Relaxivity Enhancement of Hybrid Micelles via Modulation of Water Coordination Numbers for Magnetic Resonance Lymphography.

Considerable efforts have been made to develop nanoparticle-based magnetic resonance contrast agents (CAs) with high relaxivity. The prolonged rotational correlation time (τR) induced relaxivity enhancement is commonly recognized, while the effect of the water coordination numbers (q) on the relaxivity of nanoparticle-based CAs gets less attention. Herein, we first investigated the relationship between T1 relaxivity (r1) and q in manganese-based hybrid micellar CAs and proposed a strategy to enhance the relaxivity by increasing q. Hybrid micelles with different ratios of amphiphilic manganese complex (MnL) and DSPE-PEG2000 were prepared, whose q values were evaluated by Oxygen-17-NMR spectroscopy. Micelles with lower manganese doping density exhibit increased q and enhanced relaxivity, corroborating the conception. In vivo sentinel lymph node (SLN) imaging demonstrates that DSPE-PEG/MnL micelles could differentiate metastatic SLN from inflammatory LN. Our strategy makes it feasible for relaxivity enhancement by modulating q, providing new approaches for the structural design of high-performance hybrid micellar CAs.

Diabetic foot wound ulcers management by vacuum sealing drainage: A meta-analysis.

The meta-analysis aimed to assess and compare diabetic foot wound ulcer management by vacuum sealing drainage. Using dichotomous or contentious random- or fixed-effects models, the outcomes of this meta-analysis were examined, and the odds ratio (OR) and the mean difference (MD) with 95% confidence intervals (CIs) were computed. Twenty-three examinations from 2000 to 2023 were enrolled for the present meta-analysis, including 1928 individuals with diabetic foot ulcers. Vacuum sealing drainage had significantly lower wound healing (OR, 2.35; 95% CI, 1.79-3.08, p < 0.001), lower duration of therapy (MD, -6.19; 95% CI, -10.06 to -2.32, p = 0.002), higher wound size reduction (MD, 4.22; 95% CI, 0.87-7.56, p = 0.01) and lower complication (OR, 0.32; 95% CI, 0.13-0.80, p = 0.01) compared with standard therapy in patients with diabetic foot ulcers. The examined data revealed that vacuum sealing drainage had significantly lower wound healing, duration of therapy and complication rates, as well as higher wound size reduction, compared with standard therapy in patients with diabetic foot ulcers. Yet, attention should be paid to its values since most of the selected examinations had a low sample size.

Chiral Osmium(II)/Salox Species Enabled Enantioselective γ-C(sp3)-H Amidation: Integrated Experimental and Computational Validation For the Ligand Design and Reaction Development.

Herein, multiple types of chiral Os(II) complexes have been designed to address the appealing yet challenging asymmetric C(sp3)-H functionalization, among which the Os(II)/Salox species is found to be the most efficient for precise stereocontrol in realizing the asymmetric C(sp3)-H amidation. As exemplified by the enantioenriched pyrrolidinone synthesis, such tailored Os(II)/Salox catalyst efficiently enables an intramolecular site-/enantioselective C(sp3)-H amidation in the γ-position of dioxazolone substrates, in which benzyl, propargyl and allyl groups bearing various substituted forms are well compatible, affording the corresponding chiral γ-lactam products with good er values (up to 99 : 1) and diverse functionality (>35 examples). The unique performance advantage of the developed chiral Os(II)/Salox system in terms of the catalytic energy profile and the chiral induction has been further clarified by integrated experimental and computational studies.

PEGylated Amphiphilic Gd-DOTA Backboned-Bound Branched Polymers as Magnetic Resonance Imaging Contrast Agents.

MRI contrast agents with high kinetic stability and relaxivity are the key objectives in the field. We previously reported that Gd-DOTA backboned-bound branched polymers possess high kinetic stability and significantly increased T1 relaxivity than traditional branched polymer contrast agents. In this work, non-PEGylated and PEGylated amphiphilic Gd-DOTA backboned-bound branched polymers [P(GdDOTA-C6), P(GdDOTA-C10), mPEG-P(GdDOTA-C6), and mPEG-P(GdDOTA-C10)] were obtained by sequential introduction of rigid carbon chains (1,6-hexamethylenediamine or 1,10-diaminodecane) and mPEG into the structure of Gd-DOTA backboned-bound branched polymers. It is found that the introduction of both rigid carbon chains, especially the longer one, and mPEG can increase the kinetic stability and T1 relaxivity of Gd-DOTA backboned-bound branched polymers. Among them, mPEG-P(GdDOTA-C10) possesses the highest kinetic stability (significantly higher than those of linear Gd-DTPA and cyclic Gd-DOTA-butrol) and T1 relaxivity (42.9 mM-1 s-1, 1.5 T), 11 times that of Gd-DOTA and 1.4 times that of previously reported Gd-DOTA backboned-bound branched polymers. In addition, mPEG-P(GdDOTA-C10) showed excellent MRA effect in cardiovascular and hepatic vessels at a dose (0.025 or 0.05 mmol Gd/kg BW) far below the clinical range (0.1-0.3 mmol Gd/kg BW). Overall, effective branched-polymer-based contrast agents can be obtained by a strategy in which rigid carbon chains and PEG were introduced into the structure of Gd-DOTA backbone-bound branched polymers, resulting in excellent kinetic stability and enhanced T1 relaxivity.

The inter-link of ageing, cancer and immunity: findings from real-world retrospective study.

BACKGROUND: Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. METHODS: In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. RESULTS: Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P < 0.0001). For cancer patients, the reference range of circulating percentage of PD-1+CD45+ cells, PD-1+CD3+ T cells, PD-1+CD3+CD4+ Th cells and PD-1+CD3+CD8+ CTL (Cytotoxic T Lymphocyte, CTL) were 11.2% (95% CI 10.8%-11.6%), 15.5% (95% CI 14.7%-16.0%), 15.4% (95% CI 14.9%-16.0%) and 14.5% (95% CI 14.0%-15.5%), respectively. Moreover, the reduction of CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B cell counts accompanied with age and stage advancing (P < 0.05). CD16+CD56+ NK cells decreased with stage, but elevated in aged and male cancer patients (P < 0.05). Additionally, the percentage of PD-1 positive cells varied across cancer types, raised with age and stage. Head and neck, pancreatic, gynaecological and lung demonstrated a higher level of the percentage of PD-1 positive cells than melanoma, prostate, and breast cancer (P < 0.05). CONCLUSIONS: This study provides the reference range of the percentage of PD-1 positive cells on peripheral blood, confirms the decreased immune cells and a series of immune changes accompanying with cancer, expands our real world evidence to better understand the interactions of ageing, cancer and immunity. Moreover, the circulating percentage of PD-1 positive cells shows similar tumor type distribution with tumor mutational burden (TMB), supports that it maybe a potential predictive biomarker for immune checkpoint inhibitor therapy.

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma.

BACKGROUND: The prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study's objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. METHODS: This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. RESULTS: Fifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred. CONCLUSION: Apatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable. CLINICALTRIALS.GOV IDENTIFIER: NCT03383237.

The m6 A reader MhYTP2 regulates MdMLO19 mRNA stability and antioxidant genes translation efficiency conferring powdery mildew resistance in apple.

N6 -methyladenosine (m6 A) reader protein plays an important role in trichome morphology, developmental timing and morphogenesis in Arabidopsis. However, the function of m6 A readers in plant-microbe interaction remains unclear. Here, a Malus YTH-domain family protein MhYTP2 was initially characterized as an m6 A reader. MhYTP2 overexpression increased mRNA m6 A modification level and translation efficiency. The m6 A in the exon regions appeared to destabilize the mRNAs, whereas m6 A in the untranslated regions positively correlated with the associated mRNA abundance. MhYTP2 overexpression enhanced apple powdery mildew resistance, possibly by rapidly degrading the bound mRNAs of MdMLO19 and MdMLO19-X1 and improving the translation efficiency of the antioxidant genes. To conclude, the results shed light on the apple m6 A profile, the effect of MhYTP2 on m6 A profile, and the m6 A roles in MdMLO19 and MdMLO19-X1 mRNAs stability and glutamate dehydrogenase 1-like MdGDH1L mRNA translation efficiency.

The bidirectional association of C-peptide with cardiovascular risk in nondiabetic adults and patients with newly diagnosed type 2 diabetes mellitus: a retrospective cohort study.

BACKGROUND: Recent literature reported the biological role of C-peptide, but this role is still controversial and unclear. The primary aim of this study was to investigate associations between C-peptide and cardiovascular biomarkers as well as events. METHODS: A total of 55636 participants who had a health examination from 2017 to 2021 were included. Of them, 6727 participants visited the hospital at least twice. Cardiovascular biomarkers like high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured and their relationships with fasting C-peptide were evaluated for all participants. Cardiovascular events were obtained during the last visit and their associations with C-peptide were evaluated for those participants who visited the hospital at least twice. RESULTS: Among the included participants, 11.1% had a previous type 2 diabetes mellitus (T2DM). In the participants without previous T2DM, the relationships between fasting C-peptide and hs-CRP and hs-cTnT were negative if the value of fasting C-peptide was < 1.4 ng/mL and positive if the value was ≥ 1.4 ng/mL. These relationships remained significant after adjusting for hemoglobin A1c, insulin resistance index, and its interaction with C-peptide, even if the participants were stratified by glucose metabolism status or levels of insulin resistance index. Hazard ratios of cardiovascular events were first decreased and then increased with the increasing of baseline C-peptide levels, though these associations became unsignificant using the multivariate Cox regression model. Unlike the participants without previous T2DM, the associations of C-peptide with cardiovascular biomarkers and events were not significant in the patients with previous T2DM. CONCLUSIONS: The associations of C-peptide with cardiovascular biomarkers and events were different between the participants without previous T2DM and those with previous T2DM. The effect of C-peptide on cardiovascular risk may be bidirectional, play a benefit role at a low level, and play a harmful role at a high level in the nondiabetic adults and the patients with newly diagnosed T2DM.

Long-term survival of a patient with microsatellite-stable refractory colorectal cancer with regorafenib and PD-1 inhibitor sintilimab: a case report and review of literature.

BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer worldwide and poses a serious challenge for clinicians. Previous studies have shown promising results in patients with Microsatellite Stable microsatellite-stable CRC refractory to chemotherapy upon treating with (Programmed Cell Death Protein 1) PD-1 inhibitor combined with regorafenib. Herein, we report a unique case of a patient for whom the conventional chemotherapy and radiotherapy were ineffective, but showed a prolonged stable disease with third-line treatment with regorafenib and PD-1 inhibitor, sintilimab. CASE PRESENTATION: A 64-year-old East Asian female patient was admitted to a regional cancer hospital presenting with abdominal unease due to increased stool frequency and bloody stool. Digital anal examination revealed adenocarcinoma, while genetic profiling of the tumor resections detected wild-type KRAS mutations in codon 12 and 13. Microsatellite instability (MSI) analysis for detecting germline mutations of (Mismatch-repair) MMR genes showed stable phenotype. In December 2016, Miles' resection for intestinal adhesion release and iliac vessel exploration in the rectum was performed (Tumor, Node, Metastasis [TNM]: T3N0M0; stage IIA). The adjuvant chemotherapeutic regimen consisted of a combination of capecitabine at 1.5 g (twice daily) and oxaliplatin therapy at 200 mg for three cycles from February 2016; followed by administering capecitabine tablets orally (1.5 g bid) for five cycles as post-operative palliative care. The patient tested positive for hepatic C virus, which was managed by oral antiviral agents. Following recurrence of rectal adenocarcinoma after 4 years and disease progression with a previous chemotherapeutic regimen, regorafenib was administered at 120 mg once daily combined with sintilimab 200 mg, and the patient's progress was monitored. A follow-up computerized tomography imaging in March 2020 showed disease progression, additionally presented nodule formation (TNM: T3NxM1b; stage IVB). According to Response Evaluation Criteria in Solid Tumors criteria (RECIST), the patient showed a complete response (CR) after treatment with regorafenib and sintilimab immunotherapy. CONCLUSION: Data from this clinical case report support future exploration of combination treatment of the oral multi-kinase inhibitor regorafenib with PD-1 targeted monoclonal antibodies in patients with metastatic microsatellite-stable CRC.

JNK1 regulates RANKL-induced osteoclastogenesis via activation of a novel Bcl-2-Beclin1-autophagy pathway.

JNK1 plays an important role in osteoclastogenesis in response to the osteoclastogenic cytokine receptor activator for nuclear factor-κB ligand (RANKL). JNK1 is widely accepted as an autophagy regulator under stress conditions. However, the role of JNK1-mediated autophagy in osteoclastogenesis remains largely unknown. In the current study, our data showed that JNK1 inhibition by a pharmacological inhibitor or RNA interference significantly reduced the autophagic response induced by RANKL in osteoclast precursors (OCPs) derived from bone marrow-derived macrophages. Overexpression of the key autophagy protein Beclin1 rescued autophagy deficiency and osteoclastogenesis in the presence of a JNK inhibitor (SP600125). In contrast, JNK activator (anisomycin)-induced autophagy was blocked by Beclin1 knockdown in OCPs. In addition, JNK1 inhibition increased apoptosis and blocked autophagy, whereas overexpression of Beclin1 reversed the enhanced apoptosis induced by JNK1 inhibition in OCPs. Furthermore, RANKL could induce the phosphorylation of Bcl-2, subsequently dissociating Beclin1 from the Bcl-2-Beclin1 complex, which could be blocked by JNK1 inhibition. Collectively, this study revealed that JNK1 regulated osteoclastogenesis by activating Bcl-2-Beclin1-autophagy signaling in addition to the classic c-Jun/activator protein 1 pathway, which provided the first evidence for the contribution of JNK1 signaling to OCP autophagy and the autophagic mechanism underlying JNK1-regulated osteoclastogenesis. An important osteoclastogenesis-regulating signaling pathway (JNK1-Bcl-2-Beclin1-autophagy activation) was identified, which provides novel potential targets for the clinical therapy of metabolic bone diseases.-Ke, D., Ji, L., Wang, Y., Fu, X., Chen, J., Wang, F., Zhao, D., Xue, Y., Lan, X., Hou, J. JNK1 regulates RANKL-induced osteoclastogenesis via activation of a novel Bcl-2-Beclin1-autophagy pathway.

Puerarin inhibits the migration of osteoclast precursors and osteoclastogenesis by inhibiting MCP-1 production.

Puerarin inhibits osteoclastogenesis and cells migration. This study aims to explore whether puerarin prevents osteoclastogenesis by inhibiting osteoclast precursors (OCPs) migration. The results showed that puerarin reduced MCP-1 production in OCPs, while inhibiting OCPs migration based on MCP-1. Puerarin reversed MCP-1-promoted osteoclastogenesis. CCR2 overexpression didn't increase osteoclastogenesis with puerarin. Therefore, puerarin prevents OCPs migration by reducing MCP-1, whereby inhibiting osteoclastogenesis.

Reversible and Distance-Controllable DNA Scissor: A Regenerated Electrochemiluminescence Biosensing Platform for Ultrasensitive Detection of MicroRNA.

Reversing the switching of DNA scissors with precisely control remains a compelling goal. Herein, based on strand displacement reaction within single step, the DNA scissor realized reversible switching and further controlled the distance of end strands along the movement of DNA scissor, which has been applied for the development of a regenerated sensing platform for the ultrasensitive detection of microRNA-21 (miRNA-21) with the electrochemiluminescence (ECL) complex (PEI-Ru(II)) as luminophores and diethylenetriamine (DETA) as the coreactant. In the presence of ferrocene-labeled DNA (Fc-DNA), the DETA-labeled DNA scissor clockwise switched to "off" state based on strand displacement reaction, resulting in the significant ECL quenching of Ru(II) system. Next, by using miRNA-21 as the motive fuel, the configuration of DNA scissor could be anticlockwise switched, which significantly enhanced the ECL intensity of Ru(II) complex due to the releasing of Fc-DNA and the proximity between DETA and Ru(II) complex. The reversible switching of DNA scissor led to the remarkably enhancing of ECL signal, realizing ultrasensitive detection of miRNA-21 with an excellent detection limit of 0.17 fM, which was also applied in miRNA detection successfully from different cancer cells. Impressively, the reversible switching of DNA scissor biosensor was able to realize the regeneration of the biosensing platform by adding an additional single stranded DNA (ssDNA) based on strand displacement reaction within a single step, providing a novel concept for constructing simple and sensitive regenerated biosensor.

IL-17A modulates osteoclast precursors' apoptosis through autophagy-TRAF3 signaling during osteoclastogenesis.

Osteoclasts play an important role in bone remodeling. The inflammatory cytokine IL-17A could modulate the RANKL-induced osteoclastogenesis by regulating the autophagic activity. It is well accepted that protective autophagy has an anti-apoptotic effect. It is necessary to elucidate whether IL-17A can influence the apoptosis of osteoclast precursors (OCPs) through autophagy responses during osteoclastogenesis. The results showed that apoptosis of RAW264.7-derived OCPs was promoted by high levels of IL-17A, but the opposite anti-apoptotic function was shown by low levels of IL-17A. Furthermore, the enhanced apoptosis by high levels of IL-17A was reversed by overexpression of autophagy protein Beclin1; conversely, the inhibited apoptosis by low levels of IL-17A was restored by knockdown of Beclin1. It was also found that Beclin1 suppression with Beclin1 inhibitor (spautin1) could block the reduced apoptosis by low levels of IL-17A, which was recovered by TRAF3 knockdown. Moreover, the enhanced apoptosis by high levels of IL-17A decreased following the downregulation of TRAF3. Importantly, overexpression of caspase3 further attenuated osteoclastogenesis treated by high levels of IL-17A, without significantly affecting osteoclastogenesis stimulated by low levels of IL-17A. In conclusion, IL-17A modulates apoptosis of OCPs through Beclin1-autophagy-TRAF3 signaling pathway, thereby influencing osteoclastogenesis. Therefore, our study sheds lights on the improvement of clinical strategies of dental implantation or orthodontic treatment by revealing the novel targets in the bone remodeling.

Rh(III)-Catalyzed C-H Activation/Cycloisomerization of N-Phenoxyacetamides with Enynones for One-Pot Assembly of Furylated 2-Alkenylphenols.

An efficient and practical procedure for one-pot assembly of furylated 2-alkenylphenols has been achieved via the Cp*CyRh-catalyzed regioselective redox-neutral C-H activation/5-exo-dig cyclization cascade using N-phenoxyacetamides and enynones as the viable substrates. The synthetic application of such a protocol has also been demonstrated to highlight the versatility of this transformation.

Linc00210 drives Wnt/ß-catenin signaling activation and liver tumor progression through CTNNBIP1-dependent manner.

BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiation properties, accounting for tumor initiation, metastasis and drug resistance. Long noncoding RNAs are involved in many physiological and pathological processes, including tumorigenesis. DNA copy number alterations (CNA) participate in tumor formation and progression, while the CNA of lncRNAs and their roles are largely unknown. METHODS: LncRNA CNA was determined by microarray analyses, realtime PCR and DNA FISH. Liver TICs were enriched by surface marker CD133 and oncosphere formation. TIC self-renewal was analyzed by oncosphere formation, tumor initiation and propagation. CRISPRi and ASO were used for lncRNA loss of function. RNA pulldown, western blot and double FISH were used to identify the interaction between lncRNA and CTNNBIP1. RESULTS: Using transcriptome microarray analysis, we identified a frequently amplified long noncoding RNA in liver cancer termed linc00210, which was highly expressed in liver cancer and liver TICs. Linc00210 copy number gain is associated with its high expression in liver cancer and liver TICs. Linc00210 promoted self-renewal and tumor initiating capacity of liver TICs through Wnt/ß-catenin signaling. Linc00210 interacted with CTNNBIP1 and blocked its inhibitory role in Wnt/ß-catenin activation. Linc00210 silencing cells showed enhanced interaction of ß-catenin and CTNNBIP1, and impaired interaction of ß-catenin and TCF/LEF components. We also confirmed linc00210 copy number gain using primary hepatocellular carcinoma (HCC) samples, and found the correlation between linc00210 CNA and Wnt/ß-catenin activation. Of interest, linc00210, CTNNBIP1 and Wnt/ß-catenin signaling targeting can efficiently inhibit tumor growth and progression, and liver TIC propagation. CONCLUSION: With copy-number gain in liver TICs, linc00210 is highly expressed along with liver tumorigenesis. Linc00210 drives the self-renewal and propagation of liver TICs through activating Wnt/ß-catenin signaling. Linc00210 interacts with CTNNBIP1 and blocks the combination between CTNNBIP1 and ß-catenin, driving the activation of Wnt/ß-catenin signaling. Linc00210-CTNNBIP1-Wnt/ß-catenin axis can be targeted for liver TIC elimination.

IL-17A regulates the autophagic activity of osteoclast precursors through RANKL-JNK1 signaling during osteoclastogenesis in vitro.

Interleukin-17A(IL-17A), a proinflammatory cytokine, may have effects on osteoclastic resorption in inflammation-mediated bone loss, including postmenopausal osteoporosis. IL-17A could alter autophagic activity among other tissues and cells, thereby causing corresponding lesions. The aim of this study was to clarify how IL-17A influenced osteoclastogenesis by regulating autophagy. The present study showed that IL-17A could facilitate osteoclast precursors (OCPs) autophagy and osteoclastogenesis at a low concentration. Furthermore, suppression of autophagy with chloroquine (CQ) or 3-MA could significantly attenuate the enhanced osteoclastogenesis by a low level of IL-17A. It was also found that a low level of IL-17A couldn't up-regulate OCPs autophagy after removal of RANKL(Receptor Activator for Nuclear Factor-κB Ligand), and JNK(c-Jun N-terminal kinase) inhibitor only inhibited autophagy at a low level of IL-17A. These results suggest that a low concentration of IL-17A is likely to promote autophagic activity via activating RANKL-JNK pathway during osteoclastogenesis.

LncAPC drives Wnt/ß-catenin activation and liver TIC self-renewal through EZH2 mediated APC transcriptional inhibition.

Liver tumor initiating cells (TICs), a small subset cells in tumor bulk, are responsible for liver tumor initiation, metastasis, and relapse. However, the regulatory mechanism of liver TICs remains largely unknown. Here we found a long noncoding RNA lncAPC, locating near from APC locus, was highly expressed in liver cancer and liver TICs. LncAPC was required for liver TIC self-renewal. Silencing and overexpressing lncAPC showed impaired and enhanced sphere formation capacity of liver TICs, respectively. By recruiting EZH2 to APC promoter, LncAPC inhibits APC transcription and thus drives the activation of Wnt/ß-catenin signaling. Attenuate binding between EZH2 and APC promoter was observed upon lncAPC knockdown. What is more, lncAPC-EZH2-APC axis can be targeted to eliminate liver TICs. Altogether, LncAPC promotes liver TIC self-renewal through EZH2-dependent APC transcriptional inhibition.

Effects of Stratified Vitamin D Supplementation in Middle-Aged and Elderly Individuals with Vitamin D Insufficiency.

The incidence of vitamin D deficiency is high globally, and vitamin D supplementation draws particular attention. The objective of this study was to investigate the effects of stratified vitamin D supplementation in middle-aged and elderly individuals with vitamin D insufficiency in Beijing. A total of 448 subjects aged over 40 years old were selected from a community in Beijing. Among them, 100 middle-aged and elderly people with vitamin D insufficiency were randomly selected on a voluntary basis. They were further divided into control group and intervention group. The control group received health education and lifestyle guidance, and the intervention group received lifestyle guidance and vitamin D supplementation for nine months. The doses were stratified as follows: for vitamin D insufficiency, oral vitamin D3 supplement was given at 5000 IU/w; for mild vitamin D deficiency, oral vitamin D3 supplement was given at 10 000 IU/w; for severe vitamin D deficiency, oral vitamin D3 supplement was given at 15 000 IU/w. Safety evaluation was conducted after three-month treatment. The intervention group consisted of 8%, 62%, and 30% of cases who had vitamin D insufficiency, mild vitamin D deficiency, and severe vitamin D deficiency, respectively, which were similar with the control group. It showed that the blood 25(OH)D level increased significantly in the intervention group, from 14.30±4.30 ng/ml to 33.62±6.99 ng/ml (p<0.001), in contrast to insignificant change in the control group. Stratified vitamin D supplementation effectively increased the blood 25(OH)D level, as well as the number of cases with corrected vitamin D insufficiency or deficiency.

Angiotensin-(1-7)-mediated Mas1 receptor/NF-κB-p65 signaling is involved in a cigarette smoke-induced chronic obstructive pulmonary disease mouse model.

Angiotensin-(1-7) [Ang-(1-7)] has been shown to play a significant role in the pathogenesis of lung inflammation via Mas receptor; however, its effect in chronic obstructive pulmonary disease (COPD) remains unknown. To explore the effect of Ang-(1-7) on a cigarette smoke (CS) exposure-induced COPD model, 40 C57BL/6J mice were divided into four groups (n = 10) and exposed to air or CS for 8 weeks. After that, they were treated with saline or Ang-(1-7) at 0.3 mg/kg for 2 weeks by subcutaneous infusion using osmotic pump. The day following drug/vehicle challenge, lung function was examined and bronchoalveolar lavage (BAL) was performed. Chemokine (C-X-C motif) ligand 1, interleukin-6, and tumor necrosis factor-α protein levels in BAL fluid were determined using ELISA; the corresponding mRNA levels in lung tissues were measured using RT-PCR. Mas1 receptor, pIκBα, IκBα, nuclear NF-κB-p65 protein, pERK1/2, ERK2, pp38, and p38 proteins expression in lung tissues were examined by immunohistochemical staining and western blotting. Ang-(1-7) challenge had no effect on the decreased lung function and emphysema induced by CS exposure. However, Ang-(1-7) treatment blocked CS exposure-induced lung inflammatory responses and lung fibrosis, as determined by Masson's Trichrome staining. Exposure to CS for 8 weeks caused irreversible loss of lung function and emphysema, which could not be reversed by Ang-(1-7) treatment. Thus, the beneficial effect of Ang-(1-7) may be confined to pulmonary inflammation and fibrosis.