Ubiquitin-dependent Argonauteprotein MEL1 degradation is essential for rice sporogenesis and phasiRNA target regulation.

MEIOSIS ARRESTED AT LEPTOTENE1 (MEL1), a rice (Oryza sativa) Argonaute (AGO) protein, has been reported to function specifically at premeiotic and meiotic stages of germ cell development and is associated with a novel class of germ cell-specific small noncoding RNAs called phased small RNAs (phasiRNAs). MEL1 accumulation is temporally and spatially regulated and is eliminated after meiosis. However, the metabolism and turnover (i.e. the homeostasis) of MEL1 during germ cell development remains unknown. Here, we show that MEL1 is ubiquitinated and subsequently degraded via the proteasome pathway in vivo during late sporogenesis. Abnormal accumulation of MEL1 after meiosis leads to a semi-sterile phenotype. We identified a monocot-specific E3 ligase, XBOS36, a CULLIN RING-box protein, that is responsible for the degradation of MEL1. Ubiquitination at four K residues at the N terminus of MEL1 by XBOS36 induces its degradation. Importantly, inhibition of MEL1 degradation either by XBOS36 knockdown or by MEL1 overexpression prevents the formation of pollen at the microspore stage. Further mechanistic analysis showed that disrupting MEL1 homeostasis in germ cells leads to off-target cleavage of phasiRNA target genes. Our findings thus provide insight into the communication between a monocot-specific E3 ligase and an AGO protein during plant reproductive development.

Highly efficient blue quantum-dot light-emitting diodes based on a mixed composite of a carbazole donor and a triazine acceptor as the hole transport layer.

Solution-processed thermally activated delayed fluorescence (TADF) exciplexes were employed as the hole transport layer (HTL) of blue quantum dot (QD) light-emitting diodes (QLEDs) by blending polymer donors of poly(N-vinylcarbazole) (PVK) with small molecular acceptors of 2,4,6-tris(biphenyl-3-yl)-1,3,5-triazine (T2T). As a result, the PVK:T2T HTL can harvest holes and electrons leaking from the QD active layer to form exciplex excitons and then this harvested exciton energy can be effectively transferred to the adjacent QD emitters through the Förster resonance energy-transfer process. Furthermore, the TADF exciplexes can enhance the hole mobility of the HTL due to the charge transfer process from the PVK donor to the T2T acceptor under an external electric field. The maximum current efficiency (CE) and external quantum efficiency (EQE) of the fabricated blue ZnCdS/ZnS core/shell QLEDs increase from 4.14 cd A-1 and 7.33% for the PVK HTL to 7.73 cd A-1 and 13.66% for the PVK:(5 wt%)T2T HTL, respectively. Our results demonstrate that the TADF exciplex HTL would be a facile strategy to design high-performance blue QLEDs.

Impacts of heavy metals and medicinal crops on ecological systems, environmental pollution, cultivation, and production processes in China.

Heavy metals are widely distributed in the environment due to the natural processes and anthropogenic human activities. Their migration into no contaminated areas contributing towards pollution of the ecosystems e.g. soils, plants, water and air. It is recognized that heavy metals due to their toxicity, long persistence in nature can accumulate in the trophic chain and cause organism dysfunction. Although the popularity of herbal medicine is rapidly increasing all over the world heavy metal toxicity has a great impact and importance on herbal plants and consequently affects the quality of herbal raw materials, herbal extracts, the safety and marketability of drugs. Effective control of heavy metal content in herbal plants using in pharmaceutical and food industries has become indispensable. Therefore, this review describes various important factors such as ecological and environmental pollution, cultivation and harvest of herbal plants and manufacturing processes which effects on the quality of herbal plants and then on Chinese herbal medicines which influence human health. This review also proposes possible management strategies to recover environmental sustainability and medication safety. About 276 published studies (1988-2021) are reviewed in this paper.

Association between blood arsenic concentration and dyslipidemia: Mediating effect of lipid peroxidation in the elderly.

BACKGROUND: The earlier investigations have revealed heavy metals exposure is implicated in the pathogenesis of dyslipidemia. The goal was to evaluated the relationship of blood arsenic (As) concentration with dyslipidemia in the elderly through a cross-sectional study. METHODS: The entire 360 elderly population were selected. Fasting blood specimens, demographic information, and clinical characteristics were obtained. The concentration of blood As was detected using ICP-MS. Serum 8-iso-PGF2α, a biomarker of lipid peroxidation, was measured by ELISA. RESULTS: Pearson correlative analysis hinted there were strong relationships of blood As with liver function indices in the elderly. Besides, blood As was positively associated with total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C), and apolipoprotein A-I (ApoA I). Further multivariate linear and logistic regression suggested that the incidences of TC and LDL-C elevation were upregulated with the rising tertiles of blood As. Blood As was positively related with the prevalence of dyslipidemia (OR=3.609; 95%CI: 1.353, 6.961). Additionally, serum 8-iso-PGF2α was dramatically and positively linked to the levels of blood As and lipid profiles. Mediation analyses verified that 8-iso-PGF2α partially mediated the correlations between blood As with TC (36.63%) and LDL-C (34.03%). CONCLUSION: Blood As concentration is positively related to lipid profiles in the elderly. Higher blood As concentration elevates the prevalence of dyslipidemia. Lipid peroxidation partially mediates the correlation of As exposure with dyslipidemia.

Nomogram Based on US and Clinicopathologic Characteristics: Axillary Nodal Evaluation Following Neoadjuvant Chemotherapy in Patients With Node-Positive Breast Cancer.

BACKGROUND: To develop a convenient modality to predict axillary response to neoadjuvant chemotherapy (NAC) in breast cancer patients. MATERIALS AND METHODS: In this multi-center study, a total of 1019 breast cancer patients with biopsy-proven positive lymph node (LN) receiving NAC were randomly assigned to the training and validation groups at a ratio of 7:3. Clinicopathologic and ultrasound (US) characteristics of both primary tumors and LNs were used to develop corresponding prediction models, and a nomogram integrating clinicopathologic and US predictors was generated to predict the axillary response to NAC. RESULTS: Axillary pathological complete response (pCR) was achieved in 47.79% of the patients. The expression of estrogen receptor, human epidermal growth factor receptor -2, Ki-67 score, and clinical nodal stage were independent predictors for nodal response to NAC. Location and radiological response of primary tumors, cortical thickness and shape of LNs on US were also significantly associated with nodal pCR. In the validation cohort, the discrimination of US model (area under the curve [AUC], 0.76) was superior to clinicopathologic model (AUC, 0.68); the combined model (AUC, 0.85) demonstrates strong discriminatory power in predicting nodal pCR. Calibration curves of the nomogram based on the combined model demonstrated that substantial agreement can be observed between the predictions and observations. This nomogram showed a false-negative rates of 16.67% in all patients and 10.53% in patients with triple negative breast cancer. CONCLUSION: Nomogram incorporating routine clinicopathologic and US characteristics can predict nodal pCR and represents a tool to aid in treatment decisions for the axilla after NAC in breast cancer patients.

Structural variant landscapes reveal convergent signatures of evolution in sheep and goats.

BACKGROUND: Sheep and goats have undergone domestication and improvement to produce similar phenotypes, which have been greatly impacted by structural variants (SVs). Here, we report a high-quality chromosome-level reference genome of Asiatic mouflon, and implement a comprehensive analysis of SVs in 897 genomes of worldwide wild and domestic populations of sheep and goats to reveal genetic signatures underlying convergent evolution. RESULTS: We characterize the SV landscapes in terms of genetic diversity, chromosomal distribution and their links with genes, QTLs and transposable elements, and examine their impacts on regulatory elements. We identify several novel SVs and annotate corresponding genes (e.g., BMPR1B, BMPR2, RALYL, COL21A1, and LRP1B) associated with important production traits such as fertility, meat and milk production, and wool/hair fineness. We detect signatures of selection involving the parallel evolution of orthologous SV-associated genes during domestication, local environmental adaptation, and improvement. In particular, we find that fecundity traits experienced convergent selection targeting the gene BMPR1B, with the DEL00067921 deletion explaining ~10.4% of the phenotypic variation observed in goats. CONCLUSIONS: Our results provide new insights into the convergent evolution of SVs and serve as a rich resource for the future improvement of sheep, goats, and related livestock.

A time-resolved multi-omics atlas of transcriptional regulation in response to high-altitude hypoxia across whole-body tissues.

High-altitude hypoxia acclimatization requires whole-body physiological regulation in highland immigrants, but the underlying genetic mechanism has not been clarified. Here we use sheep as an animal model for low-to-high altitude translocation. We generate multi-omics data including whole-genome sequences, time-resolved bulk RNA-Seq, ATAC-Seq and single-cell RNA-Seq from multiple tissues as well as phenotypic data from 20 bio-indicators. We characterize transcriptional changes of all genes in each tissue, and examine multi-tissue temporal dynamics and transcriptional interactions among genes. Particularly, we identify critical functional genes regulating the short response to hypoxia in each tissue (e.g., PARG in the cerebellum and HMOX1 in the colon). We further identify TAD-constrained cis-regulatory elements, which suppress the transcriptional activity of most genes under hypoxia. Phenotypic and transcriptional evidence indicate that antenatal hypoxia could improve hypoxia tolerance in offspring. Furthermore, we provide time-series expression data of candidate genes associated with human mountain sickness (e.g., BMPR2) and high-altitude adaptation (e.g., HIF1A). Our study provides valuable resources and insights for future hypoxia-related studies in mammals.

The effect of modified Qiyuan paste on mice with low immunity and sleep deprivation by regulating GABA nerve and immune system.

BACKGROUND: Low immunity and sleep disorders are prevalent suboptimal health conditions in contemporary populations, which render them susceptible to the infiltration of pathogenic factors. LJC, which has a long history in traditional Chinese medicine for nourishing the Yin and blood and calming the mind, is obtained by modifying Qiyuan paste. Dendrobium officinale Kimura et Migo has been shown to improve the immune function in sleep-deprived mice. In this study, based on the traditional Chinese medicine theory, LJC was prepared by adding D. officinale Kimura et Migo to Qiyuan paste decoction. METHODS: Indicators of Yin deficiency syndrome, such as back temperature and grip strength, were measured in each group of mice; furthermore, behavioral tests and pentobarbital sodium-induced sleep tests were performed. An automatic biochemical analyzer, enzyme-linked immunosorbent assay kit, and other methods were used to determine routine blood parameters, serum immunoglobulin (IgG, IgA, and IgM), cont (C3, C4), acid phosphatase (ACP) and lactate dehydrogenase (LDH) levels in the spleen, serum hemolysin, and delayed-type hypersensitivity (DTH) levels. In addition, serum levels of γ-aminobutyric acid (GABA) and glutamate (Glu) were detected using high-performance liquid chromatography (HPLC). Hematoxylin-eosin staining and Nissl staining were used to assess the histological alterations in the hypothalamus tissue. Western blot and immunohistochemistry were used to detect the expressions of the GABA pathway proteins GABRA1, GAD, GAT1, and GABAT1 and those of CD4+ and CD8+ proteins in the thymus and spleen tissues. RESULTS: The findings indicated that LJC prolonged the sleep duration, improved the pathological changes in the hippocampus, effectively upregulated the GABA content in the serum of mice, downregulated the Glu content and Glu/GABA ratio, enhanced the expressions of GABRA1, GAT1, and GAD, and decreased the expression of GABAT1 to assuage sleep disorders. Importantly, LJC alleviated the damage to the thymus and spleen tissues in the model mice and enhanced the activities of ACP and LDH in the spleen of the immunocompromised mice. Moreover, serum hemolysin levels and serum IgG, IgA, and IgM levels increased after LJC administration, which manifested as increased CD4+ content, decreased CD8+ content, and enhanced DTH response. In addition, LJC significantly increased the levels of complement C3 and C4, increased the number of white blood cells and lymphocytes, and decreased the percentage of neutrophils in the blood. CONCLUSIONS: LJC can lead to improvements in immunocompromised mice models with insufficient sleep. The underlying mechanism may involve regulation of the GABA/Glu content and the expression levels of GABA metabolism pathway-related proteins in the brain of mice, enhancing their specific and nonspecific immune functions.

Cobalt exposure and dyslipidemia in elderly population: the mediating role of systemic inflammation and lipid peroxidation.

Heavy metal exposure has been reported to be correlated with lipid profile alteration and dyslipidemia. While the associations between serum cobalt (Co) with lipid profile levels and risk of dyslipidemia have not been explored in elderly population, and the underlying mechanisms remain unclear. All eligible 420 elderly people were recruited in three communities of Hefei City in this cross-sectional study. Peripheral blood samples and clinical information were collected. The level of serum Co was detected through ICP-MS. The biomarkers for systemic inflammation (TNF-α) and lipid peroxidation (8-iso-PGF2α) were measured with ELISA. Each 1-unit increase of serum Co was related with 0.513 mmol/L, 0.196 mmol/L, 0.571 mmol/L, and 0.303 g/L in TC, TG, LDL-C, and ApoB, respectively. Multivariate linear and logistic regression analyses indicated that the prevalence of elevated TC, elevated LDL-C, and elevated ApoB were gradually increased according to tertiles of serum Co concentration (all P trend < 0.001). The risk of dyslipidemia was positively correlated with serum Co (OR = 3.500; 95% CI 1.630 ~ 7.517). Moreover, the levels of TNF-α and 8-iso-PGF2α were gradually risen in parallel with elevating serum Co. The elevation of TNF-α and 8-iso-PGF2α partially mediated Co-caused elevation of TC and LDL-C. Environmental Co exposure is associated with elevated lipid profile levels and dyslipidemia risk among elderly population. Systemic inflammation and lipid peroxidation partially mediate the associations of serum Co with dyslipidemia.

[Clinical Characteristics and Risk Factors in Children with Acute Leukemia Complicated with Multiple Drug Resistant Bacterial Septicemia].

OBJECTIVE: To investigate the clinical characteristics and risk factors of acute leukemia complicated with multi-drug resistant bacterial septicemia in children. METHODS: The clinical data of children with acute leukemia complicated with septicemia admitted to the Affiliated Hospital of Guangdong Medical University from January 2013 to May 2021 were retrospectively analyzed. Their flora composition and drug resistance were also analyzed. The children were divided into multi-drug resistant bacteria (MDRB) group and non-multi-drug resistant bacteria (non-MDRB) group according to the drug sensitivity results, and the differences in clinical data between the two group were compared. RESULTS: A total of 108 children had drug sensitivity results, 47 cases in the MDRB group, including 26 strians of Gram-positive bacteria (G+), the most common multi-drug resistant G+ bacteria were coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, and the most common multi-drug resistant Gram-negative bacteria G- bacteria were Escherichia coli and Klebsiella pneumoniae subspecies pneumoniae. Compared with non-MDRB group, children in MDRB group had higher C-reactive protein (CRP) level and mortality rate (P <0.001, P =0.009), lower initial empirical anti-infection efficiency (P <0.001), and were more likely to have septic shock (P =0.003). Logistic analysis showed that the risk factors of acute leukemia complicated with MDRB septicemia in children were previous MDRB infection (OR =6.763, 95% CI: 1.141-40.092, P =0.035), duration of agranulocytosis before infection≥7 days (OR =3.071, 95% CI: 1.139-8.282, P =0.027), and previous use of antimicrobial drugs within 90 days before infection (OR =7.675, 95% CI: 1.581-37.261, P =0.011). CONCLUSIONS: The clinical features of acute leukemia complicated with MDRB septicemia in children include a heavy inflammatory response, significantly elevated CRP, susceptibility to secondary septic shock, low efficiency of initial empirical anti-infective therapy, and high mortality rate. Previous MDRB infection, duration of agranulocytosis before infection≥7 days, and previous use of antimicrobial drugs within 90 days before infection are risk factors of acute leukemia complicated with MDRB septicemia in children.

Genomic Landscape of Copy Number Variations and Their Associations with Climatic Variables in the World's Sheep.

Sheep show characteristics of phenotypic diversity and adaptation to diverse climatic regions. Previous studies indicated associations between copy number variations (CNVs) and climate-driven adaptive evolution in humans and other domestic animals. Here, we constructed a genomic landscape of CNVs (n = 39,145) in 47 old autochthonous populations genotyped at a set of high-density (600 K) SNPs to detect environment-driven signatures of CNVs using a multivariate regression model. We found 136 deletions and 52 duplications that were significantly (Padj. < 0.05) associated with climatic variables. These climate-mediated selective CNVs are involved in functional candidate genes for heat stress and cold climate adaptation (e.g., B3GNTL1, UBE2L3, and TRAF2), coat and wool-related traits (e.g., TMEM9, STRA6, RASGRP2, and PLA2G3), repairing damaged DNA (e.g., HTT), GTPase activity (e.g., COPG), fast metabolism (e.g., LMF2 and LPIN3), fertility and reproduction (e.g., SLC19A1 and CCDC155), growth-related traits (e.g., ADRM1 and IGFALS), and immune response (e.g., BEGAIN and RNF121) in sheep. In particular, we identified significant (Padj. < 0.05) associations between probes in deleted/duplicated CNVs and solar radiation. Enrichment analysis of the gene sets among all the CNVs revealed significant (Padj. < 0.05) enriched gene ontology terms and pathways related to functions such as nucleotide, protein complex, and GTPase activity. Additionally, we observed overlapping between the CNVs and 140 known sheep QTLs. Our findings imply that CNVs can serve as genomic markers for the selection of sheep adapted to specific climatic conditions.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

Mitochondrial Micropeptide STMP1 Enhances Mitochondrial Fission to Promote Tumor Metastasis.

Micropeptides are a recently discovered class of molecules that play vital roles in various cellular processes, including differentiation, proliferation, and apoptosis. Here, we sought to identify cancer-associated micropeptides and to uncover their mechanistic functions. A micropeptide named short transmembrane protein 1 (STMP1) that localizes at the inner mitochondrial membrane was identified to be upregulated in various cancer types and associated with metastasis and recurrence of hepatocellular carcinoma. Both gain- and loss-of-function studies revealed that STMP1 increased dynamin-related protein 1 (DRP1) activation to promote mitochondrial fission and enhanced migration of tumor cells. STMP1 silencing inhibited in vivo tumor metastasis in xenograft mouse models. Overexpression of STMP1 led to redistribution of mitochondria to the leading edge of cells and enhanced lamellipodia formation. Treatment with a DRP1 inhibitor abrogated the promotive effect of STMP1 on mitochondrial fission, lamellipodia formation, and tumor cell migration in vitro and metastasis in vivo. Furthermore, STMP1 interacted with myosin heavy chain 9 (MYH9), the subunit of nonmuscle myosin II, and silencing MYH9 abrogated STMP1-induced DRP1 activation, mitochondrial fission, and cell migration. Collectively, this study identifies STMP1 as a critical regulator of metastasis and a novel unit of the mitochondrial fission protein machinery, providing a potential therapeutic target for treating metastases. SIGNIFICANCE: This study identifies the mitochondrial micropeptide STMP1 as a regulator of metastasis that promotes mitochondrial fission and tumor cell migration via DRP1 and MYH9.

Prominent Effects of Berbamine Hydrochloride on Alzheimer's Disease Model Mice.

Very few anti-Alzheimer's disease (AD) drugs are clinically available at present due to the complex mechanism of Alzheimer's disease. For the purpose of discovering potential anti-AD drugs in bisbenzylisoquinoline alkaloids, the anti-AD function and the mechanism of the function of berbamine hydrochloride (BBMH) were studied. Three kinds of AD model mice, double transgenic APP/PS1 AD mice, Gal-Alu AD mice induced by the intraperitoneal injection of d-galactose combined with the intragastric administration of aluminum trichloride, and Alu AD-like mice induced by stereotactic brain injection of aluminum trichloride, were administered with BBMH for 40 days at a dosage of 280 mg/kg/d. The effects of BBMH on the learning and memory behavior of the AD mice were studied through the Morris water maze experiment, and the influences of BBMH on the pathological features of AD, including the deposition of Aß, the lesions of pyramidal cells (neurons), and the formation of neurofibrillary tangles, were studied by the immunohistochemical staining, hematoxylin-eosin staining, and silver staining of the brain tissues of the mice. The water maze experiment showed that BBMH could significantly improve the learning and memory abilities of three kinds of treated mice. Immunohistochemical staining showed that BBMH could significantly reduce the deposition of Aß in the brain tissues of treated mice. Hematoxylin-eosin staining showed that BBMH could significantly alleviate the lesions of pyramidal cells in the hippocampal tissue of the mice. Silver staining showed that BBMH could significantly reduce the formation of neurofibrillary tangles in the hippocampal tissue of the mice. These results indicated that BBMH has significant anti-AD effects and the potential as an anti-AD drug. Western blot analysis of the brain tissue of the mice showed that the expression level of calpain, a Ca2+-dependent proteolytic enzyme, was significantly inhibited and the expression level of SelK, a selenoprotein mainly expressed in immune cells, was significantly increased. It is speculated that the anti-AD effect of BBMH is related to the improvement of the phagocytosis of microglial cells in brain tissues and macrophages migrated into the brain as well as the regulation of calcium homeostasis and calcium-dependent proteases in the brain tissues of the mice.

Genome-wide analysis and functional annotation of chromatin-enriched noncoding RNAs in rice during somatic cell regeneration.

BACKGROUND: Plants have the remarkable ability to generate callus, a pluripotent cell mass that acquires competence for subsequent tissue regeneration. Global chromatin remodeling is required for this cell fate transition, but how the process is regulated is not fully understood. Chromatin-enriched noncoding RNAs (cheRNAs) are thought to play important roles in maintaining chromatin state. However, whether cheRNAs participate in somatic cell regeneration in plants has not yet been clarified. RESULTS: To uncover the characteristics and functions of cheRNAs during somatic cell reprogramming in plants, we systematically investigate cheRNAs during callus induction, proliferation and regeneration in rice. We identify 2284 cheRNAs, most of which are novel long non-coding RNAs or small nucleolar RNAs. These cheRNAs, which are highly conserved across plant species, shuttle between chromatin and the nucleoplasm during somatic cell regeneration. They positively regulate the expression of neighboring genes via specific RNA motifs, which may interact with DNA motifs around cheRNA loci. Large-scale mutant analysis shows that cheRNAs are associated with plant size and seed morphology. Further detailed functional investigation of two che-lncRNAs demonstrates that their loss of function impairs cell dedifferentiation and plant regeneration, highlighting the functions of cheRNAs in regulating the expression of neighboring genes via specific motifs. These findings support cis- regulatory roles of cheRNAs in influencing a variety of rice traits. CONCLUSIONS: cheRNAs are a distinct subclass of regulatory non-coding RNAs that are required for somatic cell regeneration and regulate rice traits. Targeting cheRNAs has great potential for crop trait improvement and breeding in future.

The Mechanism of Dendrobium officinale as a Treatment for Hyperlipidemia Based on Network Pharmacology and Experimental Validation.

Materials and Methods: The active compounds in DO, their targets, and targets associated with hyperlipidemia were screened across various databases, and the hidden targets of DO in treating hyperlipidemia were forecast. The compound-target (C-T), protein-protein interaction (PPI), and compound-target-pathway (C-T-P) networks of DO were set up with Cytoscape software. The hub genes and core clusters of DO predicted to be active against hyperlipidemia were calculated by Cytoscape. The DAVID database was adopted for Gene Ontology (GO) analysis and KEGG pathway enrichment analysis. Next, we used the high-sucrose-fat diet and alcohol (HFDA)-induced hyperlipidemia rats to evaluate the hypolipidemic effect of DO. Results: In this study, we obtained 264 compounds from DO, revealed 11 bioactive compounds, and predicted 89 potential targets of DO. The network analysis uncovered that naringenin, isorhamnetin, and taxifolin might be the compounds in DO that are mainly in charge of its roles in hyperlipidemia and might play a role by modulating the targets (including PPARG, ADIPOQ, AKT1, TNF, and APOB). The pathway analysis showed that DO might affect diverse signaling pathways related to the pathogenesis of hyperlipidemia, including PPAR signaling pathway, insulin resistance, AMPK signaling pathway, and non-alcoholic fatty liver disease simultaneously. Meanwhile, in the HFDA-induced hyperlipidemia rat model, DO could significantly decrease the level of TC, TG, LDL-c, and ALT in serum, and increase HDL-c as well. The liver pathological section indicated that DO could ease liver damage and lipid cumulation. Conclusion: In summary, the biological targets of the main bioactive compounds in DO were found to distribute across multiple metabolic pathways. These findings suggest that a mutual regulatory system consisting of multiple components, targets, and pathways is a likely mechanism through which DO may improve hyperlipidemia. Validation experiments indicated that DO may treat hyperlipidemia by affecting NAFLD-related signaling pathways.

Polysaccharide, the Active Component of Dendrobium officinale, Ameliorates Metabolic Hypertension in Rats via Regulating Intestinal Flora-SCFAs-Vascular Axis.

Metabolic hypertension (MH) is the most common type of hypertension worldwide because of unhealthy lifestyles, such as excessive alcohol intake and high-sugar/high-fat diets (ACHSFDs), adopted by humans. Poor diets lead to a decrease in the synthesis of short-chain fatty acids (SCFAs), which are produced by intestinal flora and transferred by G protein-coupled receptors (GPCRs), resulting in impaired gastrointestinal function, disrupted metabolic processes, increased blood pressure (BP), and ultimately, MH. It is not clear whether Dendrobium officinale polysaccharide (DOPS) can mediate its effects by triggering the SCFAs-GPCR43/41 pathway. In this study, DOPS, with a content of 54.45 ± 4.23% and composition of mannose, glucose, and galacturonic acid at mass percentages of 61.28, 31.87, and 2.53%, was isolated from Dendrobium officinale. It was observed that DOPS, given to rats by intragastric administration after dissolution, could lower the BP and improve the abnormal lipid metabolic processes in ACHSFD-induced MH rats. Moreover, DOPS was found to increase the production, transportation, and utilization of SCFAs, while improving the intestinal flora and strengthening the intestinal barrier, as well as increasing the intestinal levels of SCFAs and the expression of GPCR43/41. Furthermore, DOPS improved vascular endothelial function by increasing the expression of GPCR41 and endothelial nitric oxide synthase in the aorta and the nitric oxide level in the serum. However, these effects were all reversed by antibiotic use. These findings indicate that DOPS is the active component of Dendrobium officinale, and it can reverse MH in rats by activating the intestinal SCFAs-GPCR43/41 pathway.

LncRNA Lnc-APUE is Repressed by HNF4α and Promotes G1/S Phase Transition and Tumor Growth by Regulating MiR-20b/E2F1 Axis.

Many long noncoding RNAs (lncRNAs) have been annotated, but their functions remain unknown. The authors found a novel lnc-APUE (lncRNA accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc-APUE level is associated with short recurrence-free survival (RFS) of HCC patients. Gain- and loss-of-function analyses showed that lnc-APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc-APUE binds to miR-20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc-APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4α) binds to the lnc-APUE promoter, represses lnc-APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4α expression is reduced in HCC tissues and low HNF4α level is correlated with high lnc-APUE expression. Collectively, a HNF4α/lnc-APUE/miR-20b/E2F1 axis in which HNF4α represses lnc-APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4α downregulation leads to lnc-APUE upregulation, which prevents the inhibition of miR-20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth.

Small RNA analysis of Perna viridis after exposure to Prorocentrum lima, a DSP toxins-producing dinoflagellate.

Diarrheic shellfish poisoning toxins (DSP toxins) are a set of the most important phycotoxins produced by some dinoflagellates. Studies have shown that DSP toxins have various toxicities such as genotoxicity, cytotoxicity, and immunotoxicity to bivalve mollusks. However, these toxicities appear decreasing with exposure time and concentration of DSP toxins. The underlying mechanism involved remains unclear. In this study, small RNA sequencing was performed in the digestive gland of the mussel Perna viridis after exposure to DSP toxins-producing dinoflagellate Prorocentrum lima for different time periods. The potential roles of miRNAs in response and detoxification to DSP toxins in the mussel were analyzed. Small RNA sequencing of 12 samples from 72 individuals was conducted by BGISEQ-500. A total of 123 mature miRNAs were identified, including 90 conserved miRNAs and 33 potential novel miRNAs. After exposure to P. lima, multiple important miRNAs displayed some alterations. Further miRNA target prediction revealed some important genes involved in cytoskeleton, apoptosis, complement system and immune stress. qPCR demonstrated that miR-71_5, miR-750_1 and novel_mir4 were significantly up-regulated at 6 h after exposure to P. lima, while miR-100_2 was significantly down-regulated after 96 h of exposure. Accordingly, putative target genes of these differentially expressed miRNAs experienced some changes. After 6 h of DSP toxins exposure, NHLRC2 and C1q-like were significantly down-regulated. After 96 h of DSP toxins exposure, NHLRC2 was significantly up-regulated. It is reasonable to speculate that the mussel P. viridis might respond to DSP toxins through miR-750_1, novel_mir4 and miR-71_5 regulating the expression of relevant target genes involved in apoptosis, cytoskeleton, and immune response, etc. This study might provide new clues to uncover the toxic response of bivalve to DSP toxins and lay a foundation for revealing the roles of miRNAs in the environmental adaptation in shellfish.

The parent-of-origin lncRNA MISSEN regulates rice endosperm development.

The cereal endosperm is a major factor determining seed size and shape. However, the molecular mechanisms of endosperm development are not fully understood. Long noncoding RNAs (lncRNAs) function in various biological processes. Here we show a lncRNA, MISSEN, that plays an essential role in early endosperm development in rice (Oryza sativa). MISSEN is a parent-of-origin lncRNA expressed in endosperm, and negatively regulates endosperm development, leading to a prominent dent and bulge in the seed. Mechanistically, MISSEN functions through hijacking a helicase family protein (HeFP) to regulate tubulin function during endosperm nucleus division and endosperm cellularization, resulting in abnormal cytoskeletal polymerization. Finally, we revealed that the expression of MISSEN is inhibited by histone H3 lysine 27 trimethylation (H3K27me3) modification after pollination. Therefore, MISSEN is the first lncRNA identified as a regulator in endosperm development, highlighting the potential applications in rice breeding.