis in mice. The protein levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17A (IL-17A) in mouse skin samples were examined using immunohistochemical staining. In vitro, IFN-γ-induced HaCaT cells with or without EHC treatment were used to evaluate the expression of keratinocyte-derived intercellular cell adhesion molecule-1 (ICAM-1) and chemokine CXC ligand 9 (CXCL9) using Western blotting and reverse transcription-quantitative polymerase chain reaction. The protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132 were utilized to validate the EHC-mediated mechanism underlying degradation of ICAM-1 and CXCL9. RESULTS: EHC improved inflammation in the imiquimod-induced psoriasis mouse model and reduced the levels of IFN-γ, TNF-α, and IL-17A in psoriatic lesions. Treatment with EHC also suppressed ICAM-1 and CXCL9 in epidermal keratinocytes. Further mechanistic studies revealed that EHC suppressed keratinocyte-derived ICAM-1 and CXCL9 by promoting ubiquitin-proteasome-mediated protein degradation rather than transcriptional repression. Seven primary compounds including ehletianol C, dehydrodiconiferyl alcohol, herpetrione, herpetin, herpetotriol, herpetetrone and herpetetrol were identified from the EHC using ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry. CONCLUSION: Topical application of EHC ameliorates psoriasis-like skin symptoms and improves the inflammation at the lesion sites. Please cite this article as: Zhong Y, Zhang BW, Li JT, Zeng X, Pei JX, Zhang YM, Yang YX, Li FL, Deng Y, Zhao Q. Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9. J Integr Med. 2023; 21(6): 584-592.

Temperature fluctuation promotes the thermal adaptation of soil microbial respiration.

The magnitude of the feedback between soil microbial respiration and increased mean temperature may decrease (a process called thermal adaptation) or increase over time, and accurately representing this feedback in models improves predictions of soil carbon loss rates. However, climate change entails changes not only in mean temperature but also in temperature fluctuation, and how this fluctuation regulates the thermal response of microbial respiration has never been systematically evaluated. By analysing subtropical forest soils from a 2,000 km transect across China, we showed that although a positive relationship between soil microbial biomass-specific respiration and temperature was observed under increased constant incubation temperature, an increasing temperature fluctuation had a stronger negative effect. Our results further indicated that changes in bacterial community composition and reduced activities of carbon degradation enzymes promoted the effect of temperature fluctuation. This adaptive response of soil microbial respiration suggests that climate warming may have a lesser exacerbating effect on atmospheric CO2 concentrations than predicted.

Low soil moisture suppresses the thermal compensatory response of microbial respiration.

The thermal compensatory response of microbial respiration contributes to a decrease in warming-induced enhancement of soil respiration over time, which could weaken the positive feedback between the carbon cycle and climate warming. Climate warming is also predicted to cause a worldwide decrease in soil moisture, which has an effect on the microbial metabolism of soil carbon. However, whether and how changes in moisture affect the thermal compensatory response of microbial respiration are unexplored. Here, using soils from an 8-year warming experiment in an alpine grassland, we assayed the thermal response of microbial respiration rates at different soil moisture levels. The results showed that relatively low soil moisture suppressed the thermal compensatory response of microbial respiration, leading to an enhanced response to warming. A subsequent moisture incubation experiment involving off-plot soils also showed that the response of microbial respiration to 100 d warming shifted from a slight compensatory response to an enhanced response with decreasing incubation moisture. Further analysis revealed that such respiration regulation by moisture was associated with shifts in enzymatic activities and carbon use efficiency. Our findings suggest that future drought induced by climate warming might weaken the thermal compensatory capacity of microbial respiration, with important consequences for carbon-climate feedback.

Prediction of recurrence-free survival and adjuvant therapy benefit in patients with gastrointestinal stromal tumors based on radiomics features.

OBJECTIVE: Development and validation of a radiomics nomogram for predicting recurrence and adjuvant therapy benefit populations in high/intermediate-risk gastrointestinal stromal tumors (GISTs) based on computed tomography (CT) radiomic features. METHODS: Retrospectively collected from 2009.07 to 2015.09, 220 patients with pathological diagnosis of intermediate- and high-risk stratified gastrointestinal stromal tumors and received imatinib treatment were randomly divided into (6:4) training cohort and validation cohort. The 2D-tumor region of interest (ROI) was delineated from the portal-phase images on contrast-enhanced (CE) CT, and radiological features were extracted. The most valuable radiological features were obtained using a Lasso-Cox regression model. Integrated construction was conducted of nomograms of radiomics characteristics to predict recurrence-free survival (RFS) in patients receiving adjuvant therapy. RESULTS: Eight radiomic signatures were finally selected. The area under the curve (AUC) of the radiomics signature model for predicting 3-, 5-, and 7-year RFS in the training and validation cohorts (training cohort AUC = 0.80, 0.84, 0.76; validation cohort AUC = 0.78, 0.80, 0.76). The constructed radiomics nomogram was more accurate than the clinicopathological nomogram for predicting RFS in GIST (C-index: 0.864 95%CI, 0.817-0.911 vs. 0.733 95%CI, 0.675-0.791). Kaplan-Meier survival curve analysis showed a greater benefit from adjuvant therapy in patients with high radiomics scores (training cohort: p < 0.0001; validation cohort: p = 0.017), while there was no significant difference in the low-score group (p > 0.05). CONCLUSION: In this study, a nomogram constructed based on preoperative CT radiomics features could be used for RFS prediction in high/intermediate-risk GISTs and assist the clinical decision-making for GIST patients.

Diet high in branched-chain amino acid promotes PDAC development by USP1-mediated BCAT2 stabilization.

BCAT2-mediated branched-chain amino acid (BCAA) catabolism is critical for pancreatic ductal adenocarcinoma (PDAC) development, especially at an early stage. However, whether a high-BCAA diet promotes PDAC development in vivo, and the underlying mechanism of BCAT2 upregulation, remain undefined. Here, we find that a high-BCAA diet promotes pancreatic intraepithelial neoplasia (PanIN) progression in LSL-KrasG12D/+ ; Pdx1-Cre (KC) mice. Moreover, we screened with an available deubiquitylase library which contains 31 members of USP family and identified that USP1 deubiquitylates BCAT2 at the K229 site. Furthermore, BCAA increases USP1 protein at the translational level via the GCN2-eIF2α pathway both in vitro and in vivo. More importantly, USP1 inhibition recedes cell proliferation and clone formation in PDAC cells and attenuates pancreas tumor growth in an orthotopic transplanted mice model. Consistently, a positive correlation between USP1 and BCAT2 is found in KC; LSL-KrasG12D/+ ; p53flox/+ ; Pdx1-Cre mice and clinical samples. Thus, a therapeutic targeting USP1-BCAT2-BCAA metabolic axis could be considered as a rational strategy for treatment of PDAC and precisive dietary intervention of BCAA has potentially translational significance.

Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA.

Folic acid, served as dietary supplement, is closely linked to one-carbon metabolism and methionine metabolism. Previous clinical evidence indicated that folic acid supplementation displays dual effect on cancer development, promoting or suppressing tumor formation and progression. However, the underlying mechanism remains to be uncovered. Here, we report that high-folate diet significantly promotes cancer development in mice with hepatocellular carcinoma (HCC) induced by DEN/high-fat diet (HFD), simultaneously with increased expression of methionine adenosyltransferase 2A (gene name, MAT2A; protein name, MATIIα), the key enzyme in methionine metabolism, and acceleration of methionine cycle in cancer tissues. In contrast, folate-free diet reduces MATIIα expression and impedes HFD-induced HCC development. Notably, methionine metabolism is dynamically reprogrammed with valosin-containing protein p97/p47 complex-interacting protein (VCIP135) which functions as a deubiquitylating enzyme to bind and stabilize MATIIα in response to folic acid signal. Consistently, upregulation of MATIIα expression is positively correlated with increased VCIP135 protein level in human HCC tissues compared to adjacent tissues. Furthermore, liver-specific knockout of Mat2a remarkably abolishes the advocating effect of folic acid on HFD-induced HCC, demonstrating that the effect of high or free folate-diet on HFD-induced HCC relies on Mat2a. Moreover, folate and multiple intermediate metabolites in one-carbon metabolism are significantly decreased in vivo and in vitro upon Mat2a deletion. Together, folate promotes the integration of methionine and one-carbon metabolism, contributing to HCC development via hijacking MATIIα metabolic pathway. This study provides insight into folate-promoted cancer development, strongly recommending the tailor-made folate supplement guideline for both sub-healthy populations and patients with cancer expressing high level of MATIIα expression.

Comparison of long-term outcomes after robotic versus laparoscopic radical gastrectomy: a propensity score-matching study.

OBJECTIVE: There is insufficient evidence to evaluate the long-term outcomes of robotic radical gastrectomy. The aim of this study was to compare the radical results and long-term outcomes of robotic and laparoscopic radical gastrectomy. METHODS: We prospectively collected and retrospectively analyzed the general clinicopathological data of gastric cancer patients treated with robotic radical gastrectomy (RG) and laparoscopic radical gastrectomy (LG) from July 2016 to July 2018 at Fujian Medical University Union Hospital. The RG cohort was matched 1:3 with the LG cohort by using propensity score matching (PSM). The primary endpoints of the study were 3-year overall survival (OS) and 3-year relapse-free survival (RFS). RESULTS: The study included 221 patients treated with RG and 1106 patients treated with LG for gastric cancer. After PSM, 211 patients were included in the RG cohort, and 663 patients were included in the LG cohort. The 3-year OS rate was 81.0% in the robotic cohort and 79.3% in the laparoscopic cohort (log-rank test, P = 0.516). The 3-year RFS rate was 78.7% in the robotic cohort and 75.6% in the laparoscopic cohort (log-rank test, P = 0.600). In the subgroup analyses, no significant differences were noted between the RG and LG cohorts in terms of 3-year OS and 3-year RFS (all P > 0.05). The therapeutic value index of each lymph node station dissection in the robotic cohort was comparable to that in the laparoscopic cohort. CONCLUSION: Robotic radical gastrectomy can achieve radical results and long-term outcomes comparable to laparoscopic surgery, and further multicenter prospective studies can be conducted to assess the clinical efficacy of robotic radical gastrectomy.

Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth.

Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

BCAA-BCKA axis regulates WAT browning through acetylation of PRDM16.

The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.

[A Review of Metabolic Stress and Development of Pancreatic Cancer].

Pancreatic ductal adenocarcinoma (PDAC) is one of the most notorious malignancies with a 5-year survival rate of less than 8%. Therefore, it is crucial to investigate the molecular mechanism underlining PDAC initiation, promotion, and progression for efficient treatment of PDAC. In order to adapt and survive in an extremely adverse microenvironment of hypoxia and insufficiency of nutrients and energy, PDAC cells undergo extensive metabolic modification triggered by intrinsic signalings which are activated by different genetic events, including mutations occurred at K RAS, TP53, and DPC4/ SMAD4, collaboratively promoting PDAC development. Notably, PDCA cells have extensive crosstalk in the form of reciprocal metabolic flux with its surrounding microenvironment to facilitate tumor advancement and therapy resistance. We herein summarize recent findings of PDAC metabolism and discuss metabolic rewiring-based therapeutic strategies.

Metabolite sensing and signaling in cancer.

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.

Acetylation promotes BCAT2 degradation to suppress BCAA catabolism and pancreatic cancer growth.

Pancreatic ductal adenocarcinoma (PDAC) is well-known for inefficient early diagnosis, with most patients diagnosed at advanced stages. Increasing evidence indicates that elevated plasma levels of branched-chain amino acids (BCAAs) are associated with an increased risk of pancreatic cancer. Branched-chain amino acid transaminase 2 (BCAT2) is an important enzyme in BCAA catabolism that reversibly catalyzes the initial step of BCAA degradation to branched-chain acyl-CoA. Here, we show that BCAT2 is acetylated at lysine 44 (K44), an evolutionarily conserved residue. BCAT2 acetylation leads to its degradation through the ubiquitin-proteasome pathway and is stimulated in response to BCAA deprivation. cAMP-responsive element-binding (CREB)-binding protein (CBP) and SIRT4 are the acetyltransferase and deacetylase for BCAT2, respectively. CBP and SIRT4 bind to BCAT2 and control the K44 acetylation level in response to BCAA availability. More importantly, the K44R mutant promotes BCAA catabolism, cell proliferation, and pancreatic tumor growth. Collectively, the data from our study reveal a previously unknown regulatory mechanism of BCAT2 in PDAC and provide a potential therapeutic target for PDAC treatment.