Knee osteoarthritis (KOA) is a common orthopedics disease and its pathological changes at early stage are the damage and loss of articular cartilage. Traditional Chinese medicine (TCM) prescription contains multiple components and has the unique advantages of the diversity of targets.We compared the traditional Chinese medical formulae (Angelicae Pubescentis and Loranthi decotion, APLD, or Duhuo Jisheng) with a western medicine (glucosamine sulfate, GS) to treat the rat arthritis models, and tracked the outcomes.

T-UCRs, a class of long non-coding RNAs that are transcribed from ultra-conserved regions (UCRs), might play an important role in development and diseases. However, the amount of T-UCRs that are conservatively expressed in the developing nervous systems of mice, monkeys and humans is still unknown. In this study, we screened the RNA sequence signals of 481 identified UCRs in an E14.5 mouse brain from the ENCODE database and found 76 UCRs that may be transcribed into T-UCRs. To verify the expression of these potential T-UCRs, we used an RT-PCR experiment and identified that 60 T-UCRs can be expressed in the E14.5 mouse brain. Furthermore, we detected the expression conservation of 76 potential T-UCRs in two comparisons: postnatal day 0 brains of a mouse and a rhesus monkey and neural stem cells of mouse and human by RT-PCR experimentation. It was found that up to 65% of these T-UCRs were expressed in mouse, rhesus monkey and human nervous systems. Next, by testing the spatiotemporal expression pattern of these T-UCRs expressed in mouse, rhesus monkey and human nervous systems, we found that approximately 30% of the T-UCRs showed a relatively high and dynamical expression during mouse brain development. Finally, through biological process and molecular function gene ontology analysis of the host genes of intronic or exonic-antisense T-UCRs, it was discovered that most of the genes were involved in RNA splicing or RNA binding. These results suggest that T-UCRs are likely to participate in nervous system development through RNA processing.

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.

Diabetic foot ulcer (DFU) is a major complication of diabetes in the elderly population. The aim of this study was to investigate the potential mechanism of DFU at the molecular level and explore a feasible therapy for it. Using data from the Gene Expression Omnibus (GEO) database, we found that phosphatase and tensin homolog (PTEN) is differentially expressed between diabetic patients and those without diabetes. We also found that PTEN expression is regulated by glucose stimulation. In addition, decreased function of human umbilical vein endothelial cells (HUVECs) was found to be associated with reduction of PTEN. We identified microRNA-152-3p (miR-152-3p) to be a putative upstream negative regulator of PTEN, and in vivo and in vitro results indicated that miR-152-3p antagonist could restore HUVEC function and accelerate wound repair. Thus, miR-152-3p-induced downregulation of PTEN appears responsible for the delayed wound healing in DFU, and miR-152-3p inhibition may effectively accelerate wound repair, thereby providing a potential target for DFU therapy.

Liver failure altered P-glycoprotein (P-gp) function and expression at blood-brain barrier (BBB), partly owing to hyperammonemia. We aimed to examine the effects of partial portal vein ligation (PVL) plus chronic hyperammonemia (CHA) on P-gp function and expression at rat BBB. Experimental rats included sham-operation (SH), PVL, CHA and PVL+CHA. The PVL+CHA rats were developed by ammonia-containing diet for 2 weeks after operation. The brain-to-plasma concentration ratios (Kp) and apparent unidirectional influx constants (Kin) of rhodamine123 and sodium fluorescein were measured to assess function of P-gp and BBB integrity, respectively. Human cerebral microvascular endothelial cells (HCMEC/D3) were used to assess effects of ammonia on P-gp expression and function. It was found that PVL+CHA significantly decreased Kp and Kin of rhodamine123 without affecting brain distribution of fluorescein. The P-gp expressions in membrane protein in cortex and hippocampus were significantly increased in CHA and PVL +CHA rats, especially in PVL + CHA rats, while remarkably increased phosphorylated ERK1/2 was only found in PVL +CHA rats. Expressions of tight junction proteins claudin-5 and occluding in rat brain remained unchanged. In vitro data showed that NH4Cl increased reactive oxygen species, membrane expression and function of P-gp as well as phosphorylated ERK1/2 levels in HCMEC/D3. The NH4Cl-induced alterations were reversed by reactive oxygen species scavenger N-acetylcysteine and ERK1/2 inhibitor U0126. In conclusion, PVL+CHA increased function and membrane translocation of P-gp at rat BBB partly via ammonia. Reactive oxygen species/ERK1/2 pathway activation may be one of the reasons that ammonia upregulated P-gp expression and function at BBB.

Recent impressive advances in cancer immunotherapy have been largely derived from cellular immunity. The role of humoral immunity in carcinogenesis has been less understood. Based on our previous observations we hypothesize that an immunoglobulin subtype IgG4 plays an essential role in cancer immune evasion.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

The benefits and risks of inhibiting the proliferation and migration of vascular smooth muscle cells (VSMCs) in atherosclerosis (AS) remain a subject of debate. In this study, we investigated the effect of ferulic acid (FA) on the proliferation and migration of VSMCs induced by platelet-derived growth factor (PDGF) and the associated mechanism and used ApoE-/- mice to study whether the effect of FA on VSMC proliferation and migration is beneficial in alleviating AS plaques. It was found that FA not only reduced blood lipid levels but also promoted the production of nitric oxide (NO) by MOVAS cells through the endothelial nitric oxide synthase (eNOS) pathway, inhibited the migration and proliferation of VSMCs induced by PDGF, promoted the expression of p21 in VSMCs, and exerted a therapeutic effect against AS.

The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.

As the indication for immunotherapy is rapidly expanding, it is crucial to accurately identify patients who are likely to respond. Infiltration of B cells into many tumor types correlates with a good response to immune checkpoint inhibitor (ICI) therapy. However, B cells' roles in the anti-tumor response are far from clear.

As a common complication in elderly patients after surgery/anesthesia, postoperative cognitive dysfunction (POCD) is mainly characterized by memory, attention, motor, and intellectual retardation. Neuroinflammation is one of the most uncontroversial views in POCD. The sevoflurane-induced neurotoxicity has attracted widespread attention in recent years. However, its mechanism has not been determined. This study aimed to observe the effects of sevoflurane on cognitive function and the changes in inflammatory indices and autophagy protein expression in the prefrontal cortex in aged rats.

As one of the most important crops in the world, rice (Oryza sativa) is a model plant for metabolome research. Although many studies have focused on the analysis of specific tissues, the changes in metabolite abundance across the entire life cycle have not yet been determined. In this study, combining both targeted and nontargeted metabolite profiling methods, a total of 825 annotated metabolites were quantified in rice samples from different tissues covering the entire life cycle. The contents of metabolites in different tissues of rice were significantly different, with various metabolites accumulating in the plumule and radicle during seed germination. Combining these data with transcriptome data obtained from the same time period, we constructed the Rice Metabolic Regulation Network. The metabolites and co-expressed genes were further divided into 12 clusters according to their accumulation patterns, with members within each cluster displaying a uniform and clear pattern of abundance across development. Using this dataset, we established a comprehensive metabolic profile of the rice life cycle and used two independent strategies to identify novel transcription factors-namely the use of known regulatory genes as bait to screen for new networks underlying lignin metabolism and the unbiased identification of new glycerophospholipid metabolism regulators on the basis of tissue specificity. This study thus demonstrates how guilt-by-association analysis of metabolome and transcriptome data spanning the entire life cycle in cereal crops provides novel resources and tools to aid in understanding the mechanisms underlying important agronomic traits.

In this study, we investigated whether transcutaneous electrical acupoint stimulation (TEAS) could improve cognitive function in VD rats by regulating PINK1/Parkin-mediated mitophagy. VD rat model was prepared by modified 2-vessel occlusion (2-VO) and randomly divided into four groups: Sham group (Sham), Model group (Model), TEAS group (TEAS), and TEAS + 3-MA group (T +3 -MA). In the T +3 -MA group, autophagy inhibitor (3-MA) was injected into the lateral ventricle. After modeling, Y maze (YM), new object recognition test (NORT), Morris water maze (MWM), immunofluorescence, and Western blot were used to observe the effects of TEAS on VD rats. Behavioral experiments revealed that TEAS effectively improved the learning and memory ability of VD rats. Immunofluorescence results showed that TEAS could upregulate LC3 expression. Western blot results showed that TEAS upregulated the expression of PINK1, Parkin, and LC3-II, and downregulated the expression of LC3-I and p62 in VD rats. T +3 -MA group shows the opposite trend to TEAS group. This study demonstrates that TEAS ameliorates cognitive function through PINK1/Parkin-mediated mitophagy in VD rats.

The coconut is an important tropical economical crop and exhibits high tolerance to various types of salinity stress. However, little is known about the molecular mechanism underlying its salt tolerance. In this study, RNA-Seq was applied to examine the different genes expressed in four coconut varieties when exposed to a salt environment, resulting in the generation of data for 48 transcriptomes. Comparative transcriptome analysis showed that some genes involved in cutin and wax biosynthesis were significantly upregulated in salt treatment compared to the control, including CYP86A4, HTH, CER1, CER2, CER3, DCR, GPAT4, LTP3, LTP4, and LTP5. In particular, the expression of CER2 was induced more than sixfold, with an RPKM value of up to 205 ten days after salt treatment in Hainan Tall coconut, demonstrating superior capacity in salt tolerance compared to dwarf coconut varieties. However, for yellow dwarf and red dwarf coconut varieties, the expression level of the CER2 gene was low at four different time points after exposure to salt treatment, suggesting that this gene may contribute to the divergence in salt tolerance between tall and dwarf coconut varieties. Cytological evidence showed a higher abundance of cuticle accumulation in tall coconut and severe damage to cuticular wax in dwarf coconut.

Neurogenesis is a complex process that depends on the delicate regulation of spatial and temporal gene expression. In our previous study, we found that transcribed ultra-conserved regions (T-UCRs), a class of long non-coding RNAs that contain UCRs, are expressed in the developing nervous systems of mice, rhesus monkeys, and humans. In this study, we first detected the full-length sequence of T-uc.189, revealing that it was mainly concentrated in the ventricular zone (VZ) and that its expression decreased as the brain matured. Moreover, we demonstrated that knockdown of T-uc.189 inhibited neurogenesis. In addition, we found that T-uc.189 positively regulated the expression of serine-arginine-rich splicing factor 3 (Srsf3). Taken together, our results are the first to demonstrate that T-uc.189 regulates the expression of Srsf3 to maintain normal neurogenesis during cortical development.

Ewing sarcoma (ES) is a cancer that may originate from stem mesenchymal or neural crest cells and is highly prevalent in children and adolescents. In recent years, targeted therapies against immune-related genes have shown good efficacy in a variety of cancers. However, effective targets for immunotherapy in ES are yet to be developed. In our study, we first identified the immune-associated differential hub gene NPM1 by bioinformatics methods as a differentially expressed gene, and then validated it using real time-PCR and western blotting, and found that this gene is not only closely related to the immune infiltration in ES, but also can affect the proliferation and apoptosis of ES cells, and is closely related to the survival of patients. The results of our bioinformatic analysis showed that NPM1 can be a hub gene in ES and an immunotherapeutic target to reactivate immune infiltration in patients with ES. In addition, treatment with NPM1 promoted apoptosis and inhibited the proliferation of ES cells. The NPM1 inhibitor NSC348884 can induce apoptosis of ES cells in a dose-dependent manner and is expected to be a potential therapeutic agent for ES.

The three-dimensional organization of the genome in the nucleus plays an integral role in many biological processes, including gene expression. The genome is folded into DNA loops that bring together distal regulatory elements and genes. Cohesin, a ring-shaped protein complex, is a major player in the formation of DNA loops. Cohesin is composed of a core trimer and one of two variant STAG subunits, STAG1 or STAG2. It is not understood whether variant STAG proteins give rise to cohesin complexes with distinct functions. Recent studies have begun to characterize the roles of STAG1 and STAG2, with partially contradictory results.

Glioma, the most common primary malignancy in the brain, has high recurrence and lethality rates, and thus, elucidation of the molecular mechanisms of this incurable disease is urgently needed. Poly-pyrimidine tract binding protein (PTBP1, also known as hnRNP I), an RNA-binding protein, has various mechanisms to promote gliomagenesis. However, the mechanisms regulating PTBP1 expression are unclear. Herein, we report a novel natural antisense noncoding RNA, PTB-AS, whose expression correlated positively with PTBP1 mRNA. We found that PTB-AS significantly promoted the proliferation and migration in vivo and in vitro of glioma cells. PTB-AS substantially increased the PTBP1 level by directly binding to its 3' UTR and stabilizing the mRNA. Furthermore, staphylococcal nuclease domain-containing 1 (SND1) dramatically increased the binding capacity between PTB-AS and PTBP1 mRNA. Mechanistically, PTB-AS could mask the binding site of miR-9 in the PTBP1-3' UTR; miR-9 negatively regulates PTBP1. To summarize, we revealed that PTB-AS, which maintains the PTBP1 level through extended base pairing to the PTBP1 3' UTR with the assistance of SND1, could significantly promote gliomagenesis.

Non-alcoholic fatty liver (NAFLD) and its related metabolic syndrome have become major threats to human health, but there is still a need for effective and safe drugs to treat these conditions. Here we aimed to identify potential drug candidates for NAFLD and the underlying molecular mechanisms.

Plants have evolved many metabolites to meet the demands of growth and adaptation. Although strigolactones (SLs) play vital roles in controlling plant architecture, their function in regulating plant metabolism remains elusive. Here we report the integrative metabolomic and transcriptomic analyses of two rice SL mutants, d10 (a biosynthesis mutant) and d14 (a perception mutant). Both mutants displayed a series of metabolic and transcriptional alterations, especially in the lipid, flavonoid, and terpenoid pathways. Levels of several diterpenoid phytoalexins were substantially increased in d10 and d14, together with the induction of terpenoid gene cluster and the corresponding upstream transcription factor WRKY45, an established determinant of plant immunity. The fact that WRKY45 is a target of IPA1, which acted as a downstream transcription factor of SL signaling, suggests that SLs contribute to plant defense through WRKY45 and phytoalexins. Moreover, our data indicated that SLs may modulate rice metabolism through a vast number of clustered or tandemly duplicated genes. Our work revealed a central role of SLs in rice metabolism. Meanwhile, integrative analysis of the metabolome and transcriptome also suggested that SLs may contribute to metabolite-associated growth and defense.