The present study was aimed at exploring the protective effects of Salvianolic acid B (SalB) against paraquat (PQ)-induced lung injury in mice. Lung fibrotic injuries were induced in mice by a single intragastrical administration of 300mg/kg PQ, then the mice were administrated with 200mg/kg, 400mg/kg SalB, 100mg/kg vitamin C (Vit C) and dexamethasone (DXM) for 14days. PQ-triggered structure distortion, collagen overproduction, excessive inflammatory infiltration, pro-inflammatory cytokine release, and oxidative stress damages in lung tissues and mortality of mice were attenuated by SalB in a dose-dependent manner. Furthermore, SalB was noted to enhance the expression and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and reduce expression of the reactive oxygen species-generating enzyme Nox4 [NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase-4]. SalB also inhibited the increasing expression of transforming growth factor (TGF)-β1 and the phosphorylation of its downstream target Smad3 which were enhanced by PQ. These results suggest that SalB may exert protective effects against PQ-induced lung injury and pulmonary fibrosis. Its mechanisms involve the mediation of Nrf2/Nox4 redox balance and TGF-β1/Smad3 signaling.

Contact hypersensitivity (CHS) mouse model induced by 2, 4-dinitrofluorobenzene (DNFB) is thought to be a T helper 1 (Th1)-dominant response and used for investigating anti-inflammatory and immunosuppressive agents. However, it is hardly used for screening large-scale drugs because of the large number of animals and complex mechanisms involved in-vivo. In this study, we focused on whether T lymphocytes from CHS mouse model could maintain the state of immune response in-vitro and explored a suitable time for drugs screening. The results showed that CD4(+) T cells of CHS mice were higher compared with those in normal group. The expression of T-bet and GATA3 showed a Th1 shift and the levels of interleukin (IL)-2 and IL-4 also showed similar trend. Furthermore, IL-6 produced by T lymphocytes from CHS mice had a high level too. Then, we detected the effects of dexamethasone (DEX), cyclosporine A (CsA) and mycophenolate mofetil (MMF) on T lymphocytes in-vitro, and the data displayed that these immunosuppressive drugs could all inhibit the proliferation of T lymphocytes significantly. These findings suggested that T lymphocytes from CHS mice could mimic a similar immune response in-vitro, and it's also a suitable method for screening anti-inflammatory and immunosuppressive agents.

A subset of patients started on a selective serotonin reuptake inhibitor (SSRI) initially experience increased anxiety, which can lead to early discontinuation before therapeutic effects are manifest. The neural basis of this early SSRI effect is not known. Presynaptic dorsal raphe neuron (DRN) 5-HT1A receptors are known to have a critical role in affect processing. Thus we investigated the effect of acute citalopram on emotional processing and the relationship between DRN 5-HT1A receptor availability and amygdala reactivity. Thirteen (mean age 48±9 years) healthy male subjects received either a saline or citalopram infusion intravenously (10 mg over 30 min) on separate occasions in a single-blind, random order, crossover design. On each occasion, participants underwent a block design face-emotion processing task during fMRI known to activate the amygdala. Ten subjects also completed a positron emission tomography (PET) scan to quantify DRN 5-HT1A availability using [11C]CUMI-101. Citalopram infusion when compared with saline resulted in a significantly increased bilateral amygdala responses to fearful vs neutral faces (left p=0.025; right p=0.038 FWE-corrected). DRN [11C]CUMI-101 availability significantly positively correlated with the effect of citalopram on the left amygdala response to fearful faces (Z=2.51, p=0.027) and right amygdala response to happy faces (Z=2.33, p=0.032). Our findings indicate that the initial effect of SSRI treatment is to alter processing of aversive stimuli and that this is linked to DRN 5-HT1A receptors in line with evidence that 5-HT1A receptors have a role in mediating emotional processing.

Pseudolaric acid B (PB), isolated from the extract of the root bark of Pseudolarix kaempferi Gordon, has been used as a traditional remedy for the treatment of skin diseases. However, the information of PB on atopic dermatitis (AD) remains largely unknown. In the present study, oral administration with PB improved the severity scores of AD-like skin lesions dose-dependently in NC/Nga mice through reducing serum IgE, pro-inflammatory cytokines, and the infiltration of inflammatory cells. In addition, PB significantly attenuated the levels of IL-17 and IL-22, and the proportion of Th17 cells in NC/Nga mice, as well as decreased IL-17-induced inflammation in RAW264.7 cells. Moreover, PB inhibited the phosphorylation of IκBα and miR-155 expression both in NC/Nga mice and in IL-17-stimulated RAW264.7 cells, which could be reversed by GW9662, a specific antagonist for PPARγ. The incorporation of GW9662 reversed the inhibitory effect of PB on the RORγ-mediated activation of the Il17 promoter. Transfection with PPARγ luciferase reporter gene further demonstrated the enhancement of PB on PPARγ transactivation. These findings indicate that PB could ameliorate AD-like skin lesions by inhibiting IL-17-induced inflammation in a PPARγ-dependent manner, which would provide experimental evidence of PB for the therapeutic potential on AD and other inflammatory skin diseases.

A wide variety of prokaryotes possess DNA modifications consisting of sequence-specific phosphorothioates (PT) inserted by members of a five-gene cluster. Recent genome mapping studies revealed two unusual features of PT modifications: short consensus sequences and partial modification of a specific genomic site in a population of bacteria. To better understand the mechanism of target selection of PT modifications that underlies these features, we characterized the substrate recognition of the PT-modifying enzymes termed DptC, D and E in a cell extract system from Salmonella. The results revealed that double-stranded oligodeoxynucleotides underwent de novo PT modification in vitro, with the same modification pattern as in vivo, i. e., GpsAAC/GpsTTC motif. Unexpectedly, in these in vitro analyses we observed no significant effect on PT modification by sequences flanking GAAC/GTTC motif, while PT also occurred in the GAAC/GTTC motif that could not be modified in vivo. Hemi-PT DNA also served as substrate of the PT-modifying enzymes, but not single-stranded DNA. The PT-modifying enzymes were then found to function as a large protein complex, with all of three subunits in tetrameric conformations. This study provided the first demonstration of in vitro DNA PT modification by PT-modifying enzymes that function as a large protein complex.

Cortical gyrification of the brain represents the folding characteristic of the cerebral cortex. How the brain cortical gyrification changes from childhood to old age in healthy human subjects is still unclear. Additionally, studies have shown regional gyrification alterations in patients with major psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). However, whether the lifespan trajectory of gyrification over the brain is altered in patients diagnosed with major psychiatric disorders is still unknown. In this study, we investigated the trajectories of gyrification in three independent cohorts based on structural brain images of 881 subjects from age 4 to 83. We discovered that the trajectory of gyrification during normal development and aging was not linear and could be modeled with a logarithmic function. We also found that the gyrification trajectories of patients with MDD, BD and SCZ were deviated from the healthy one during adulthood, indicating altered aging in the brain of these patients.

The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers.

Accumulating data have implicated that long noncoding RNA (lncRNA) plays an important role in osteoarthritis (OA), which may function as a competitive endogenous RNA (ceRNA) of microRNAs (miRNAs). lncRNA IGHCγ1 has been demonstrated to regulate inflammation and autoimmunity. Nonetheless, the altering effect of IGHCγ1 in OA remains unclear. This study is aimed at investigating the mechanism and function of lncRNA IGHCγ1 in OA. CCK-8, EdU, and transwell assays were used to estimate macrophage proliferation and migration. Fluorescence in situ hybridization (FISH) was performed to estimate the local expression of lncRNA IGHCγ1 in macrophages. Luciferase reporter assay was adopted to validate the ceRNA role of IGHCγ1 as miRNA sponge. lncRNA IGHCγ1 was primarily localized in macrophage cytoplasm and upregulated in OA. miR-6891-3p inhibited macrophage proliferation, migration, and inflammatory response by targeting TLR4, while lncRNA IGHCγ1 promoted TLR4 expression by functioning as a ceRNA for miR-6891-3p through the NF-κB signal in macrophages. This study strongly supports that lncRNA IGHCγ1 regulates inflammatory response via regulating the miR-6891-3p/TLR4/NF-κB axis in macrophages.

Converging evidence increasingly implicates shared etiologic and pathophysiological characteristics among major psychiatric disorders (MPDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). Examining the neurobiology of the psychotic-affective spectrum may greatly advance biological determination of psychiatric diagnosis, which is critical for the development of more effective treatments. In this study, ensemble clustering was developed to identify subtypes within a trans-diagnostic sample of MPDs. Whole brain amplitude of low-frequency fluctuations (ALFF) was used to extract the low-dimensional features for clustering in a total of 944 participants: 581 psychiatric patients (193 with SZ, 171 with BD, and 217 with MDD) and 363 healthy controls (HC). We identified two subtypes with differentiating patterns of functional imbalance between frontal and posterior brain regions, as compared to HC: (1) Archetypal MPDs (60% of MPDs) had increased frontal and decreased posterior ALFF, and decreased cortical thickness and white matter integrity in multiple brain regions that were associated with increased polygenic risk scores and enriched risk gene expression in brain tissues; (2) Atypical MPDs (40% of MPDs) had decreased frontal and increased posterior ALFF with no associated alterations in validity measures. Medicated Archetypal MPDs had lower symptom severity than their unmedicated counterparts; whereas medicated and unmedicated Atypical MPDs had no differences in symptom scores. Our findings suggest that frontal versus posterior functional imbalance as measured by ALFF is a novel putative trans-diagnostic biomarker differentiating subtypes of MPDs that could have implications for precision medicine.

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin‑6 (IL‑6) and tumor necrosis factor‑α (TNF‑α) were evaluated by ELISA. The expressions of IκBα and NF‑κB p65 were examined by reverse transcription‑quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL‑6, TNF‑α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF‑κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS‑induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI.

A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial-mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.

Xiaojin Pills was first recorded during the Qing Dynasty and have a history of nearly 300 years. It is the first choice among Chinese patent medicines for the clinical treatment of diseases of the mammary glands in contemporary traditional Chinese medicine. It was also widely used in the treatment of breast cancer, lung cancer, thyroid cancer, and other malignant tumors. Its initial administration method was "taken orally after soaking with Chinese baijiu"; however, the method was changed to "taken orally with water" within the last 40 years. There is no scientific evidence for the difference in efficacy against breast cancer between the two methods of administration.

Antidepressants are first-line treatments for major depressive disorder (MDD), but 40-60% of patients will not respond, hence, predicting response would be a major clinical advance. Machine learning algorithms hold promise to predict treatment outcomes based on clinical symptoms and episode features. We sought to independently replicate recent machine learning methodology predicting antidepressant outcomes using the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) dataset, and then externally validate these methods to train models using data from the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) dataset.

Post-translational modifications (PTMs) play pivotal roles in controlling the stability and activity of the tumor suppressor p53 in response to distinct stressors. Here we report an unexpected finding of a short chain fatty acid modification of p53 in human cells. Crotonic acid (CA) treatment induces p53 crotonylation, but surprisingly reduces its protein, but not mRNA level, leading to inhibition of p53 activity in a dose dependent fashion. Surprisingly this crotonylation targets serine 46, instead of any predicted lysine residues, of p53, as detected in TCEP-probe labeled crotonylation and anti-crotonylated peptide antibody reaction assays. This is further confirmed by substitution of serine 46 with alanine, which abolishes p53 crotonylation in vitro and in cells. CA increases p53-dependent glycolytic activity, and augments cancer cell proliferation in response to metabolic or DNA damage stress. Since serine 46 is only found in human p53, our studies unveil an unconventional PTM unique for human p53, impairing its activity in response to CA. Because CA is likely produced by the gut microbiome, our results also predict that this type of PTM might play a role in early human colorectal neoplasia development by negating p53 activity without mutation of this tumor suppressor gene.

The DNA phosphorothioate (PT) modification existing in many prokaryotes, including bacterial pathogens and commensals, confers multiple characteristics, including restricting gene transfer, influencing the global transcriptional response, and reducing fitness during exposure to chemical mediators of inflammation. While PT-containing bacteria have been investigated in a variety of environments, they have not been studied in the human microbiome. Here, we investigated the distribution of PT-harboring strains and verified their existence in the human microbiome. We found over 2000 PT gene-containing strains distributed in different body sites, especially in the gastrointestinal tract. PT-modifying genes are preferentially distributed within several genera, including Pseudomonas, Clostridioides, and Escherichia, with phylogenic diversities. We also assessed the PT modification patterns and found six new PT-linked dinucleotides (CpsG, CpsT, ApsG, TpsG, GpsC, ApsT) in human fecal DNA. To further investigate the PT in the human gut microbiome, we analyzed the abundance of PT-modifying genes and quantified the PT-linked dinucleotides in the fecal DNA. These results confirmed that human microbiome is a rich reservoir for PT-containing microbes and contains a wide variety of PT modification patterns.

Traumatic colon injury (TCI) is a common disease during wartime. Prolongation of posttraumatic survival time is an effective approach to patient outcome improvement. However, there is a lack of basic research in this field. This study aimed to elucidate the mechanisms underlying TCI progression and to develop novel regimens to buy time for TCI patients on the battlefield.

Current next-generation RNA-sequencing (RNA-seq) methods do not provide accurate quantification of small RNAs within a sample, due to sequence-dependent biases in capture, ligation and amplification during library preparation. We present a method, absolute quantification RNA-sequencing (AQRNA-seq), that minimizes biases and provides a direct, linear correlation between sequencing read count and copy number for all small RNAs in a sample. Library preparation and data processing were optimized and validated using a 963-member microRNA reference library, oligonucleotide standards of varying length, and RNA blots. Application of AQRNA-seq to a panel of human cancer cells revealed >800 detectable miRNAs that varied during cancer progression, while application to bacterial transfer RNA pools, with the challenges of secondary structure and abundant modifications, revealed 80-fold variation in tRNA isoacceptor levels, stress-induced site-specific tRNA fragmentation, quantitative modification maps, and evidence for stress-induced, tRNA-driven, codon-biased translation. AQRNA-seq thus provides a versatile means to quantitatively map the small RNA landscape in cells.

The relationship between circular RNAs (circRNAs) and many types of cancer has been of great interest. A novel circRNA, circBFAR, has been identified, but the functions of circBFAR and its underlying mechanism in gastric cancer (GC) have not been reported. This study was designed to investigate the role of circBFAR in GC and its downstream miRNA targets. Quantitative real-time polymerase reaction was used to detect the expression of circBFAR and miRNAs. Cell counting kit-8 and EdU were used to detect the proliferation of GC cells. Measurement of the extracellular acidification rate, oxygen consumption rate and lactate acid production were performed to assess the glycolysis levels. The results showed that circBFAR exhibited higher expression in GC tissues and cell lines. circBFAR was proven to promote GC proliferation by targeting the miR-513a-3p/hexokinase 2 (HK2) axis. Inhibition of circBFAR also led to a significant decrease in the glycolysis levels. In this study, we found a circBFAR/miR-513a-3p/HK2 axis in GC and revealed the relationship between circBFAR and glycolysis for the first time. circBFAR may serve as a novel target of GC individualized therapy.

Nearly a quarter of bipolar disorder (BD) patients were misdiagnosed as major depressive disorder (MDD) patients, which cannot be corrected until mania/hypomania develops. It is important to recognize these obstacles so that the appropriate treatment can be initiated. Thus, we sought to distinguish patients with BD from MDD, especially to identify misdiagnosed BD before mania/hypomania, and further explore potential trait features that allow accurate differential diagnosis independent of state matters. Functional magnetic resonance imaging scans were performed at baseline on 92 MDD patients and 48 BD patients. The MDD patients were then followed up for more than two years. After follow-up, 23 patients transformed into BD (tBD), and 69 patients whose diagnoses remained unchanged were eligible for unipolar depression (UD). A support vector machine classifier was trained on the amygdala-based functional connectivity (FC) of 48 BD and 50 UD patients using a novel region-based feature selection. Then, the classifier was tested on the dataset, encompassing tBD and the remaining UD. It performed well for known BD and UD and can also distinguish tBD from UD with an accuracy of 81%, sensitivity of 82.6%, specificity of 79%, and AUC of 74.6%, respectively. Feature selection results revealed that ten regions within the cortico-limbic neural circuit contributed most to classification. Furthermore, in the FC comparisons among diseases, BD and tBD shared almost overlapped FC patterns in the cortico-limbic neural circuit, and both of them presented pronounced differences in most regions within the circuit compared with UD. The FC values of the most discriminating brain regions had no prominent correlations with the severity of depression, anxiety, and mania/hypomania (FDR correction). It suggests that BD possesses some trait features in the cortico-limbic neural circuit, rendering it dichotomized by the classifier based on known-diagnosis data.

Reaumuria soongorica (Pall.) Maxim., a resurrection semi-shrub, is a typical constructive and dominant species in desert ecosystems in northwestern China. However, the gene expression characteristics of R. soongorica under drought stress have not been elucidated. Digital gene expression analysis was performed using Illumina technique to investigate differentially expressed genes (DEGs) between control and PEG-treated samples of R. soongorica. A total of 212,338 and 211,052 distinct tags were detected in the control and PEG-treated libraries, respectively. A total of 1,325 genes were identified as DEGs, 379 (28.6%) of which were up-regulated and 946 (71.4%) were down-regulated in response to drought stress. Functional annotation analysis identified numerous drought-inducible genes with various functions in response to drought stress. A number of regulatory proteins, functional proteins, and proteins induced by other stress factors in R. soongorica were identified. Alteration in the regulatory proteins (transcription factors and protein kinase) may be involved in signal transduction. Functional proteins, including flavonoid biosynthetic proteins, late embryogenesis abundant (LEA) proteins, small heat shock proteins (sHSP), and aquaporin and proline transporter may play protective roles in response to drought stress. Flavonoids, LEA proteins and sHSP function as reactive oxygen species scavenger or molecular chaperone. Aquaporin and proline transporters regulate the distribution of water and proline throughout the whole plant. The tolerance ability of R. soongorica may be gained through effective signal transduction and enhanced protection of functional proteins to reestablish cellular homeostasis. DEGs obtained in this study may provide useful insights to help further understand the drought-tolerant mechanism of R. soongorica.