Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.

Ergosterols with rare peroxide, oxetane ring moiety, and a lactone ring from Aspergillus spectabilis and their immunosuppressive activities.

Ten ergostane-type steroids, including seven undescribed ones named spectasteroids A-G, were obtained from Aspergillus spectabilis. Their structures and absolute configurations were determined based on HRESIMS, NMR, ECD calculations, and single-crystal X-ray diffraction analyses. Structurally, spectasteroid A was a unique example of aromatic ergostane-type steroid that featured a rare peroxide ring moiety; spectasteroid B contained a rare oxetane ring system formed between C-9 and C-14; and spectasteroid C was an unusual 3,4-seco-ergostane steroid with an extra lactone ring between C-3 and C-9. Spectasteroids F and G specifically showed inhibitory effects against concanavalin A-induced T lymphocyte proliferation and lipopolysaccharide-induced B lymphocyte proliferation, with IC50 values ranging from 2.33 to 4.22 µM. Spectasteroid F also showed excellent antimultidrug resistance activity, which remarkable enhanced the inhibitory activity of PTX on the colony formation of SW620/Ad300 cells.

Novel annual nitrogen management strategy improves crop yield and reduces greenhouse gas emissions in wheat-maize rotation systems under limited irrigation.

Excessive irrigation and nitrogen application have long seriously undermined agricultural sustainability in the North China Plain (NCP), leading to declining groundwater tables and intensified greenhouse gas (GHG) emissions. Developing low-input management practices that meet the growing food demand while reducing environmental costs is urgently needed. Here, we developed a novel nitrogen management strategy for a typical winter wheat-summer maize rotation system in the NCP under limited irrigation (wheat sowing irrigation only (W0) or sowing and jointing irrigation (W1)) and low nitrogen input (360 kg N ha-1, about 70 % of traditional annual nitrogen input). Novel nitrogen management strategy promoted efficient nitrogen fertilizer uptake and utilization by both crops via optimization of nitrogen fertilizer allocation between the two crops, i.e., increasing nitrogen inputs to wheat (from 180 to 240 kg N ha-1) while reducing nitrogen inputs to maize (from 180 to 120 kg N ha-1). Three-year field study demonstrated that integrated management practices combining novel nitrogen management strategy with limited irrigation increased annual yields and PFPN by 1.9-5.7 %, and reduced TGE by 55-68 kg CO2-eq ha-1 and GHGI by 2.2-10.3 %, without any additional cost. Our results provide agricultural operators and policymakers with practical and easy-to-scalable integrated management strategy, and offer key initiative to promote grain production in the NCP towards agriculture sustainable intensification with high productivity and efficiency, water conservation and emission reduction.

Prenyllongnols A-D, New Prenylated Acylphloroglucinols that Fight Concanavalin A-Induced Autoimmune Hepatitis.

Autoimmune hepatitis is a serious hepatic disorder with unknown nosogenesis, and natural products have been deemed to be one of the most significant sources of new drugs against this disease. Prenyllongnols A-D (1-4), four undescribed prenylated acylphloroglucinols, were isolated from Hypericum longistylum. Compounds 1-4 exhibited remarkable immunosuppressive activities in murine splenocyte proliferation under the induction of concanavalin A (Con A), and IC50 values ranged from 2.98 ± 0.21 to 6.34 ± 0.72 µM. Furthermore, in a Con A-challenged autoimmune hepatitis mouse model, the mice in the group that were pretreated with isolate 2 significantly ameliorated liver injury and decreased proinflammatory cytokine production. Notably, natural product 2 was the first prenylated acylphloroglucinol to protect against concanavalin A-induced autoimmune hepatitis. This finding underscores the potential of prenylated acylphloroglucinol-type metabolites as promising candidates for designing novel immunosuppressors in the quest for new antiautoimmune hepatitis drugs.

Three new amide derivatives from the fungus Alternaria brassicicola.

Three new amide derivatives (alteralkaloids A-C, 1-3) and three known alkaloids (4-6) were afforded after phytochemical investigation of fungus Alternaria brassicicola. The structures of these compounds were confirmed by NMR spectroscopic and HRESIMS data. Furthermore, the absolute configuration of 1 was determined using the single-crystal X-ray diffraction analysis. Compounds 1-3 belong to a class of amide derivatives that have not been found in nature before, sharing the same characteristic signals of the butyl moiety and amide group. These isolated compounds mentioned above were tested for the cytotoxic activity.

Spectasterols, Aromatic Ergosterols with 6/6/6/5/5, 6/6/6/6, and 6/6/6/5 Ring Systems from Aspergillus spectabilis.

Spectasterols A-E (1-5), aromatic ergosterols with unique ring systems, were isolated from Aspergillus spectabilis. Compounds 1 and 2 possess a 6/6/6/5/5 ring system with an additional cyclopentene, while 3 and 4 have an uncommon 6/6/6/6 ring system generated by the D-ring expansion via 1,2-alkyl shifts. Compound 3 exhibited cytotoxic activity (IC50 6.9 µM) and induced cell cycle arrest and apoptosis in HL60 cells. Compound 3 was anti-inflammatory; it decreased COX-2 levels at the transcription and protein levels and inhibited the nuclear translocation of NF-κB p65.

SMARCA4-Deficient Undifferentiated Tumor Achieved by Transbronchial Mediastinal Cryobiopsy Additional to Needle Aspiration.

Lung cancer is the leading cause of deaths from malignant neoplasms worldwide, and a satisfactory biopsy that allows for histological and other analyses is critical for its diagnosis. Guidelines have recommended endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as the reference standard for the staging of lung cancer. However, the relatively limited sample volume retrieved by needle aspiration might restrict the diagnostic capacity of EBUS-TBNA in other uncommon thoracic tumors. Transbronchial mediastinal cryobiopsy is a recently developed sampling strategy for mediastinal lesions, which demonstrates added diagnostic value to conventional needle aspiration. Here, we present a case of thoracic SMARCA4-deficient undifferentiated tumor successfully diagnosed by mediastinal cryobiopsy additional to EBUS-TBNA.

Degradation of carbamazepine over MOFs derived FeMn@C bimetallic heterogeneous electro-Fenton catalyst.

A highly efficient heterogeneous electro-Fenton (Hetero-EF) catalyst with core-shell structure was successfully prepared by calcination of Mn-doped Mil-53 (Fe) precursor at high temperature. FeMn@C-800/2 prepared at pyrolysis temperature of 800 °C and Fe:Mn molar doping ratio of 2:1 showed the best catalytic performance for the degradation of carbamazepine (CBZ). The characterization, properties and stability of FeMn@C-800/2 were systematically investigated, obtaining the apparent first-order reaction rate of Hetero-EF was 8.9 and 17.8 times higher than that on Fe@C-800 and Mn@C-800 at the optimized conditions of current density 10 mA cm-2, catalyst dosage of 50 mg L-1 and initial pH 4.0, respectively. The incorporation of Mn promoted the generation of more Fe0 and Fe3C during the pyrolysis process, and enhanced the internal micro-electrolysis between Fe0 and carbon shell. At the same time, the presence of Mn0 also promoted the regeneration of Fe2+, and improved the activity of iron-carbon heterogeneous catalysis in the EF process, so as to degrade organic pollutants more effectively. This work would help to gain insight into the design of MOFs derived Fe-Mn bimetal catalyst and its mechanism for enhanced heterogeneous electro-Fenton.

Altered dynamic spontaneous neural activity in minimal hepatic encephalopathy.

Background and aims: Abnormal regional neural activity has been identified by the analysis of the static amplitude of low-frequency fluctuation (ALFF) in the setting of minimal hepatic encephalopathy (MHE). Brain activity is highly dynamic. This work sought to evaluate the temporal variability of ALFF to reveal MHE-related alterations in the dynamics of spontaneous neural activity. Methods: A total of 29 healthy controls and 49 patients with cirrhosis [including 20 patients with MHE and 29 patients without MHE (NHE)] who underwent resting-state functional magnetic resonance imaging and Psychometric Hepatic Encephalopathy Score (PHES) examination were enrolled in this investigation. Utilizing a sliding-window approach, we calculated the dynamic ALFF (dALFF) variability to reflect the temporal dynamics of regional neural activity. An analysis of the correlation between dALFF variability and PHES was performed, and receiver operating characteristic (ROC) curve analysis to determine the potential of the dALFF variability index in identifying MHE was completed. Results: The dALFF variability in the bilateral precuneus/posterior cingulate gyrus and left middle frontal gyrus progressively decreased from NHE to MHE group. In cirrhotic patients, the value of dALFF variability in the bilateral precuneus/posterior cingulate gyrus was positively correlated with their neurocognitive performance (r = 0.383 and P = 0.007). The index of dALFF variability in the bilateral precuneus/posterior cingulate gyrus could be used to distinguish NHE and MHE patients, with moderate power (area under the ROC curve = 0.712 and P = 0.012). Conclusion: Our findings highlight the existence of aberrant dynamic brain function in MHE, which could underlie the neural basis of cognitive impairments and could be associated with the development of the disease. Analyzing dALFF could facilitate new biomarker identification for MHE.

Two new nucleoside derivatives isolated from the marine-derived Aspergillus versicolor and their intramolecular transesterification.

Two new nucleoside derivatives, kipukasins M (1a) and N (1b), along with one known analogue, kipukasin J (2), were obtained from the marine-derived fungus Aspergillus versicolor, which was isolated from the mud collected in the South China Sea. The structures of compounds 1a and 1b were elucidated by extensive spectroscopic analysis, mainly including 1D & 2D NMR and HRESIMS data, and the absolute configuration of 1a was further confirmed by single-crystal X-ray diffraction analysis. Interestingly, intramolecular transesterification occurs in compounds 1a and 1b, which exist as a pair of inseparable regioisomers. All isolated compounds were tested for the cytotoxic and antimicrobial activities.

Transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: a randomised trial.

BACKGROUND: Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigatory technique for mediastinal nodal staging in lung cancer. However, EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield in mediastinal lesions of certain aetiologies. We have previously shown that EBUS-guided transbronchial mediastinal cryobiopsy can provide intact samples with greater volume. METHODS: This randomised study determined the diagnostic yield and safety of transbronchial mediastinal cryobiopsy monitored by endosonography for the diagnosis of mediastinal lesions. Patients with a mediastinal lesion of ≥1 cm in the short axis were recruited. Following identification of the mediastinal lesion by linear EBUS, fine-needle aspiration and cryobiopsy were sequentially performed in a randomised order. Primary end-points were diagnostic yield, defined as the percentage of patients for whom mediastinal biopsy provided a definite diagnosis, and procedure-related adverse events. RESULTS: In total, 197 patients were enrolled and randomly allocated. The overall diagnostic yield was 79.9% and 91.8% for TBNA and transbronchial mediastinal cryobiopsy, respectively (p=0.001). Diagnostic yields were similar for metastatic lymphadenopathy (94.1% versus 95.6%, p=0.58), while cryobiopsy was more sensitive than TBNA in uncommon tumours (91.7% versus 25.0%, p=0.001) and benign disorders (80.9% versus 53.2%, p=0.004). No significant differences in diagnostic yield were detected between "TBNA first" and "Cryobiopsy first" groups. We observed two cases of pneumothorax and one case of pneumomediastinum. CONCLUSIONS: Transbronchial cryobiopsy performed under EBUS guidance is a safe and useful approach that offers diagnostic histological samples of mediastinal lesions.

TWIST1 induces phenotypic switching of vascular smooth muscle cells by downregulating p68 and microRNA-143/145.

TWIST1 is an important basic helix-loop-helix protein linked to multiple physiological and pathological processes. Although TWIST1 is believed to be involved in vascular pathogenesis, its effects on homeostasis of smooth muscle cells (SMCs) remain poorly understood. Here, we show that TWIST1 protein levels were significantly elevated during SMC phenotypic switching in vivo and in vitro. TWIST1 overexpression promoted phenotypic switching of SMCs, while siRNA targeting of TWIST1 prevented cell transition. Mechanistically, TWIST1 decreased the level of microRNA-143/145, which governs smooth muscle marker gene transcription. In addition, TWIST1 repressed p68 mRNA and protein expression, a crucial modulator of SMC behavior and microRNA biogenesis. Our co-immunoprecipitation assay demonstrated a previously unrecognized molecular interaction between TWIST1 and p68 protein. Finally, we found that TWIST1 triggered SMC phenotypic switching and suppressed microRNA-143/145 expression by promoting the proteasomal degradation of p68. These data suggest a novel role of TWIST1 in the regulation of SMC homeostasis by modulating p68/microRNA-143/145 axis.

One new spirocyclic lactone and one new benzopyran derivative from Aspergillus terreus.

One new spirocyclic lactone, terreinlactone C (1), and one new benzopyran derivative, 2,2-dimethyl-3-hydroxychroman-6-aldehyde (2), were discovered from the fungus Aspergillus terreus. The chemical structures of compounds 1 and 2 were elucidated by detailedly analyzing NMR and HRESIMS data. Compound 1 is the first natural product with a 1-oxaspiro[4.5]decan-2-one ring system and a possible biogenetic pathway is proposed. Two compounds were tested for their cytotoxic activities against five human cancer cell lines.[Formula: see text].

Dongtinganthracenes A-D: Bioxanthracene derivatives from Penicillium sp. DT10 derived from wetland soil obtained from Dongting Lake.

Four undescribed bioxanthracene derivatives, dongtinganthracenes A-D, along with a previously reported analog, ES-242-3, were obtained from the solid culture broth of the fungus Penicillium sp. DT10, which was isolated from wetland soil obtained from Dongting Lake. Their structures and absolute configurations were elucidated based on extensive NMR analyses, mass spectroscopic analyses, and ECD calculations. Dongtinganthracene A represents the first 7',8'-seco-bioxanthracene produced via oxidation, and dongtinganthracenes A-D show a much higher degree of oxidation in aromatic rings compared with normal naturally occurring bioxanthracene derivatives. Dongtinganthracenes B and D and ES-242-3 exhibit cytotoxic activity, while dongtinganthracene A shows inhibitory activity against LPS-induced NO production.

Primary Mediastinal Seminoma Achieved by Transbronchial Mediastinal Cryobiopsy.

Mediastinal biopsy is essential for the clinical diagnosis of mediastinal disease. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a well-established approach for obtaining diagnostic samples from mediastinal masses or enlarged lymph nodes which is proven to be minimally invasive and effective. However, the insufficiency of intact samples acquired might restrict the diagnostic efficacy of EBUS-TBNA for mediastinal lesions such as rare malignancy and granulomatous disorder. We here present an EBUS-guided approach for the cryobiopsy of mediastinal diseases that is capable of providing larger amounts of intact tissue with few observed complications.

Mangiterpenes A-C and 2',3'-seco-manginoid C, four sesquiterpene/monoterpene-shikimate-conjugated spirocyclic meroterpenoids from Guignardia mangiferae.

Mangiterpenes A-C and 2',3'-seco-manginoid C, four undescribed sesquiterpene/monoterpene-shikimate-conjugated meroterpenoids with spiro ring systems, were isolated from Guignardia mangiferae. The structures and absolute configurations of these compounds were established by comprehensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Mangiterpenes A-C represent the first examples of sesquiterpene-shikimate-conjugated spirocyclic meroterpenoids, and 2',3'-seco-manginoid C features an unexpected 2',3'-seco-manginoids skeleton. Mangiterpene C strongly inhibited the production of NO inducted by LPS, with an IC50 value of 5.97 µM. It showed an anti-inflammatory effect by means of blocking in the NF-κB signaling pathway and decreasing the expression of inflammatory mediators.

Dongtingnoids A-G: Fusicoccane Diterpenoids from a Penicillium Species.

Five new diterpenoid glycosides, dongtingnoids A-E (1-5), two new diterpenoid aglycones, dongtingnoids F and G (6 and 7), and two known analogues, cotylenins E and J (8 and 9), belonging to the fusicoccane family, were isolated from the fungus Penicillium sp. DT10, which was derived from wetland soil from Dongting Lake. Their structures and absolute configurations were elucidated based on spectroscopic analyses, acid hydrolysis, ECD calculations, and X-ray crystallography. Dongtingnoid C (3) is the first 16-nor-fusicoccane diterpenoid glycoside reported and is proposed to form by oxidative demethylation. Compounds 1, 4, and 5 showed comparable seed-germination-promoting activities to that previously reported for the growth regulator cotylenin E (8).

Antibacterial activity against drug-resistant microbial pathogens of cytochalasan alkaloids from the arthropod-associated fungus Chaetomium globosum TW1-1.

By feeding 1-methyl-l-tryptophan (1-MT) into cultures of the arthropod-associated fungus Chaetomium globosum TW1-1, three novel cytochalasan alkaloids, termed as armochaetoglosins A-C (1-3), together with five known analogues, namely prochaetoglobosin I (4), chaetoglobosin T (5), chaetoglobosin C (6), armochaetoglobin Y (7), and chaetoglobosin Vb (8), were isolated and characterized. Their structures including absolute configurations were elucidated by means of NMR spectroscopy, single-crystal X-ray crystallography, and comparison of the experimental electronic circular dichroism (ECD) spectra. Structurally, compounds 1-3 represented the first examples of 1'-N-methyl-chaetoglobosins, which were possibly biosynthesized from the additive 1-MT rather than tryptophan. Additionally, compound 3 showed the highest antibacterial activity against K. pneumoniae and ESBL-E. coli with MIC values of 4.0 µg/mL and 16.0 µg/mL, respectively, wherein the inhibitory effect of 3 against K. pneumoniae was stronger than that of the clinically used antibiotic meropenem, with an MIC value of 8 µg/mL. Our findings may provide new chemical templates for the development of new antibacterial agents against drug-resistant microbial pathogens.

Hyperattenins L and M, two new polyprenylated acylphloroglucinols with adamantyl and homoadamantyl core structures from Hypericum attenuatum.

Hyperattenins L (1) and M (2), two new benzoylated polyprenylated phloroglucinol derivatives possessing unusual adamantyl and homoadamantyl core structures, were isolated from the aerial parts of Hypericum attenuatum. Their structures were determined by extensive NMR spectroscopic methods. Compound 1 possesses an unusual tetracyclo[6.3.1.11,10.01,5]tridecane skeleton, representing the second report of natural product with this carbon skeleton. Compound 2 features an unexpected 2,3,13-trioxapentacyclo[7.5.3.17,11.05,16.012,16]octodecane ring system formed by the fusion of 2,3,8-trioxabicyclo[4.3.1]decane moiety to the tricycle[4.3.1.13,8]undecane core. Both compounds were evaluated for their cytotoxic activities against five human cancer cell lines and compound 1 showed excellent inhibitory activities against HL-60, A-549, and MCF-7 cell lines with IC50 values of 3.86, 4.34, and 5.78µM, respectively.