Abnormal global alternative RNA splicing in COVID-19 patients.

Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.

E3 ligase Smurf1 protects against misfolded SOD1 in neuronal cells by promoting its K63 ubiquitylation and aggresome formation.

K63-linked polyubiquitination of the neurodegenerative disease-associated misfolded protein copper-zinc superoxide dismutase 1 (SOD1) is associated with the formation of inclusion bodies. Highly expressed E3 ligase Smad ubiquitylation regulatory factor 1 (Smurf1) promotes cellular homeostasis through the enhanced capability of aggregate degradation. However, it is not well explored the role of Smurf1 in the dynamics of SOD1 aggresomes. In this study, we report that Smurf1 promotes the recruitment of SOD1 to form aggresomes. Mechanistically, Smurf1 interacts with mutant SOD1 to promote aggresome formation by modification of its K63-linked polyubiquitination. Moreover, overexpressed Smurf1 enhances mutant SOD1 aggresome formation and autophagic degradation to prevent cell death. Thus, our data suggest that Smurf1 plays an important role in attenuating protein misfolding-induced cell toxicity by both driving the sequestration of misfolded SOD1 into aggresomes and autophagic degradation.

IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Value of biplane transrectal ultrasonography plus micro-flow imaging in preoperative T staging and rectal cancer diagnosis in combination with CEA/CA199 and MRI.

BACKGROUND: Rectal cancer is one of the most common malignant tumors and has a high incidence rate and fatality rate. Accurate preoperative T staging of rectal cancer is critical for the selection of appropriate rectal cancer treatment. Various pre-operative imaging methods are available, and the identification of the most accurate method for clinical use is essential for patient care. We investigated the value of biplane transrectal ultrasonography (TRUS) combined with MFI in preoperative staging of rectal cancer and explored the value of combining TRUS plus MFI with CEA/CA199 and MRI. METHODS: A total of 87 patients from Daping Hospital with rectal cancer who underwent TRUS examination plus MFI were included. Grades of MFI were determined by Alder classification. Among the total patients, 64 underwent MRI and serum CEA/CA199 tests additionally within one week of TRUS. Pathological results were used as the gold standard for cancer staging. Concordance rates between TRUS, MRI, and CEA/CA199 for tumors at different stages were compared. RESULTS: There were no significant differences between the Alder classification and pathological T staging. The concordance rate of TRUS and MFI for rectal cancer T staging was 72.4% (K = 0.615, p < 0.001). Serum CEA and CA199 levels were significantly different in tumors at different stages and increased progressively by pathological stage (p < 0.001); the accuracy rate was 71.88% (K = 0.599, p < 0.001), while that of MRI was 51.56% (K = 0.303, p < 0.001), indicating that TRUS had higher consistency in the preoperative T staging of rectal cancer. The combination of TRUS, MRI, and CEA/CA199 yielded an accuracy rate of 90.6%, which was higher than that of any method alone. CONCLUSIONS: Preoperative T staging of rectal cancer from biplane TRUS plus MFI was highly consistent with postoperative pathological T staging. TRUS combined with MRI and serum CEA/CA199 had a greater value in the diagnosis of rectal cancer and a higher diagnostic rate than any examination alone.

Rice body synovitis in systemic lupus erythematosus.

Rice bodies (RBs) synovitis in the shoulder joints of systemic lupus erythematosus patients is a rare clinical condition that has not been previously reported. Despite the fact that the diagnosis of RBs synovitis has primarily relied on MRI imaging, ultrasound has been used less frequently. In this report, we discuss a 43-year-old female diagnosed with systemic lupus erythematosus who presented with pain and swelling in the right shoulder. The ultrasound findings were typical, and the patient was diagnosed with RBs synovitis, as she had no history of tuberculosis or rheumatoid arthritis. Subsequently, the patient underwent ultrasound-guided percutaneous biopsy and surgical excision, which led to a good postoperative outcome. Based on this case, a literature review of RBs synovitis over the past 2 decades indicates that rice bodies synovitis is rare in clinical presentation accompanied by SLE. Moreover, ultrasound has not been extensively employed for diagnosing this condition. It is important to note the pivotal role of ultrasound in detecting RBs synovitis, and it should be the preferred method for early detection. Therefore, ultrasound physicians should be well informed about this condition to enhance diagnostic precision.

Anaplastic lymphoma kinase expression in PDGFRA-mutated gastrointestinal stromal tumors probably correlates with poor prognosis.

BACKGROUND: Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). METHODS: A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. RESULTS: Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA-mutant GISTs (7.7%, 4/52) but negative for c-KIT-mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. CONCLUSION: Our study revealed 7.7% (4/52) of ALK expression in PDGFRA-mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA-mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.

Transcriptional and proteomic insights into the host response in fatal COVID-19 cases.

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

Synaptic loss in a mouse model of euthyroid Hashimoto's thyroiditis: possible involvement of the microglia.

BACKGROUND: Hashimoto's thyroiditis (HT) is an autoimmune illness that renders individuals vulnerable to neuropsychopathology even in the euthyroid state, the mechanisms involved remain unclear. We hypothesized that activated microglia might disrupt synapses, resulting in cognitive disturbance in the context of euthyroid HT, and designed the present study to test this hypothesis. METHODS: Experimental HT model was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Morris Water Maze was measured to determine mice spatial learning and memory. The synaptic parameters such as the synaptic density, synaptic ultrastructure and synaptic-markers (SYN and PSD95) as well as the interactions of microglia with synapses were also determined. RESULTS: HT mice had poorer performance in Morris Water Maze than controls. Concurrently, HT resulted in a significant reduction in synapse density and ultrastructure damage, along with decreased synaptic puncta visualized by immunostaining with synaptophysin and PSD-95. In parallel, frontal activated microglia in euthyroid HT mice showed increased engulfment of PSD95 and EM revealed that the synaptic structures were visible within the microglia. These functional alterations in microglia corresponded to structural increases in their attachment to neuronal perikarya and a reduction in presynaptic terminals covering the neurons. CONCLUSION: Our results provide initial evidence that HT can induce synaptic loss in the euthyroid state with deficits might be attributable to activated microglia, which may underlie the deleterious effects of HT on spatial learning and memory.

Mouse Bone Marrow Mesenchymal Stem Cells Inhibit Sepsis-Induced Lung Injury in Mice via Exosomal SAA1.

Sepsis is a global disease burden, and approximately 40% of cases develop acute lung injury (ALI). Bone marrow mesenchymal stromal cells (BMSCs) and their exosomes are widely used in treating a variety of diseases including sepsis. As an acute phase protein, serum amyloid A1 (SAA1) regulates inflammation and immunity. However, the role of SAA1 in BMSCs-exosomes in septic lung injury remains to be elucidated. Exosomes derived from serum and BMSCs were isolated by ultracentrifugation. SAA1 was silenced or overexpressed in mouse BMSCs using lentiviral plasmids, containing either SAA1-targeting short interfering RNAs or SAA1 cDNA. Sepsis was induced by cecal ligation and puncture (CLP). LPS was used to induce ALI in mice. Mouse alveolar macrophages were isolated by flow cytometry. Levels of SAA1, endotoxin, TNF-α, and IL-6 were measured using commercial kits. LPS internalization was monitored by immunostaining. RT-qPCR or immunoblots were performed to test gene and protein expressions. Serum exosomes of patients with sepsis-induced lung injury had significantly higher levels of SAA1, endotoxin, TNF-α, and IL-6. Overexpression of SAA1 in BMSCs inhibited CLP- or LPS-induced lung injury and decreased CLP- or LPS-induced endotoxin, TNF-α, and IL-6 levels. Administration of the SAA1 blocking peptide was found to partially inhibit SAA1-induced LPS internalization by mouse alveolar macrophages and reverse the protective effect of SAA1. In conclusion, BMSCs inhibit sepsis-induced lung injury through exosomal SAA1. These results highlight the importance of BMSCs, exosomes, and SAA1, which may provide novel directions for the treatment of septic lung injury.

Application of Restriction Site-Associated DNA Sequencing (RAD-Seq) for Copy Number Variation and Triploidy Detection in Human.

At present, low-pass whole-genome sequencing (WGS) is frequently used in clinical research and in the screening of copy number variations (CNVs). However, there are still some challenges in the detection of triploids. Restriction site-associated DNA sequencing (RAD-Seq) technology is a reduced-representation genome sequencing technology developed based on next-generation sequencing. Here, we verified whether RAD-Seq could be employed to detect CNVs and triploids. In this study, genomic DNA of 11 samples was extracted employing a routine method and used to build libraries. Five cell lines of known karyotypes and 6 triploid abortion tissue samples were included for RAD-Seq testing. The triploid samples were confirmed by STR analysis and also tested by low-pass WGS. The accuracy and efficiency of detecting CNVs and triploids by RAD-Seq were then assessed, compared with low-pass WGS. In our results, RAD-Seq detected 11 out of 11 (100%) chromosomal abnormalities, including 4 deletions and 1 aneuploidy in the purchased cell lines and all triploid samples. By contrast, these triploids were missed by low-pass WGS. Furthermore, RAD-Seq showed a higher resolution and more accurate allele frequency in the detection of triploids than low-pass WGS. Our study shows that, compared with low-pass WGS, RAD-Seq has relatively higher accuracy in CNV detection at a similar cost and is capable of identifying triploids. Therefore, the application of this technique in medical genetics has a significant potential value.

Therapeutic Perspective of Temozolomide Resistance in Glioblastoma Treatment.

Glioblastoma (GB) is the most lethal form of primary brain neoplasm. TMZ is the first-line standard treatment, but the strong resistance constrains the efficacy in clinical use. GB contains glioma stem cells (GSCs), which contribute to TMZ resistance, promote cell survival evolvement, and repopulate the tumor mass. This review summarizes the TMZ-resistance mechanisms and discusses several potential therapies from the conservative opinion of GSC-targeted therapy orientation to the current view of TMZ resistance-aimed efficacy, which will provide an understanding of the role of heterogeneity in drug resistance and improve therapeutic efficacy in general.

Cloning and identification of a new repressor of 3,17ß-Hydroxysteroid dehydrogenase of Comamonas testosteroni.

BACKGROUND: 3,17ß-hydroxysteroid dehydrogenase (3,17ß-HSD) is a key enzyme in the metabolic pathway for steroid compounds catabolism in Comamonas testosteroni. Tetracycline repressor (TetR) family, repressors existing in most microorganisms, may play key roles in regulating the expression of 3,17ß-HSD. Previous reports showed that three tetR genes are located in the contig58 of C. testosteroni ATCC 11996 (GenBank: AHIL01000049.1), among which the first tetR gene encoded a potential repressor of 3,17ß-HSD by sensing environmental signals. However, whether the other proposed tetR genes act as repressors of 3,17ß-HSD are still unknown. METHODS AND RESULTS: In the present study, we cloned the second tetR gene and analyzed the regulatory mechanism of the protein on 3,17ß-HSD using electrophoretic mobility shift assay (EMSA), gold nanoparticles (AuNPs)-based assay, and loss-of-function analysis. The results showed that the second tetR gene was 660-bp, encoding a 26 kD protein, which could regulate the expression of 3,17ß-HSD gene via binding to the conserved consensus sequences located 1100-bp upstream of the 3,17ß-HSD gene. Furthermore, the mutant strain of C. testosteroni with the second tetR gene knocked-out mutant expresses good biological genetic stability, and the expression of 3,17ß-HSD in the mutant strain is slightly higher than that in the wild type under testosterone induction. CONCLUSIONS: The second tetR gene acts as a negative regulator in 3,17ß-HSD expression, and the mutant has potential application in bioremediation of steroids contaminated environment.

Postoperative pain treatment with transmuscular quadratus lumborum block and fascia iliaca compartment block in patients undergoing total hip arthroplasty: a randomized controlled trial.

BACKGROUND: Patients often suffer moderate or even severe pain after total hip arthroplasty; such pain seriously affects early postoperative recovery. This study aimed to investigate the analgesic efficacy of ultrasound-guided transmuscular quadratus lumborum block combined with fascia iliaca compartment block for elderly patients undergoing total hip arthroplasty. METHODS: Fifty-four patients scheduled for total hip arthroplasty were included in this randomized controlled study. The patients were randomly assigned to receive only transmuscular quadratus lumborum block (group Q) or transmuscular quadratus lumborum block combined with fascia iliaca compartment block (group QF) with ultrasound guidance. Postoperatively in both groups, paracetamol 1 g was regularly administered at 6 h intervals and patient-controlled intravenous analgesia was administered. The primary outcome was cumulative sufentanil consumption via patient-controlled intravenous analgesia 24 h postoperatively. The secondary outcomes included pain degree, time to the first analgesic requirement, joint range of motion, quality of recovery, and the incidence of postoperative complications. RESULTS: Fifty patients were included, and their data were analyzed. The cumulative sufentanil consumption in group QF was significantly lower during the first 24 h after surgery than that in group Q, and the cumulative sufentanil consumption in group QF was reduced at 6-12 and 12-18 h after surgery. The postoperative pain intensity was lower in group QF than in group Q (linear mixed-effects model, the main effect of treatment: P < 0.001). Compared with group Q, group QF had higher quality of recovery and joint range of movement. The time to the first analgesic requirement was longer in group QF than in group Q (log-rank, P < 0.001). There was no statistically significant difference in complications postoperatively between the two groups. CONCLUSIONS: Our study provides a multimodal, opioid-sparing analgesic regimen for elderly patients undergoing total hip arthroplasty. The combination of transmuscular quadratus lumborum block and fascia iliaca compartment block provides a significant advantage for early postoperative functional recovery. Further studies are required to confirm the minimum effective dose. TRIAL REGISTRATION: The study was registered on the 21st December 2020 (retrospectively registered) on the Chinese Clinical Trial Registry: ChiCTR2000038686 .

PLZF suppresses differentiation of mouse spermatogonial progenitor cells via binding of differentiation associated genes.

Promyelocytic leukaemia zinc finger (PLZF) is a key factor in inhibiting differentiation of spermatogonial progenitor cells (SPCs), but the underlying mechanisms are still largely unknown. In this study, the regulation of PLZF on Kit, Stra8, Sohlh2, and Dmrt1 (SPCs differentiation related genes) was investigated. We found some PLZF potential binding sites existed in the promoters of Kit, Stra8, Sohlh2, and Dmrt1. Additionally, the expressions of KIT, STRA8, SOHLH2, and DMRT1 were upregulated when PLZF was knockdown in SPCs. Furthermore, chromatin immunoprecipitation quantitative polymerase chain reaction revealed PLZF directly bound to the promoters of Kit, Stra8, Sohlh2, and Dmrt1. Besides, dual luciferase assay verified PLZF repressed those gene expressions. Collectively, our finding indicate that PLZF binds to the promoter regions of Kit, Stra8, Sohlh2, and Dmrt1 to regulate SPCs differentiation, which facilitate us to further understand the regulatory mechanism of PLZF in SPCs fates.

TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by selective loss of motor neurons in brain and spinal cord. TAR DNA-binding protein 43 (TDP-43) was identified as a major component of disease pathogenesis in ALS, frontotemporal lobar degeneration (FTLD), and other neurodegenerative disease. Despite the fact that TDP-43 is a multi-functional protein involved in RNA processing and a large number of TDP-43 RNA targets have been discovered, the initial toxic effect and the pathogenic mechanism underlying TDP-43-linked neurodegeneration remain elusive. In this study, we found that loss of TDP-43 strongly induced a nuclear translocation of TFEB, the master regulator of lysosomal biogenesis and autophagy, through targeting the mTORC1 key component raptor. This regulation in turn enhanced global gene expressions in the autophagy-lysosome pathway (ALP) and increased autophagosomal and lysosomal biogenesis. However, loss of TDP-43 also impaired the fusion of autophagosomes with lysosomes through dynactin 1 downregulation, leading to accumulation of immature autophagic vesicles and overwhelmed ALP function. Importantly, inhibition of mTORC1 signaling by rapamycin treatment aggravated the neurodegenerative phenotype in a TDP-43-depleted Drosophila model, whereas activation of mTORC1 signaling by PA treatment ameliorated the neurodegenerative phenotype. Taken together, our data indicate that impaired mTORC1 signaling and influenced ALP may contribute to TDP-43-mediated neurodegeneration.

AKT3 Is a Pivotal Molecule of Cadherin-22 and GDNF Family Receptor-α1 Signal Pathways Regulating Self-Renewal in Female Germline Stem Cells.

Female germline stem cells (FGSCs) are rare population residing in cortex of ovary, with the potential to rescue female infertility caused by ovary failure. Recently, we reported that cadherin-22 (CDH22), a member of cadherin family, regulates self-renewal of mouse FGSCs via interaction with JAK-STAT signal pathway and ß-catenin. In this study, the expression profiles of FGSCs and spermatogonial stem cells (SSCs) were analyzed to further reveal their similarity and difference, and AKT3 was predicted as a pivotal molecule for FGSCs self-renewal. Then, we demonstrated that CDH22 interacted with PI3K to phosphorylate AKT3 and subsequently enhanced the expression levels of N-myc and cyclin family in FGSCs to promote self-renewal. Moreover, glial cell line-derived neurotrophic factor (GDNF) was identified as an essential factor for FGSCs self-renewal with a more complicated mechanism: GDNF-GFRA1 activates AKT3 via PI3K or Src family kinase (SFK), and SFK upregulates its target genes, Bcl6b, Etv5, and Lhx1, to promote self-renewal of FGSCs. However, Src, the key intermediate factor for SSCs, was not the functional molecule of SFK family in the GDNF signal network of FGSCs. Based on the observations of bioinformatics analysis and molecular evidence, we demonstrate the underlying links of potential factors which are critical to the self-renewal in FGSC and imply the therapeutic potentials of FGSCs in cure of female infertility. Stem Cells 2019;37:1095-1107.

Inhibition of miR-103a-3p suppresses lipopolysaccharide-induced sepsis and liver injury by regulating FBXW7 expression.

Inflammation, apoptosis, and oxidative stress are involved in septic liver dysfunction. Herein, the role of miR-103a-3p/FBXW7 axis in lipopolysaccharides (LPS)-induced septic liver injury was investigated in mice. Hematoxylin-eosin staining was used to evaluate LPS-induced liver injury. Quantitative real-time polymerase chain reaction was performed to determine the expression of microRNA (miR) and messenger RNA, and western blot analysis was conducted to examine the protein levels. Dual-luciferase reporter assay was used to confirm the binding between miR-103a-3p and FBXW7. Both annexin V-fluoresceine isothiocyanate/propidium iodide staining and caspase-3 activity were employed to determine cell apoptosis. First, miR-103a-3p was upregulated in the septic serum of mice and patients with sepsis, and miR-103a-3p was elevated in the septic liver of LPS-induced mice. Then, interfering miR-103a-3p significantly decreased apoptosis by suppressing Bax expression and upregulating Bcl-2 levels in LPS-induced AML12 and LO2 cells, and septic liver of mice. Furthermore, inhibition of miR-103a-3p repressed LPS-induced inflammation by downregulating the expression of tumor necrosis factor, interleukin 1ß, and interleukin 6 in vitro and in vivo. Meanwhile, interfering miR-103a-3p obviously attenuated LPS-induced overactivation of oxidation via promoting expression of antioxidative enzymes, including catalase, superoxide dismutase, and glutathione in vitro and in vivo. Moreover, FBXW7 was a target of miR-103a-3p, and overexpression of FBXW7 significantly ameliorated LPS-induced septic liver injury in mice. Finally, knockdown of FBXW7 markedly reversed anti-miR-103a-3p-mediated suppression of septic liver injury in mice. In conclusion, interfering miR-103a-3p or overexpression of FBXW7 improved LPS-induced septic liver injury by suppressing apoptosis, inflammation, and oxidative reaction.

[Breeding of a new cultivar "Chuanjianghuang 1" of Sichuan Dao-di herbs Curcumae Longae Rhizoma and Curcumae Radix].

The systematic breeding method was adopted to breed a new good cultivar of Curcuma longa, named "Chuanjianghuang 1". From 2014 to 2015, two consecutive years of multi-point test were carried out in Shuangliu, Chongzhou and Wenjiang. The biological characters, phenology, agronomic characters, yield and quality indexes of "Chuanjianghuang 1" were comprehensively evaluated. The results showed that compared with local traditional species, the rhizome yield of the new cultivar "Chuanjianghuang 1" increased by 20.61%.The average content of volatile oil was higher than 24.17% and the average content of curcumin in root tuber was higher than 26.62%. The yield of root tuber increased by 54.59%.The average content of volatile oil is higher than 36.28% and the average content of curcuminoids is higher than 25.31%. Compared with "Huangsi Yujin 1", "Chuanjianghuang 1" increased the average yield of rhizome by 123.68%,the volatile oil increased by an average of 7.69%and the curcumin content increased by an average of 58.23%. The average content of volatile oil is higher than 52.82% and the average content of curcuminoids in root tuber was higher than 38.34%. The new variety "Chuanjianghuang 1" has better yield than the local traditional species, and the internal quality of rhizome and root tuber is better. Compared with "Huangsi Yujin 1", the yield of rhizome is significantly increased, and the internal quality of rhizome and root tuber is better, especially the content of curcumin in rhizome and curcuminoids in root tuber is significantly higher than that of "Huangsi Yujin 1". "Chuanjianghuang 1" is high yield, good quality, good stability and strong adaptability, which is suitable for cultivation and promotion in Chengdu Jinma River Basin, such as Shuangliu, Chongzhou, Wenjiang.

A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation.

Mutations in optineurin (OPTN) are associated with several human disorders including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma (POAG). OPTN is known to be a multifunctional autophagy receptor that plays important roles in NF-κB signaling, vesicle trafficking, maintenance of the Golgi apparatus and autophagy. Given that a loss of neurons and an abnormal aggregation of disease proteins are two key features of neurodegenerative diseases, protein quality control systems are considered to be tightly associated with neurodegeneration. In this study, we investigated the involvement of the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway, two major intracellular protein quality control systems, in the regulation of wild-type (WT) OPTN, ALS-linked mutant E478G OPTN and POAG-linked mutant E50K OPTN. Our data revealed that the UPS, not the autophagy-lysosome pathway, is the major system for degradation and aggregation of OPTN. Moreover, we found that Hrd1, an E3 ubiquitin ligase, could play an important role in the protein quality control of OPTN. Our results demonstrated that overexpression of Hrd1 increased the proteasomal degradation and microtubule-dependent aggresome formation of OPTN in the microtubular organizing center, whereas knockdown of Hrd1 stabilized OPTN and inhibited aggresome formation of OPTN.

Hashimoto's thyroiditis impairs embryo implantation by compromising endometrial morphology and receptivity markers in euthyroid mice.

BACKGROUND: Although thyroid dysfunction caused by Hashimoto's thyroiditis (HT) is believed to be related to implantation failure due to the underdevelopment of the receptive uterus, it is unknown whether HT itself, even in the euthyroid state, impairs embryo implantation associated with endometrial receptivity defects. To address whether HT itself can affect endometrial receptivity accompanied by implantation alterations, a euthyroid HT model was established in mice. METHODS: Female NOD mice were immunized twice with thyroglobulin and adjuvant to induce the experimental HT model. Four weeks after the second treatment, the mice were normally mated, and pregnant ones were sacrificed in implantation window for thyroid-related parameter and steroid hormones measurements by electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay and implantation site number calculation by uptake of Chicago Blue dye. In addition, certain morphological features of endometrial receptivity were observed by hematoxylin-eosin staining and scanning electron microscopy, and the expression of other receptivity markers were analyzed by immunohistochemistry, RT-qPCR or Western Blot. RESULTS: HT mice displayed intrathyroidal monocyte infiltration and elevated serum thyroid autoantibody levels without thyroid dysfunction, defined as euthyroid HT in humans. Euthyroid HT resulted in implantation failure, fewer pinopodes, retarded pinopode maturation, and inhibited expression of receptivity markers: estrogen receptor α (ERα), integrin ß3, leukemia inhibitory factor (LIF), and cell adhesion molecule-1 (ICAM-1). Interestingly, despite this compromised endometrial receptivity response, no statistical differences in serum estradiol or progesterone level between groups were found. CONCLUSIONS: These findings are the first to indicate that HT induces a nonreceptive endometrial milieu in the euthyroid state, which may underlie the detrimental effects of HT itself on embryo implantation.