Study on the design, synthesis, and activity of anti-tumor staple peptides targeting MDM2/MDMX.

Staple peptides, which have a significantly enhanced pharmacological profile, are promising therapeutic molecules due to their remarkable resistance to proteolysis and cell-penetrating properties. In this study, we designed and synthesized a series of PMI-M3-based dual-targeting MDM2/MDMX staple peptides and compared them with straight-chain peptides. The staple peptide SM3-4 screened in the study induced apoptosis of tumor cells in vitro at low µM concentrations, and the helix was significantly increased. Studies have shown that the enhancement of staple activity is related to the increase in helicity, and SM3-4 provides an effective research basis for dual-targeted anti-tumor staple peptides.

Coronary inflammation based on pericoronary adipose tissue attenuation in type 2 diabetic mellitus: effect of diabetes management.

BACKGROUND: Coronary inflammation plays crucial role in type 2 diabetes mellitus (T2DM) induced cardiovascular complications. Both glucose-lowering drug interventions (GLDIS) and glycemic control (GC) status potentially correlate coronary inflammation, as indicated by changes in pericoronary adipose tissue (PCAT) attenuation, and thus influence cardiovascular risk. This study evaluated the impact of GLDIS and GC status on PCAT attenuation in T2DM patients. METHODS: This retrospective study collected clinical data and coronary computed tomography angiography (CCTA) images of 1,342 patients, including 547 T2DM patients and 795 non-T2DM patients in two tertiary hospitals. T2DM patients were subgroup based on two criteria: (1) GC status: well: HbA1c < 7%, moderate: 7 ≤ HbA1c ≤ 9%, and poor: HbA1c > 9%; (2) GLDIS and non-GLDIS. PCAT attenuations of the left anterior descending artery (LAD-PCAT), left circumflex artery (LCX-PCAT), and right coronary artery (RCA-PCAT) were measured. Propensity matching (PSM) was used to cross compare PCAT attenuation of non-T2DM and all subgroups of T2DM patients. Linear regressions were conducted to evaluate the impact of GC status and GLDIS on PCAT attenuation in T2DM patients. RESULTS: Significant differences were observed in RCA-PCAT and LCX-PCAT between poor GC-T2DM and non-T2DM patients (LCX: - 68.75 ± 7.59 HU vs. - 71.93 ± 7.25 HU, p = 0.008; RCA: - 74.37 ± 8.44 HU vs. - 77.2 ± 7.42 HU, p = 0.026). Higher PCAT attenuation was observed in LAD-PCAT, LCX-PCAT, and RCA-PCAT in non-GLDIS T2DM patients compared with GLDIS T2DM patients (LAD: - 78.11 ± 8.01 HU vs. - 75.04 ± 8.26 HU, p = 0.022; LCX: - 71.10 ± 8.13 HU vs. - 68.31 ± 7.90 HU, p = 0.037; RCA: - 78.17 ± 8.64 HU vs. - 73.35 ± 9.32 HU, p = 0.001). In the linear regression, other than sex and duration of diabetes, both metformin and acarbose were found to be significantly associated with lower LAD-PCAT (metformin: ß coefficient = - 2.476, p=0.021; acarbose: ß coefficient = - 1.841, p = 0.031). CONCLUSION: Inadequate diabetes management, including poor GC and lack of GLDIS, may be associated with increased coronary artery inflammation in T2DM patients, as indicated by PCAT attenuation on CCTA, leading to increased cardiovascular risk. This finding could help healthcare providers identify T2DM patients with increased cardiovascular risk, develop improved cardiovascular management programs, and reduce subsequent cardiovascular related mortality.

Efficacy of Qingpeng ointment (a Tibetan medicine) for acute gouty arthritis: a multi-center, randomized, double-blind, placebo-controlled trial.

BACKGROUND: This study aims to assess the efficacy and safety of Qingpeng ointment (QPO), a Tibetan medicine for alleviating symptoms in individuals with acute gouty arthritis (AGA). METHODS: This study was a randomized, double-blind, placebo-controlled trial that involved individuals with AGA whose joint pain, as measured on a visual analog scale (VAS) from 0 to 10, was equal to or greater than 3. The participants were randomly assigned to either the QPO or the placebo group and received their respective treatments twice daily for seven consecutive days. In case of intolerable pain, the participants were allowed to use diclofenac sodium sustained-release tablets as a rescue medicine. The primary outcomes measured were joint pain and swelling, while the secondary outcomes included joint mobility, redness, serum uric acid levels, C-reactive protein levels, and the amount of remaining rescue medicine. Any adverse events that occurred during the trial were also recorded. RESULTS: A total of 203 cases were divided into two groups, with balanced baselines: 102 in the QPO group and 101 in the placebo group. For joint pain, differences between the groups were notable in the VAS scores [1.75 (0, 3.00) versus 2.00 (1.00, 3.50); P = 0.038], changes in VAS [5.00 (3.00, 6.00) versus 4.00 (2.00, 6.00); P = 0.036], and disappearance rate [26.47% compared to 15.84%; P = 0.046] after treatment. Concerning joint swelling, significant between-group differences were observed in the VAS scores [1.00 (0, 2.30) versus 2.00 (0.70, 3.00); P = 0.032] and disappearance rate [33.33% compared to 21.78%; P = 0.046] at treatment completion. The QPO group exhibited a statistically significant mobility improvement compared to the placebo group (P = 0.004). No significant differences were found in other secondary outcomes. Five patients, four from the QPO group and one from the other, encountered mild adverse events, primarily skin irritation. All of these cases were resolved after dosage reduction or discontinuation of the medication. CONCLUSIONS: Compared to the placebo, QPO exhibits positive effects on AGA by alleviating pain, reducing swelling, and enhancing joint mobility, without causing significant adverse effects. TRIAL REGISTRATION: ISRCTN34355813. Registered on 25/01/2021.

PLAU promotes growth and attenuates cisplatin chemosensitivity in ARID1A-depleted non-small cell lung cancer through interaction with TM4SF1.

Loss of ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, contributes to malignant progression in multiple cancers including non-small cell lung cancer (NSCLC). In the search for key genes mediating the aggressive phenotype caused by ARID1A loss, we analyzed 3 Gene Expression Omnibus (GEO) datasets that contain RNA sequencing data from ARID1A-depleted cancer cells. PLAU was identified as a common gene that was induced in different cancer cells upon ARID1A depletion. Overexpression of PLAU positively modulated NSCLC cell growth, colony formation, cisplatin resistance, and survival under serum deprivation. Moreover, enforced expression of PLAU enhanced tumorigenesis of NSCLC cells in nude mice. Mechanistically, PLAU interacted with TM4SF1 to promote the activation of Akt signaling. TM4SF1-overexpressing NSCLC cells resembled those with PLAU overepxression. Knockdown of TM4SF1 inhibited the growth and survival and increased cisplatin sensitivity in NSCLC cells. The interaction between PLAU and TM4SF1 led to the activation of Akt signaling that endowed ARID1A-depleted NSCLC cells with aggressive properties. In addition, treatment with anti-TM4SF1 neutralizing antibody reduced the growth, cisplatin resistance, and tumorigenesis of ARID1A-depleted NSCLC cells. Taken together, PLAU serves as a target gene of ARID1A and promotes NSCLC growth, survival, and cisplatin resistance by stabilizing TM4SF1. Targeting TM4SF1 may be a promising therapeutic strategy for ARID1A-mutated NSCLC.

Lower limb arterial calcification and its clinical relevance with peripheral arterial disease.

Lower limb arterial calcification (LLAC) is associated with an increased risk of mortality and it predicts poor outcomes after endovascular interventions in patients with peripheral artery disease (PAD). Detailed histological analysis of human lower artery specimens pinpointed the presence of LLAC in two distinct layers: the intima and the media. Intimal calcification has been assumed to be an atherosclerotic pathology and it is associated with smoking and obesity. It becomes instrumental in lumen stenosis, thereby playing a crucial role in disease progression. On the contrary, medial calcification is a separate process, systematically regulated and linked with age advancement, diabetes, and chronic kidney disease. It prominently interacts with vasodilation and arterial stiffness. Given that both types of calcifications frequently co-exist in PAD patients, it is vital to understand their respective mechanisms within the context of PAD. Calcification can be easily identifiable entity on imaging scans. Considering the highly improved abilities of novel imaging technologies in differentiating intimal and medial calcification within the lower limb arteries, this review aimed to describe the distinct histological and imaging features of the two types of LLAC. Additionally, it aims to provide in-depth insight into the risk factors, the effects on hemodynamics, and the clinical implications of LLAC, either occurring in the intimal or medial layers.

Circumferential degree of tibial artery calcification is associated with infrapopliteal endovascular revascularization outcomes in patients with chronic limb-threatening ischemia.

BACKGROUND: Tibial artery calcification (TAC) is correlated with an increased risk of amputation and mortality in patients with chronic limb-threatening ischemia (CLTI). The association between calcification characteristics and adverse limb events of CLTI. However, it has not been assessed. This study aims to assess the relationship between the characteristics of TAC based on computed tomography angiography (CTA) scans and postoperative outcomes in patients with CLTI undergoing infrapopliteal endovascular therapy. METHODS: This was a retrospective study of patients who underwent infrapopliteal endovascular revascularization for CLTI and had a preoperative CTA scan. Based on CTA, TAC was divided into the following categories: annularity, thickness, continuity and severity. Cox regression models using generalized estimating equations were performed to assess the relationship between calcification characteristics and postoperative outcomes. The outcomes evaluated were the occurrence of all cause mortality (ACM) and unplanned amputation. RESULTS: Among the 148 patients undergoing endovascular, there were 50 (33.8%) patients died and 26 (17.6%) patients underwent unplanned amputation. Annular calcification was more common in the ACM group than in the non-ACM group. No significant differences were found between the two groups with regard to the probability of calcification in the thickness and the continuity (P>0.05). Patients in the unplanned amputation group had significantly annular, thin and continuity calcifications (P<0.05) than those in the non-unplanned amputation group. The presence of annular calcification was an independent predictor of ACM (hazard ratio (HR), 3.186; 95% confidence interval (CI), 1.781-5.702; P<0.001) and unplanned amputation (HR, 3.739; 95% CI, 1.707-8.191; P<0.05). CONCLUSIONS: Among patients with CLTI, the occurrence of annular calcification in the tibial artery are related to a greater chance of ACM and unplanned amputation in the postoperative period. The circumferential degree of TAC of the operated limb can be considered as a marker of clinical prognosis in this group of patients.

Investigating the potential associated factors and developing a risk model for interstitial lung disease in Chinese patients with systemic lupus erythematosus.

OBJECTIVE: This study aimed to explore the risk factors for interstitial lung disease (ILD) in Chinese patients with systemic lupus erythematosus (SLE). PATIENTS AND METHODS: This study recruited 40 SLE patients with ILD (SLE-ILD) and 40 SLE patients without ILD (SLE-non-ILD). Clinical data were collected from all patients, including basic clinical characteristics, affected organ systems, biochemical indexes, autoantibodies, and immunocytes. RESULTS: Compared with the SLE-non-ILD patients, SLE-ILD patients presented older age (p < 0.001), dry cough (p = 0.006), "velcro-like" crackles (p = 0.021), Raynaud's phenomenon (p = 0.040), elevated complement 3 (C3) level (p = 0.044), and lower SLE disease activity index score (p = 0.013) and cluster of difference-3 cell count (p = 0.043). Multivariate logistic regression analysis showed that older age (p < 0.001, odds ratio [OR]: 1.212), female sex (p = 0.022, OR: 37.075), renal involvement (p = 0.011, OR: 20.039), C3 level (p = 0.037, OR: 63.126), immunoglobulin (Ig) M level (p = 0.005, OR: 5.082), and positive anti-U1 small ribonucleoprotein antibody (anti-nRNP) result (p = 0.003, OR: 19.886) were independent ILD risk factors in SLE patients. Consequently, the ILD risk model in patients with SLE was constructed based on statistically significant variables from the multivariate logistic regression analysis, which significantly correlated with ILD risk, with an area under the curve of 0.887 (95% confidence interval: 0.815-0.960) using receiver operating characteristic curve analysis. CONCLUSION: Age, female sex, renal involvement, C3 level, IgM level, and a positive anti-nRNP result are independent risk factors for ILD. Furthermore, their combination model is closely associated with an increased ILD risk in Chinese patients with SLE.

Current career situations of Chinese pharmacovigilance professionals working for pharmaceutical companies: an exploratory survey.

BACKGROUND: Pharmacovigilance in China has experienced rapid development in the past 30 years. The implementation of Good Pharmacovigilance Practice in China since the end of 2021 heralds a new era of pharmacovigilance affairs, which puts forward higher requirements for the quantity and quality of pharmacovigilance personnel. This study aimed to preliminarily explore the current career situations of pharmacovigilance professionals working in China for pharmaceutical companies. METHODS: A questionnaire was adapted from research in the USA and Europe with the help of several pharmacovigilance experts. Snowball sampling was used to conduct an exploratory survey to obtain the frequency of basic demographic information, work status, and career expectations of pharmacovigilance professionals working for pharmaceutical companies. RESULTS: The personnel engaged in pharmacovigilance work for pharmaceutical companies were mainly medical or pharmaceutical undergraduates within 3 years of graduation. Their work intensity and pressure were relatively high. The training provided by their universities and enterprises could not well meet their needs to improve their job competence. Although they were optimistic about pharmacovigilance and will not change their career, most of them were planning to change their employers. CONCLUSION: There was a gap between the demand and supply of pharmacovigilance personnel. Relevant regulatory authorities and industry associations should guide higher education institutions to collaborate with pharmacovigilance specialists to strengthen pharmacovigilance education for medical or pharmaceutical students, on the basis of which pharmacovigilance certification courses and continuing education courses can be developed. Meanwhile, pharmaceutical enterprises should consider reasonably adjusting work intensity and income to avoid a high turnover rate.

MiRNA-494 specifically inhibits SIRT3-mediated microglia activation in sepsis-associated encephalopathy.

Background: Sepsis-associated encephalopathy (SAE) is characterized by the activation of inflammatory cascades, in which microglia play a key role. The activation of Recombinant Sirtuin 3 (SIRT3) was shown to significantly reduce the susceptibility of microglia to inflammatory stress. The purpose of this study is to determine whether miRNA-494 can regulate the activation and oxidative stress of SAE microglia through SIRT3. Methods: An SAE rat model was established, and the expression of Ionized calcium bindingadaptor molecule-1 (Iba-1) in rat brain tissue was detected by immunohistochemistry. Enzyme-linked immuno sorbent assay was performed to detect the expression of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) in brain tissue. Real time quantitative PCR was performed to detect the relative expression of SIRT3 and related miRNAs, while Western blot was used to detect the protein expression of SIRT3. Rat microglia cells were cultured in vitro. After miRNA-494 was transfected, the expression of TNF-α and IL-6 was detected. Western blot was used to detect the protein expression of SIRT3 and Iba-1 in microglia. Results: The results showed that the expression of Iba-1 in the brain tissue of the SAE model group increased, and the expression of inflammatory factors TNF-α and IL-6 increased significantly (P<0.01). The expression of SIRT3 protein and mRNA in the brain tissue of the SAE model group also significantly increased (P<0.05). The relative expression of miRNA-494 in the SAE model group was significantly lower than that in the control group (P<0.01). After miRNA-494 was transfected into microglia, cells were treated with lipopolysaccharide. In the miRNA transfection group, the expression levels of TNF-α and IL-6 were significantly lower than those in the negative control (NC) group (P<0.01), and the protein expression levels of Iba-1 and SIRT3 were also significantly lower than those in the NC (P<0.01). Conclusions: MiRNA-494 may further regulate the activation of microglia in SAE by regulating mitochondrial function, providing basic research data for the development of new SAE treatment methods.

Hypertension Exacerbates Severity and Outcomes of COVID-19 in Elderly Patients: A Retrospective Observational Study.

OBJECTIVE: To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older. METHODS: This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression. RESULTS: Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P<0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P<0.001] and a significantly lower probability of survival (P<0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19. CONCLUSION: The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.

Global Limb Anatomic Staging System Score correlates with the clinical outcomes in chronic limb threatening ischemia patients.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) affects millions of people and causes health care burden around the globe. Global Limb Anatomic Staging System (GLASS) was proposed as a new anatomic system for integrating the complexity of threatened limb. METHODS: We retrospectively classified computed tomography angiography images of threatened limbs into GLASS stages between January 2018 and April 2020. Comorbidities, limb treatments, and outcomes including amputation-free survival (AFS), reintervention and mortality were compared and the likelihood of benefit from revascularization was estimated according to GLASS. Kaplan-Meier estimate was used to determine the rates of endpoint events at 1 year. Multivariate analysis was performed to identify predictors of those outcomes. RESULTS: In our study, 285 threatened limbs in 263 patients were stratified including GLASS stage I disease (N.=53, 19%), stage II (N.=129; 45%) and stage III (N.=103; 36%) disease. The percentage of limbs undergoing endovascular revascularization and minor amputation increased significantly with increasing GLASS stage. On Kaplan-Meier analysis, increasing GLASS stage was associated with 1-year reduced AFS (stage I: 96.1%, stage II: 94.1%, stage III: 83.9%; log rank P=0.016). The percentage of 1-year reintervention rate in infrapopliteal GLASS grade 3-4 (15%) was significantly higher than the percentage of reintervention in infrapopliteal GLASS grade 0-2 (5%) (Log rank P=0.002). Infrapopliteal GLASS grade 3 and 4 was the independent predictor of reduced AFS. CONCLUSIONS: GLASS stage correlated with intensity of limb treatment and with clinical outcomes at 1 year. Infrapopliteal GLASS grade 3 and 4 independently predicted the reduced amputation-free survival.

Gene profiling of metastatic small intestinal squamous cell carcinoma after lung squamous cell carcinoma surgery: a case report.

Background: Isolated metachronous metastatic small intestinal squamous cell carcinoma is rare, and it is sometimes is difficult to determine whether small intestinal squamous cell carcinoma is metastatic by immunohistochemistry alone. At present, there is no literature analyzing the gene profile of metastatic small intestinal squamous cell carcinoma. Case Description: We met a 62-year-old male patient who had a history of lung squamous cell carcinoma surgery. He was admitted for simultaneous jejunal squamous all carcinoma, gastric adenocarcinoma, rectal adenocarcinoma. Endoscopic resection was performed for gastric cancer and rectal cancer, surgical resection was performed for jejunal squamous cell carcinoma, and docetaxel adjuvant chemotherapy were performed after surgery. No tumor recurrence was found in the reexamination in august 2021, and the patient was still alive during telephone follow-up before submission. This case presented two key challenges: (I) we could not determine whether the small intestinal squamous cell carcinoma was primary or metastatic; and (II) whether the patient, who had four different cancers, carried a genetic mutation that causes disease. We performed next generation sequencing (NGS) on four kinds of tissues and white blood cells, and found that the EGFR gene exhibited the same pathogenic mutation in both the lung and small intestine (c.2155G>Tp.G719C and c.2303G>Tp.S768I), and that the PPM1D gene had the same unidentified mutation (c.1787A>G:p.H596R) in two organs, therefore jejunal squamous cell carcinoma is considered as metastasis of lung squamous cell carcinoma. We found the FGFR4 mutation (c.1162g>A:p.g388r) in the blood and four kinds of tissues, which may be pathogenic and significantly increase the risk of cancer in patients. Conclusions: Genetic testing helped us identify the source of metastases, helped us find two rare mutations in the squamous cell carcinoma EGFR gene, and helped us find that FGFR4 (c.1162G>A:p.G388R) mutation may play an important role in tumor development.

Silver-promoted solid-phase guanidinylation enables the first synthesis of arginine glycosylated Samoamide A cyclopeptide analogue.

Cyclization and glycosylation serve as effective approaches for enhancing the drug properties of peptides. Distinct from typical glycosylation, atypical arginine N-glycosylation has drawn increasing attention due to its fundamental role in various cellular procedures and signaling pathways. We previously developed a robust strategy for constructing arginine N-glycosylated peptides characterized by silver-promoted solid-phase guanidinylation. Modeled after cyclic octapeptide Samoamide A, an antitumor peptide composed of eight hydrophobic amino acids extracted from cyanobacteria, herein we first performed arginine scanning to determine an optimal position for replacement with arginine. Consequently, the first synthesis of arginine glycosylated Samoamide A cyclopeptide analogue was described combining solid-phase glycosylation with solution-phase cyclization. The resultant SA-HH-TT displayed enhanced water solubility compared with the non-glycosylated SA-HH-TT. Notably, our method provides a universal strategy for synthesizing arginine N-glycosylated cyclopeptides.

A Pan-Cancer Analysis of SLC12A5 Reveals Its Correlations with Tumor Immunity.

BACKGROUND: Solute carrier family 12 member 5 (SLC12A5) has been reported to play an oncogenic role in certain malignancies. Its prognostic roles and immune mechanisms of action in human cancers, however, remain largely unknown. METHODS: Data derived from TCGA, GEPIA, and TIMER databases were utilized to delve into the expressing patterns, prognostic values, clinical significances, and tumor immunity of SLC12A5 in tumors. Additionally, the association of SLC12A5 expressions with tumor mutation burden (TMB), methyltransferases, and mismatch repairs (MMRs) was also analyzed. RESULTS: Herein, we observed that SLC12A5 was significantly overexpressed in various malignancies, and SLC12A5 levels correlated with overall survival, disease-specific survival, and tumor stage of certain cancers. Furthermore, we noticed that SLC12A5 was distinctly associated with methyltransferases, mismatch repair proteins, TMB, and MSI in human cancers. CONCLUSIONS: SLC12A5 may act as a potential prognostic and immunological biomarker and therapeutic target for human cancers.

The comprehensive investigation of transcription factor AP-2 alpha in lung adenocarcinoma.

BACKGROUND: Transcription factor AP-2 alpha (TFAP2A) has been reported to participate in various tumors. However, the transcriptional levels and prognostic values of TFAP2A remain elusive in lung adenocarcinoma (LUAD). The purpose of the present study was to investigate the impact of the TFAP2A in LUAD. METHODS: The transcriptional levels and prognostic effects of TFAP2A were explored in patients with LUAD using various online databases, including the GEPIA, Oncomine, and Kaplan-Meier plotter databases. Meanwhile, meta-analyses were performed to verify the expression levels and prognostic effects of TFAP2A in LUAD using the Lung Cancer Explorer (LCE) database. In addition, target genes of TFAP2A were identified in the Animal TFDB3.0 dataset. RESULTS: Our comprehensively study indicated the mRNA expression levels of TFAP2A in LUAD were significantly higher than that of normal controls. In the survival analyses, higher TFAP2A levels were related to the shortened survival time of patients with LUAD. Meanwhile, the meta-analyses based on the LCE database also suggested the overexpressed TFAP2A led to worsen prognosis of patients with LUAD. Finally, the cell division cycle 6 (CDC6) and aurora kinase A (AURKA) were regarded as two target genes of TFAP2A. CONCLUSIONS: We have performed comprehensive analyses for TFAP2A in patients with LUAD. Patients with higher TFAP2A levels demonstrated worsen prognosis than those with lower TFAP2A levels. The CDC6 and AURKA might be two target genes of TFAP2A. Further molecular biological experiments were required to study the mechanisms of TFAP2A in LUAD.

Rational design of stapled peptides targeting phosphorylated GSK3ß for regulating osteoclast differentiation.

Glycogen synthase kinase-3ß (GSK-3ß), has been reported to show essential roles in osteoclast differentiation. Modeled after FRATtide, a peptide derived from a GSK-3 binding protein, here we designed and synthesized a series of stapled peptides targeting phosphorylated GSK3ß, and evaluated the corresponding biological activities. The results indicated that stapled peptides with better helical contents and proteolytic stability than the linear ones showed improved biological activity in inhibiting osteoclast differentiation. Among them, FRC-2 and FRN-2 showed promising prospects for treating osteoporosis.

Synthesis and anti-osteoporosis activity of novel Teriparatide glycosylation derivatives.

Osteoporosis is a metabolic bone disease that is characterized by low bone mass and micro-architectural deterioration of bones. The mechanism underlying this disease implicates an imbalance between bone resorption and bone remodeling. In 2002, the US Food and Drug Administration (FDA) approved Teriparatide for the treatment of osteoporosis, and so far, this compound is the only permitted osteoanabolic. However, as a structurally flexible linear peptide, this drug may be further optimized. In this study, we develop a series of novel N-acetyl glucosamine glycosylation derivatives of Teriparatide and examine their characteristics. Of the analyzed compounds, PTHG-9 exhibits enhanced helicity, greater protease stability, and increased osteoblast differentiation promoting ability compared with the original Teriparatide. Accordingly, PTHG-9 is suggested as a therapeutic candidate for postmenopausal osteoporosis (PMOP) and other related diseases. The successful development of an enhanced osteoporosis drug proves that the method proposed herein can be used to effectively enhance the chemical and biological properties of linear peptides with various biological functions.

The clinical application value of multi-slice spiral CT enhanced scans combined with multiplanar reformations images in preoperative T staging of rectal cancer.

This study aims to evaluate the diagnostic accuracy and clinical application value of multi-slice spiral CT (MSCT) enhanced scans combined with multiplanar reformations (MPRs) images compared with postoperative pathological results in preoperative T staging of rectal cancer.One hundred sixty-eight consecutive patients with rectal cancer were admitted in our hospital between January 2013 and October 2018. Conventional MSCT plain scans, multi-phase dynamic contrast-enhanced scans, and MPRs were performed in all patients before surgical operation. The preoperative T staging of the rectal cancer lesions was evaluated using MSCT enhanced scans combined with MPRs, which was verified by postoperative pathological results. The diagnostic accuracy of MSCT enhanced scans combined with MPRs in evaluating T staging of the rectal cancer lesions were analyzed by χ test and Kappa test.Compared with postoperative pathology, T staging using MSCT enhanced scans combined with MPRs had overall accuracy of 85.7%. Consistency between MSCT enhanced scans combined with MPRs and postoperative pathological staging was effective for T staging (Kappa = 0.658, χ = 4.200, P = .122).Conventional MSCT enhanced scans combined with MPRs are simple and feasible. It is consistent with the pathological diagnosis of evaluating T staging in the rectal cancer lesions. It can provide reliable imaging evidence for the preoperative evaluation of primary rectal cancer, especially in patients with magnetic resonance imaging (MRI) contraindications, or in grass-roots hospitals due to lack of MRI equipment.

A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/ß-catenin signalling pathway.

The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a ß-catenin-binding domain of Axin (469-482) and develop a new category of stapled peptides with the retention of the native side chains. These stapled peptides exhibit high α-helicity, strong proteolytic stability and good cell permeability. Biochemical experiments demonstrate that these stapled peptides can activate ß-catenin more efficiently than canonical stapled peptides due to the presence of extra side chains. We expect that the new side-chain-retention stapling method would expand the scope of the all-hydrocarbon stapled peptide strategy by retaining some important peripheral residues for protein-protein interactions or preserving key hydrophilic side chains to improve solubility.

Plasmid-encoding vasostatin inhibited the growth and metastasis of human hepatocellular carcinoma cells.

The growth and metastasis of solid tumors depends on angiogenesis. Anti-angiogenesis therapy may represent a promising therapeutic option. Vasostatin, the N-terminal domain of calreticulin, is a very potent endogenous inhibitor of angiogenesis and tumor growth. In this study, we attempted to investigate whether plasmid-encoding vasostatin complexed with cationic liposome could suppress the growth and metastasis of hepatocellular carcinoma in vivo and discover its possible mechanism of action. Apoptosis induction of pSecTag2B-vasostatin plasmid on murine endothelial cells (MS1) was examined by flow cytometric analysis in vitro. Nude mice bearing HCCLM3 tumor received pSecTag2B-vasostatin, pSecTag2B-Null, and 0.9 % NaCl solution, respectively. Tumor net weight was measured and survival time was observed. Microvessel density within tumor tissues was determined by CD31 immunohistochemistry. H&E staining of lungs and TUNEL assay of primary tumor tissues were also conducted. The results displayed that pSecTag2B-vasostatin could inhibit the growth and metastasis of hepatocellular carcinoma xenografts and prolong survival time compared with the controls in vivo. Moreover, histologic analysis revealed that pSecTag2B-vasostatin treatment increased apoptosis and inhibited angiogenesis. The present data may be of importance to the further exploration of this new anti-angiogenesis approach in the treatment of hepatocellular cancer.