In the present study, we prepared pea peptides with high angiotensin-converting enzyme (ACE) inhibitory activity in vitro using an enzymatic hydrolysis of pea protein and compounded them with clam peptides to obtain a pea-clam double peptide. The effects of the two-peptide composite and pea peptides on hypertension and the damage-repair of corresponding organs were studied in spontaneously hypertensive rats (SHRs). We found that both pea peptides and the two-peptide composite significantly reduced the blood pressure upon a single or long-term intragastric administration, with the two-peptide composite being more effective. Mechanistically, we found that the two-peptide composite could regulate the renal renin-angiotensin system (RAS), rebalance gut microbial dysbiosis, decrease renal and myocardial fibrosis, and improve renal and cardiac function and vascular remodeling. Additionally, hippocampal lesions caused by hypertension were also eliminated after two-peptide composite administration. Our research provides a scientific basis for the use of this two-peptide composite as a safe antihypertension ingredient in functional foods.

Five novel tyrosine-decahydrofluorene analogues, xenoacremones D−H (1−5), each bearing a fused 6/5/6 tricarbocyclic core and a 13-membered para-cyclophane ring system, were isolated from the endophytic fungus Xenoacremonium sinensis. Compound 1 was a novel polyketide synthase−nonribosomal peptide synthetase (PKS−NRPS) tyrosine-decahydrofluorene hybrid containing a 6/5/6/6/5 ring system. Their structures were elucidated from comprehensive spectroscopic analysis and electronic circular dichroism (ECD) calculations. All compounds were evaluated for their inhibitory activities on LPS-induced NO production in macrophages and their cytotoxicities against the NB4 and U937 cell lines. Compounds 3 and 5 exhibited potent anti-inflammatory activities in vitro. Compounds 1 and 3−5 displayed significant antiproliferative activity against the tumor cell lines (IC50 < 20 µM).

UHMK1, a serine/threonine kinase with a U2AF homology motif, is implicated in RNA processing and protein phosphorylation. Increasing evidence has indicated its involvement in tumorigenesis. However, it remains to be elucidated whether UHMK1 plays a role in the development of colorectal cancer (CRC). Here, we demonstrated that UHMK1 was frequently upregulated in CRC samples compared with adjacent normal tissue and high expression of UHMK1 predicted poor outcomes. Knockdown of UHMK1 by siRNAs restrained CRC cell proliferation and increased oxaliplatin sensitivity, whereas overexpression of UHMK1 promoted CRC cell growth and oxaliplatin resistance, suggesting that UHMK1 plays important oncogenic roles in CRC. Mechanistically, we showed that UHMK1 had a significant effect on IL6/STAT3 signaling by interacting with STAT3. The interaction of UHMK1 with STAT3 enhanced STAT3 activity in regulating gene transcription. Furthermore, we found that STAT3 could in turn transcriptionally activate UHMK1 expression in CRC cells. The complementary experiments for cell growth and oxaliplatin resistance indicated the interdependent relationship between UHMK1 and STAT3. Thus, these collective findings uncovered a new UHMK1/STAT3 positive feedback regulatory loop contributing to CRC development and chemoresistance.

Cervical cancer is among the most cancer types, with an extremely high global incidence and mortality. Ferroptosis is a newly reported programmed cell death process that differs from apoptosis, autophagy, and necroptosis. Circular RNAs (circRNAs) are covalently closed loops generated from back-splicing pre-mRNAs, with high stability, and are abundant in the physical environment. Here, we explored the effect of circACAP2 on ferroptosis of cervical cancer. We observed that the depletion of circACAP2 by siRNAs was validated in cervical cancer cells. The cervical cancer cell viability was inhibited by circACAP2 knockdown as well. The levels of lipid ROS, iron, and Fe2+ were reduced by circACAP2 depletion in cervical cancer cells. The circACAP2 served as a ceRNA of miR-193a-5p and directly interacted with miR-193a-5p in cervical cancer cells. miR-193a-5p was able to target GPX4 and circACAP2 promoted GPX4 expression by sponging miR-193a-5p in cervical cancer cells. The knockdown of circACAP2 inhibited the cervical cancer cell viability, but the miR-193a-5p inhibitor or GPX4 overexpression could reverse the effect in the cells. The inhibition of miR-193a-5p or GPX4 overexpression repressed the circACAP2 depletion-induced levels of lipid ROS, iron, and Fe2+ in cervical cancer cells. Clinically, the expression of circACAP2 and GPX4 was upregulated, and miR-193a-5p expression was downregulated in clinical cervical cancer samples. The expression of miR-193a-5p was negatively correlated with circACAP2 and GPX4, while the circACAP2 expression was positively correlated with GPX4 in the samples. Therefore, we concluded that circular RNA circACAP2 repressed ferroptosis of cervical cancer during malignant progression by miR-193a-5p/GPX4.

microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through translational repression and mRNA destabilization. During canonical miRNA biogenesis, several miRNA isoforms, or isomiRs, are produced from a single precursor miRNA. Templated isomiRs are generated through Drosha or Dicer cleavage at alternate positions on either the primary or the precursor miRNAs, generating truncated or extended 5' and/or 3' miRNA ends. As changes to the mature miRNA sequence can alter miRNA gene target repertoire, we investigated the extent of templated isomiR prevalence, providing a profiling map for templated isomiRs across stages of C. elegans development. While most miRNA loci did not produce abundant templated isomiRs, a substantial number of miRNA loci produced isomiRs were just as, or more, abundant than their annotated canonical mature miRNAs. 3' end miRNA alterations were more frequent than the seed-altering 5' end extensions or truncations. However, we identified several miRNA loci that produced a considerable amount of isomiRs with 5' end alterations, predicted to target new, distinct sets of genes. Overall, the presented annotation of templated isomiR dynamics across C. elegans developmental stages provides a basis for further studies into miRNA biogenesis and the intriguing potential of functional miRNA diversification through isomiR production.

Substantial ultrafine zinc particles exist in air pollutions. The level of Zn concentrations in serum and tissue could affect patients with myocardial infarction (MI). The aim of the study is to investigate the change of cardiac functions and peripheral hemodynamics in MI rats after long-term inhalation of ultrafine Zn particles. Coronary artery ligation surgery was performed to induce MI in Wistar rats. The inhalation of ultrafine Zn particles was carried out for 6 weeks after the operation. Physiological and hemodynamic measurements and computational biomechanics analysis were demonstrated in eight groups of rats at postoperative 4 and 6 weeks. There was no statistical significance between shams and shams with inhalation of ultrafine Zn particles. There were significant impairments of cardiac and hemodynamic functions in MI rats. In comparison with MI rats, the inhalation of ultrafine Zn particles for 4 weeks slowed down the progression from MI to heart failure, but the inhalation for 6 weeks accelerated the process. The long-term inhalation of ultrafine zinc particles induced excessive accumulation of zinc in serum and tissue, which deteriorated cardiac and hemodynamic dysfunctions in MI rats. The findings suggested the importance for regulating Zn intake of MI patients as well as looking at ways to lower zinc concentrations in air pollutions.

Objective: To investigate the value of computed tomography-guided percutaneous lung biopsy (CT-PLB) combined with rapid on-site evaluation (ROSE) in the diagnosis of peripheral pulmonary lesions (PPLs). Methods: A total of 108 patients who diagnosed with PPLs by chest CT examination were prospectively collected and randomly divided into ROSE group (n = 56) and No-ROSE group (n = 52). Both groups received CT-PLB and pathological examination. The smear submitted for ROSE was stained using Diff Quik dye. The accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), number of punctures, puncture time and incidence of complications were compared between the two groups. Results: The accuracy, sensitivity, specificity, PPV, and NPV of the ROSE group were 89.29%, 87.50%, 91.67%, 93.33%, and 84.62%, respectively. The number of punctures in the ROSE group was significantly lower than that in the No-ROSE group (P < .05). The incidence of pneumothorax and hemoptysis in the ROSE group were lower than those in the No-ROSE group, but there was no statistical difference between the two groups (P > .05). ROSE has good concordance with routine pathological examination in the diagnosis of unidentified PPLs (Kappa = 0.786, P < .01). Conclusions: CT-PLB combined with ROSE is a safe and effective method for the diagnosis of PPLs.

In this study, graphene oxide (GO) was successfully prepared using the improved Hummers method, and the prepared GO powder was dissolved in distilled water and subjected to ultrasonic stripping. Diclofenac potassium (DCFP) was selected as a model drug to systematically evaluate the adsorption mechanism of DCFP by GO. Different reaction models were constructed to fit the adsorption kinetics and adsorption isotherms of DCFP on GO, in order to further explore the underlying adsorption mechanism. The results demonstrated that the pseudo-second-order kinetic model and Freundlich model could better delineate the adsorption process of DCFP by GO. Both π-π stacking and hydrophobic interaction were mainly involved in the adsorption process, and there were electrostatic interaction and hydrogen bonding at the same time. Then, the xanthan gum-graft-poly(acrylic acid)/GO (XG-g-PAA/GO) composite hydrogel was synthesized by in situ polymerization as a slow-release drug carrier. For this reason, a XG-g-PAA/GO-DCFP composite hydrogel was synthesized, and its in vitro drug release and pharmacokinetic data were assessed. The results showed that the synthesized XG-g-PAA/GO composite hydrogel had a certain mechanical strength and uniform color, indicating that GO is evenly distributed in this composite hydrogel. Moreover, the results of a swelling ratio test demonstrated that the swelling ratios of the XG-g-PAA/GO composite hydrogel were significantly increased with increasing pH values, implying that this material is sensitive to pH. The in vitro drug release experiment showed that the cumulative release of DCFP after 96 h was significantly higher in artificial intestinal fluid than in artificial gastric fluid. These findings indicate that the XG-g-PAA/GO-DCFP composite hydrogel exhibits pH sensitivity under physiological conditions. Besides, the results of in vivo pharmacokinetic analysis revealed that the t 1/2 of DCFP group was 2.03 ± 0.35 h, while that of the XG-g-PAA/GO-DCFP composite hydrogel group was 10.71 ± 2.04 h, indicating that the synthesized hydrogel could effectively prolong the drug action time. Furthermore, the AUC(0-t) of the DCFP group was 53.99 ± 3.18 mg L-1 h-1, while that of the XG-g-PAA/GO-DCFP composite hydrogel group was 116.79 ± 14.72 mg L-1 h-1, suggesting that the bioavailability of DCFP is greatly enhanced by this composite hydrogel. In conclusion, this study highlights that the XG-g-PAA/GO-DCFP composite hydrogel can be applied as a sustained-release drug carrier.

Western-style diet (WSD) is associated with inflammatory bowel disease (IBD) prevalence. However, the impact of WSD on IBD development and its underlying mechanism remain unclear. Transcriptomics and metabolomics could be beneficial for identifying key factors in WSD-related experimental IBD susceptibility. However, no such study has been conducted yet. We aimed to analyze the implications of WSD for experimental colitis susceptibility in mice and its underlying mechanism using these high-throughput technologies.

Removal of 5' cap on cellular mRNAs by the African swine fever virus (ASFV) decapping enzyme g5R protein (g5Rp) is beneficial to viral gene expression during the early stages of infection. As the only nucleoside diphosphate-linked moiety X (Nudix) decapping enzyme encoded in the ASFV genome, g5Rp works in both the degradation of cellular mRNA and the hydrolyzation of the diphosphoinositol polyphosphates. Here, we report the structures of dimeric g5Rp and its complex with inositol hexakisphosphate (InsP6). The two g5Rp protomers interact head to head to form a dimer, and the dimeric interface is formed by extensive polar and nonpolar interactions. Each protomer is composed of a unique N-terminal helical domain and a C-terminal classic Nudix domain. As g5Rp is an mRNA-decapping enzyme, we identified key residues, including K8, K94, K95, K98, K175, R221, and K243 located on the substrate RNA binding interfaces of g5Rp which are important to RNA binding and decapping enzyme activity. Furthermore, the g5Rp-mediated mRNA decapping was inhibited by InsP6. The g5Rp-InsP6 complex structure showed that the InsP6 molecules occupy the same regions that primarily mediate g5Rp-RNA interaction, elucidating the roles of InsP6 in the regulation of the viral decapping activity of g5Rp in mRNA degradation. Collectively, these results provide the structural basis of interaction between RNA and g5Rp and highlight the inhibitory mechanism of InsP6 on mRNA decapping by g5Rp. IMPORTANCE ASF is a highly contagious hemorrhagic viral disease in domestic pigs which causes high mortality. Currently, there are still no effective vaccines or specific drugs available against this particular virus. The protein g5Rp is the only viral mRNA-decapping enzyme, playing an essential role in the machinery assembly of mRNA regulation and translation initiation. In this study, we solved the crystal structures of g5Rp dimer and complex with InsP6. Structure-based mutagenesis studies revealed critical residues involved in a candidate RNA binding region, which also play pivotal roles in complex with InsP6. Notably, InsP6 can inhibit g5Rp activity by competitively blocking the binding of substrate mRNA to the enzyme. Our structure-function studies provide the basis for potential anti-ASFV inhibitor designs targeting the critical enzyme.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer globally, with average age of cancer patients becoming younger gradually. It is of significance to gain a comprehensive understanding of molecular mechanism underlying NSCLC.

Stemness and chemoresistance contribute to cervical cancer recurrence and metastasis. In the current study, we determined the relevant players and role of N6-methyladenine (m6A) RNA methylation in cervical cancer progression.

Colorectal cancer (CRC) is one of the most common cancers in China, and most CRC patients have already reached an advanced stage by the time of initial diagnosis. Due to the loss of health as a result of cancer, it has consequence on the treatment which may affect the psychophysical and social impairment of CRC patients. These indicators (psychophysical, function and social impairment) affect the health-related quality of life (HRQOL). There are limited studies that focus on advanced CRC patients in China. This study aimed to assess the HRQOL and its associated factors of advanced CRC patients in China.

The occurrence of head and neck squamous cell carcinoma (HNSCC) is closely related to the immune system. The integration of traditional treatment methods and immunotherapy will be the future development direction of cancer treatment. But immunotherapy also has its limitations: a lot of basic research is going on, but the translation from basic to clinical is still not enough, and there are still few drugs approved for use.This study aimed to explore the clinical significance of the tumor immune microenvironment in HNSCC.

To date, the combinational cancer therapy of anticancer and antiangiogenic agents represents a promising strategy to improve antitumor outcomes in clinics. However, combination therapy with drugs having distinct properties, such as solubility, limits the likelihood of simultaneous delivery. In our study, we aimed to develop a codelivery nanoparticulate system of hydrophilic doxorubicin (DOX) and hydrophobic itraconazole (ITZ) using liposomes coated with Pluronic® P123 (ITZ/DOX-PLip). The prepared ITZ/DOX-PLip exhibited a unimodal size distribution and high loading efficiency with sustained release profiles. Furthermore, cytotoxicity against 4T1 murine breast cancer cells and cellular uptake results revealed that the inhibitory effect of ITZ/DOX-Plip on tumor growth was superior to that of free DOX or DOX-loaded liposome (DOX-Lip), which was primarily attributed to the significantly higher intercellular DOX content. Cytotoxicity against HUVEC and wound healing tests confirmed that ITZ and ITZ formulations could inhibit the growth and migration of endothelial cells. In addition, in xenograft 4T1 bearing BALB/c mice, biodistribution experiments revealed that higher drug accumulation in tumors and decreased distribution in heart were observed for ITZ/DOX-PLip as compared to free DOX. Remarkably, ITZ/DOX-PLip significantly reduced tumor volume, tumor weight, liver metastasis and microvessel density in comparison with the same dose of ITZ injection or DOX-Lip. Overall, this Pluronic® P123 modified liposome-based codelivery system represents a promising nano-platform for combination therapy in cancers.

Aggregation of amyloid-β protein (Aβ) is hypothesized to be a seminal neuropathological event in Alzheimer's disease (AD). Recombinant expression and purification of Aβ represents a common basis for investigating the molecular mechanisms of amyloid formation and toxicity. Herein, we report a novel high-yield expression and purification method for Aβ42 based on fusion with maltose binding protein (MBP) followed by the soluble polypeptide linker (NANP)3 and a modified tobacco etch virus (TEV) cleavage site before the Aβ42. We obtained a final yield of ∼18 mg L-1 of recombinant Aβ42 that was confirmed by SDS-PAGE, protein immunoblotting and MALDI-TOF. Finally, thioflavin T fluorescence and atomic force microscopy revealed that the recombinant Aβ42 aggregated into long, branched fibrils. Furthermore, the aggregates of the recombinant peptide had a strong cytotoxic effect on PC12 cells. The method described here can therefore be used to efficiently express the soluble fusion protein MBP-Aβ42 and obtain high-purity Aβ42 peptide, which can be used to understand the molecular mechanism of Aβ42 fibrillization and screen new candidate drugs for AD.

Since December 2019, pneumonia caused by a novel coronavirus (SARS-CoV-2), namely 2019 novel coronavirus disease (COVID-19), has rapidly spread from Wuhan city to other cities across China. The present study was designed to describe the epidemiology, clinical characteristics, treatment, and prognosis of 74 hospitalized patients with COVID-19.Clinical data of 74 COVID-19 patients were collected to analyze the epidemiological, demographic, laboratory, radiological, and treatment data. Thirty-two patients were followed up and tested for the presence of the viral nucleic acid and by pulmonary computed tomography (CT) scan at 7 and 14 days after they were discharged.Among all COVID-19 patients, the median incubation period for patients and the median period from symptom onset to admission was all 6 days; the median length of hospitalization was 13 days. Fever symptoms were presented in 83.78% of the patients, and the second most common symptom was cough (74.32%), followed by fatigue and expectoration (27.03%). Inflammatory indicators, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) of the intensive care unit (ICU) patients were significantly higher than that of the non-ICU patients (P < .05). However, 50.00% of the ICU patients had their the ratio of T helper cells to cytotoxic T cells (CD4/CD8) ratio lower than 1.1, whose proportion is much higher than that in non-ICU patients (P < .01).Compared with patients in Wuhan, COVID-19 patients in Anhui Province seemed to have milder symptoms of infection, suggesting that there may be some regional differences in the transmission of SARS-CoV-2 between different cities.

Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in synovial sarcoma. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human synovial sarcoma cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, coincorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF subcomplexes that contained equal levels of SMARCB1 regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis. SIGNIFICANCE: The protein level of BAF component SMARCB1 is reduced in synovial sarcoma but plays a defining role, incorporating into PBAF and SS18-SSX-containing canonical BAF complexes. Reduced levels of SMARCB1 derive from whole-complex degradation of canonical BAF driven by SS18-SSX, with relative increases in the abundance of other BAF-family subtypes.See related commentary by Maxwell and Hargreaves, p. 2375.This article is highlighted in the In This Issue feature, p. 2355.

Epigenetic regulation disorder is important in the onset and pathogenesis of inflammatory bowel disease (IBD). SETD2, a trimethyltransferase of histone H3K36, is frequently mutated in IBD samples with a high risk of developing colorectal cancer (CRC). However, functions of SETD2 in IBD and colitis-associated CRC remain largely undefined. Here, we found that SETD2 modulates oxidative stress to attenuate colonic inflammation and tumorigenesis in mice. SETD2 expression became decreased in IBD patients and dextran sodium sulfate (DSS)-induced colitic mice. Setd2Vil-KO mice showed increased susceptibility to DSS-induced colitis, accompanied by more severe epithelial barrier disruption and markedly increased intestinal permeability that subsequently facilitated inflammation-associated CRC. Mechanistically, we found that Setd2 depletion resulted in excess reactive oxygen species (ROS) by directly down-regulating antioxidant genes, which led to defects in barrier integrity and subsequently inflammatory damage. Moreover, overexpression of antioxidant PRDX6 in Setd2Vil-KO intestinal epithelial cells (IECs) largely alleviated the overproductions of ROS and improved the cellular survival. Together, our findings highlight an epigenetic mechanism by which SETD2 modulates oxidative stress to regulate intestinal epithelial homeostasis and attenuate colonic inflammation and tumorigenesis. SETD2 might therefore be a pivotal regulator that maintains the homeostasis of the intestinal mucosal barrier.

2-Hyroxypropyl-beta-cyclodextrin (HPβCD) is being used to treat Niemann-Pick C1, a fatal neurodegenerative disease caused by abnormal cholesterol metabolism. HPβCD slows disease progression, but unfortunately causes severe, rapid onset hearing loss by destroying the outer hair cells (OHC). HPβCD-induced damage is believed to be related to the expression of prestin in OHCs. Because prestin is postnatally upregulated from the cochlear base toward the apex, we hypothesized that HPβCD ototoxicity would spread from the high-frequency base toward the low-frequency apex of the cochlea. Consistent with this hypothesis, cochlear hearing impairments and OHC loss rapidly spread from the high-frequency base toward the low-frequency apex of the cochlea when HPβCD administration shifted from postnatal day 3 (P3) to P28. HPβCD-induced histopathologies were initially confined to the OHCs, but between 4- and 6-weeks post-treatment, there was an unexpected, rapid and massive expansion of the lesion to include most inner hair cells (IHC), pillar cells (PC), peripheral auditory nerve fibers, and spiral ganglion neurons at location where OHCs were missing. The magnitude and spatial extent of HPβCD-induced OHC death was tightly correlated with the postnatal day when HPβCD was administered which coincided with the spatiotemporal upregulation of prestin in OHCs. A second, massive wave of degeneration involving IHCs, PC, auditory nerve fibers and spiral ganglion neurons abruptly emerged 4-6 weeks post-HPβCD treatment. This secondary wave of degeneration combined with the initial OHC loss results in a profound, irreversible hearing loss.