Discrepancies between general and central obesity in arterial stiffness: observational studies and Mendelian randomization study.

BACKGROUND: Obesity has been linked to arterial stiffness, while no consensus was reached on the association. We aimed to clarify the association of general and central obesity with arterial stiffness by combining observational studies and Mendelian randomization (MR) study. METHODS: Two cross-sectional studies were performed in UK Biobank and Fuqing Cohort, respectively. Two-sample MR study was conducted using summary data of GWASs from GIANT consortium and UK Biobank. General obesity and central obesity were measured using body mass index (BMI) and waist circumference (WC), respectively. Arterial stiffness was measured by arterial stiffness index (ASI) in UK Biobank or branchial-ankle pulse wave velocity (baPWV) in Fuqing Cohort. RESULTS: Two observational studies found a consistent positive association of BMI and WC with arterial stiffness when adjusting for age, sex, education, smoking, alcohol drinking, physical activity, and LDL cholesterol. However, when additionally adjusting for metabolic traits (i.e., systolic blood pressure, diastolic blood pressure, blood glucose, triglycerides, high-density lipoprotein cholesterol, and WC or BMI), the association with BMI changed to be inverse. As compared to the lowest quintile group, the adjusted ORs across groups of second to fifth quintile were 0.93, 0.90, 0.83, and 0.72 in UK Biobank and 0.88, 0.65, 0.63, and 0.50 in Fuqing Cohort. In contrast, the positive relationship with WC remained stable with the adjusted ORs of 1.23, 1.46, 1.60, and 1.56 in UK Biobank and 1.35, 1.44, 1.77, and 1.64 in Fuqing Cohort. MR analyses provided supportive evidence of the negative association with BMI (OR = 0.97, 95%CI = 0.94-1.00) and the positive association with WC (OR = 1.14, 95%CI = 1.08-1.20). CONCLUSIONS: Observational and genetic analyses provide concordant results that central obesity is independently related to arterial stiffness, while the role of general obesity depends on metabolic status.

High-temperature-insensitivity high-power Yb-doped fiber laser directly in-band pumping by 1018 nm laser diodes.

In this Letter, we demonstrate a high-power ytterbium-doped fiber laser (YDFL) based on a directly in-band pumping scheme (DIPS) which employs 1018 nm laser diodes (LDs) as pump sources. The wavelength of the LDs is designed theoretically, considering the distribution of Yb3+ absorption cross section (σa) as well as quantum defect (QD). The flat distribution of σa around 1018 nm ensures excellent temperature insensitivity and flexibility for the YDFL. Besides, lower QD and more compact structure promise higher optical-to-optical (O-O) and electrical-to-optical (E-O) efficiencies. Based on the experimental setup, as the cooling temperature of the 1018 nm LDs ranges from 6 to 23°C, an output power of 2 kW level is achieved that varies by only 2.01% without adjusting the operating current of the LDs subjectively. The output power is then scaled up to 5 kW level. Furthermore, there is a great potential to achieve higher output power and E-O efficiency in YDFLs based on the DIPS.

Association Between Serum Bilirubin, Lipid Levels, and Prevalence of Femoral and Carotid Atherosclerosis: A Population-Based Cross-Sectional Study.

BACKGROUND: Bilirubin may prevent lipid peroxidation and have important antiatherosclerotic effects. We determined associations of serum bilirubin and lipid with peripheral atherosclerosis. METHODS: We included 4290 participants (35% men; median age, 60 years) from the southeast China who underwent B-mode ultrasound examination. Increased intima-media thickness or a focal structure encroaching into the arterial lumen by at least 0.5 mm or >50% of the surrounding intima-media thickness value was regarded as having atherosclerosis. Fasting serum bilirubin and lipid levels were measured. Cholesterol/(HDL [high-density lipoprotein] cholesterol+bilirubin), and LDL (low-density lipoprotein cholesterol)/(HDL+bilirubin) ratios were calculated. Unconditional and multinomial logistic regression models were used to examine associations of bilirubin or lipid with prevalence of peripheral atherosclerosis. Mediation analyses were performed to assess the effect of bilirubin on atherosclerosis risk mediated via lipid. RESULTS: Compared with participants with the lowest levels of bilirubin, those with the highest tertile were less likely to have carotid or femoral atherosclerosis (odds ratios were 0.55-0.74). The highest levels of bilirubin significantly reduced the odds of concurrent carotid and femoral atherosclerosis by 35% to 45%. Participants with the highest levels of cholesterol, LDL, cholesterol/(HDL+bilirubin), and LDL/(HDL+bilirubin) ratios had 2.8- to 3.7-fold increased odds of concurrent carotid and femoral atherosclerosis. LDL accounted for 25.65% of the total bilirubin-atherosclerosis association. LDL and cholesterol mediated the associations between direct bilirubin and atherosclerosis (proportion: 20.40%, 9.67%, respectively). CONCLUSIONS: Increased serum bilirubin levels are inversely associated with the prevalence of carotid or femoral atherosclerosis. LDL and cholesterol may mediate these associations.

Design and synthesis of TH19P01-Camptothecin based hybrid peptides inducing effective anticancer responses on sortilin positive cancer cells.

Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1.

Synthesis and structural optimization of oncolytic peptide LTX-315.

Oncolytic peptides represented potential novel candidates for anticancer treatments especially drug-resistant cancer cell lines. One of the most promising and extensively studied is LTX-315, which is considered as the first in class oncolytic peptide and has entered phase I/II clinical trials. Nevertheless, the shortcomings including poor proteolytic stability, moderate anticancer durability and high synthesis costs may hinder the widespread clinical applications of LTX-315. In order to reduce the synthesis costs, as well as develop derivatives possessing both high protease-stability and durable anticancer efficiency, twenty LTX-315-based derived-peptides were designed and efficiently synthesized. Especially, through solid-phase S-alkylation, as well as the optimized peptide cleavage condition, the derived peptides could be prepared with drastically reduced synthesis cost. The in vitro anticancer efficiency, serum stability, anticancer durability, anti-migration activity, and hemolysis effect were systematically investigated. It was found that derived peptide MS-13 exhibited comparable anticancer efficiency and durability to those of LTX-315. Strikingly, the D-type peptide MS-20, which is the enantiomer of MS-13, was demonstrated to possess significantly high proteolytic stability and sustained anticancer durability. In general, the cost-effective synthesis and stability-guided structural optimizations were conducted on LTX-315, affording the highly hydrolysis resistant MS-20 which possessed durable anticancer activity. Meanwhile, this study also provided a reliable reference for the future optimization of anticancer peptides through the solid-phase S-alkylation and L-type to D-type amino acid substitutions.

d-type peptides based fluorescent probes for "turn on" sensing of heparin.

Developing "turn on" fluorescent probes was desirable for the detection of the effective anticoagulant agent heparin in clinical applications. Through combining the aggregation induced emission (AIE) fluorogen tetraphenylethene (TPE) and heparin specific binding peptide AG73, the promising "turn on" fluorescent probe TPE-1 has been developed. Nevertheless, although TPE-1 could achieve the sensitive and selective detection of heparin, the low proteolytic stability and undesirable poor solubility may limit its widespread applications. In this study, seven TPE-1 derived fluorescent probes were rationally designed, efficiently synthesized and evaluated. The stability and water solubility were systematically estimated. Especially, to achieve real-time monitoring of proteolytic stability, the novel Abz/Dnp-based "turn on" probes that employ the internally quenched fluorescent (IQF) mechanism were designed and synthesized. Moreover, the detection ability of synthetic fluorescent probes for heparin were systematically evaluated. Importantly, the performance of d-type peptide fluorescent probe XH-6 indicated that d-type amino acid substitutions could significantly improve the proteolytic stability without compromising its ability of heparin sensing, and attaching solubilizing tag 2-(2-aminoethoxy) ethoxy) acid (AEEA) could greatly enhance the solubility. Collectively, this study not only established practical strategies to improve both the water solubility and proteolytic stability of "turn on" fluorescent probes for heparin sensing, but also provided valuable references for the subsequent development of enzymatic hydrolysis-resistant d-type peptides based fluorescent probes.

The association between serum magnesium and chronic kidney disease in Chinese adults: a cross-sectional study.

BACKGROUND: Magnesium (Mg) is both an essential macro-element and a known catalyst, and it plays a vital role in various physiological activities and mechanisms in relation to chronic kidney disease (CKD). However, epidemiological evidence involving this is limited and not entirely consistent. This study aims to explore the association of serum Mg concentrations with the risk of CKD among general Chinese adults. METHODS: A total of 8,277 Chinese adults were included in the wave of 2009 from the China Health and Nutrition Survey (CHNS). The primary outcome was the risk of CKD, which was defined as the estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multivariable logistic regression model was used to examine the relationship of serum Mg concentrations with the risk of CKD. RESULTS: Included were 8,277 individuals, with an overall CKD prevalence of 11.8% (n = 977). Compared with the first quartile of serum Mg, the multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for participants in the second, third, and fourth quartiles of serum Mg were 0.74 (0.58, 0.93), 0.87 (0.69, 1.11) and 1.29 (1.03, 1.61), respectively. Similar results were observed in our several sensitivity analyses. Restricted cubic spline analysis demonstrated a nonlinear (similar "J"-shaped) association between serum Mg concentrations and the risk of CKD (Pnonlinearity <0.001), with a threshold at around a serum Mg value of 2.2 mg/dL. CONCLUSIONS: Our results suggested a similar "J"-shaped association between serum Mg concentration and the risk of CKD among Chinese adults. Further large prospective studies are needed to verify these findings.

A comparative analysis of the clinical pregnancy and perinatal outcomes between oocyte vitrification and embryo vitrification based on the propensity score matching method.

PURPOSE: This study investigated the safety and effectiveness of oocyte vitrification by comparing the clinical pregnancy and perinatal outcomes between transfer cycles of vitrified oocytes and those of vitrified embryos. METHODS: A retrospective cohort study was conducted to analyze the clinical data of patients who underwent cleavage-stage embryo transfer at the Department of Reproductive Medicine between January 2011 and June 2021. Seventy-seven transfer cycles of fresh cleavage-stage embryos developed from vitrified-thawed oocytes (oocyte vitrification group) and 2170 transfer cycles of vitrified-thawed cleavage-stage embryos developed from fresh oocytes (embryo vitrification group) were included. Further, 293 cases were selected from the embryo vitrification group after applying propensity score matching at 1:4. The primary outcomes were miscarriage rate, live birth rate, and neonatal birth weight. RESULTS: No statistically significant differences were observed in the baseline data, pregnancy, perinatal outcomes, or neonatal outcomes for either singleton or twin births between the two groups after matching. Backwards stepwise regression was used to analyze the length of gestation. The age of female participants (ß = - 0.410, 95% CI = - 1.339 ~ - 0.620, P < 0.001) had a statistically significant effect. CONCLUSION: Oocyte vitrification results in similar clinical pregnancy and perinatal outcomes as does embryo vitrification; hence, it is a relatively safe assisted reproductive technique.

Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification.

Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various tumors, making it an important target for cancer treatment. Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Recently, a study showed that modification with dehydroalanine (Dha) can also lead to abnormal activation of MEK1, which has the potential to promote tumor development. In this study, we used molecular dynamics simulations and metadynamics to explore the mechanism of abnormal activation of MEK1 caused by the Dha modification and predicted the inhibitory effects of four FDA-approved MEK1 inhibitors on the Dha-modified MEK1. The results showed that the mechanism of abnormal activation of MEK1 caused by the Dha modification is due to the movement of the active segment, which opens the active pocket and exposes the catalytic site, leading to sustained abnormal activation of MEK1. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors.

The choline-binding proteins PspA, PspC, and LytA of Streptococcus pneumoniae and their interaction with human endothelial and red blood cells.

Streptococcus pneumoniae is a Gram-positive opportunistic pathogen that can colonize the upper respiratory tract. It is a leading cause of a wide range of infectious diseases, including community-acquired pneumonia and meningitis. Pneumococcal infections cause 1-2 million deaths per year, most of which occur in developing countries. Here, we focused on three choline-binding proteins (CBPs), i.e., PspC, PspA, and LytA. These pneumococcal proteins have different surface-exposed regions but share related choline-binding anchors. These surface-exposed pneumococcal proteins are in direct contact with host cells and have diverse functions. We explored the role of the three CBPs on adhesion and pathogenicity in a human host by performing relevant imaging and functional analyses, such as electron microscopy, confocal laser scanning microscopy, and functional quantitative assays, targeting biofilm formation and the hemolytic capacity of S. pneumoniae. In vitro biofilm formation assays and electron microscopy experiments were used to examine the ability of knockout mutant strains lacking the lytA, pspC, or pspA genes to adhere to surfaces. We found that LytA plays an important role in robust synthesis of the biofilm matrix. PspA and PspC appeared crucial for the hemolytic effects of S. pneumoniae on human red blood cells. Furthermore, all knockout mutants caused less damage to endothelial cells than wild-type bacteria, highlighting the significance of each CPB for the overall pathogenicity of S. pneumoniae. Hence, in addition to their structural function within the cell wall of S. pneumoniae, each of these three surface-exposed CBPs controls or mediates multiple steps during bacterial pathogenesis.

Intrinsic SERS Fingerprints of Aptamer-Peptide Conjugates for Direct High-Specific Profiling Abnormal Protein Levels in Cancer Patients.

Surface-enhanced Raman spectroscopy (SERS) with ultrasensitive vibrational fingerprints enables quick identification and trace detection of various kinds of molecules. But proteins usually have low Raman cross sections and are difficult to generate recognizable signals in direct SERS detection. Recently, nucleic acid-peptide conjugates are emerging with great potential in structuring, assembling, catalyzing, sensing, etc., and the coupling of aptamers further enables superior biological recognition and programmability. Here, we develop the aptamer-peptide conjugates as a new kind of SERS probe for direct high-specific profiling abnormal protein levels in cancer patients. The aptamer conjugated with glutathione (GSH) functions as both the recognition element and the SERS reporters that can simultaneously generate SERS fingerprints of both peptides and nucleic acids. This kind of biocompatible probe appears to have excellent performance in high-salt environments and realizes rapid, simple, and multisignal detection of thrombin (TB). Data-driven soft independent modeling of class analogy (DD-SIMCA) is used to distinguish SERS profiles of actual blood samples and realize the identification and classification of cancer patients. Furthermore, the effect of low-temperature storage time on blood samples is analyzed by tracking the changes of SERS profiles; the results hint that plasma samples stored under 4 °C for more than 2 days could generate false negative results due to TB hydrolysis, which has important implications for clinical sample analysis. This kind of nucleic acid-peptide conjugate provides new ideas for SERS sensing strategy in the future.

Amplification of random lasing enables a 10-kW-level high-spectral-purity Yb-Raman fiber laser.

By amplifying the cascaded random Raman fiber laser (RRFL) oscillator and ytterbium fiber laser oscillator, we present the first, to the best of our knowledge, demonstration of a 10-kW-level high-spectral-purity all-fiber ytterbium-Raman fiber amplifier (Yb-RFA). With a carefully designed backward-pumped RRFL oscillator structure, the parasitic oscillation between the cascaded seeds is avoided. Leveraging the RRFL with full-open-cavity as the Raman seed, the Yb-RFA realizes 10.7-kW Raman lasing at 1125 nm, which is beyond the operating wavelengths of all the reflection components used in the system. The spectral purity of the Raman lasing reaches 94.7% and the 3-dB bandwidth is 3.9 nm. This work paves a way to combine the temporal stability of the RRFL seed and the power scaling of Yb-RFA, enabling the wavelength extension of high-power fiber lasers with high spectral purity.

Recent advances and prospects of Bacillus amyloliquefaciens as microbial cell factories: from rational design to industrial applications.

Bacillus amyloliquefaciens is one of the most characterized Gram-positive bacteria. This species has unique characteristics that are beneficial for industrial applications, including its utilization of: cheap carbon as a substrate, a transparent genetic background, and large-scale robustness in fermentation. Indeed, the productivity characteristics of B. amyloliquefaciens have been thoroughly analyzed and further optimized through systems biology and synthetic biology techniques. Following the analysis of multiple engineering design strategies, B. amyloliquefaciens is now considered an efficient cell factory capable of producing large quantities of multiple products from various raw materials. In this review, we discuss the significant potential advantages offered by B. amyloliquefaciens as a platform for metabolic engineering and industrial applications. In addition, we systematically summarize the recent laboratory research and industrial application of B. amyloliquefaciens, including: relevant advances in systems and synthetic biology, various strategies adopted to improve the cellular performances of synthetic chemicals, as well as the latest progress in the synthesis of certain important products by B. amyloliquefaciens. Finally, we propose the current challenges and essential strategies to usher in an era of broader B. amyloliquefaciens use as microbial cell factories.

Meal timing of dietary total antioxidant capacity and its association with all-cause, CVD and cancer mortality: the US national health and nutrition examination survey, 1999-2018.

BACKGROUND: The association of the meal timing of dietary total antioxidant capacity (DAC) with mortality is unclear. We aimed to investigate the association between the meal timing of DAC and all-cause, cardiovascular disease (CVD), and cancer mortality in general adult populations. METHODS: A total of 56,066 adults who participated in the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were recruited for this study. Dietary intake (quantity and timing) was evaluated by nonconsecutive 24-h dietary recalls. The main exposure variables were the DAC across three meals (total, breakfast, lunch, and dinner; without coffee) and the difference between dinner and breakfast DAC (Δ = dinner-breakfast; without coffee). The outcomes were all-cause, CVD, and cancer mortality. The adjusted hazard ratios [aHRs] and 95% confidence intervals [CI] were imputed by Cox proportional hazards regression. RESULTS: Among the 56,066 participants, there were 8566 deaths from any cause, including 2196 from CVD and 1984 from cancer causes. Compared to participants in the lowest quintiles of the total DAC, those in the highest quintiles had 34% and 27% decreased risks of all-cause and CVD mortality, respectively (all-cause mortality: aHRs 0.66 [95% CI 0.57-0.76]; CVD mortality: aHRs 0.73 [95% CI 0.57-0.94]). More importantly, participants in the highest quintiles of the dinner DAC, but not those in that of breakfast or lunch, had a 24% decrease in all-cause mortality (aHRs 0.76 [95% CI 0.67-0.87]) compared with those in the lowest quintiles. Inverse associations were further confirmed for Δ DAC (aHRs 0.84 [95% CI 0.74-0.96]). Above associations did not change when including DAC from snacks or tea. Mediation analysis showed that the total associations of total, dinner or Δ DACs with reduced all-cause mortality were 24%, 13% and 6%, respectively, mediated by serum CRP. Additionally, all-cause mortality was decreased by 7% in models replacing 10% breakfast DAC (aHRs 0.93 [95% CI 0.9-0.97]) with an equivalent proportion of dinner DAC. For cancer mortality, no statistical significance was detected in the adjusted models. CONCLUSIONS: The findings emphasize the putative beneficial relationship of a diet rich in antioxidants and meal timing on serum CRP and all-cause mortality.

FOXO4 mediates resistance to oxidative stress in lens epithelial cells by modulating the TRIM25/Nrf2 signaling.

Oxidative stress damage to the lens is a key factor in most cataracts. Forkhead box O 4 (FOXO4), a member of the forkhead box O family, plays a pivotal role in oxidative stress. FOXO4 is upregulated in lens of age-related cataract patients, but its role in cataract has not been elucidated. Herein, we investigated the role and mechanism of FOXO4 during oxidative stress damage in lens epithelial cells. H2O2 treatment enhanced FOXO4 expression in HLEpiC cells. Short hairpin RNAs mediated FOXO4 silence aggravated H2O2-induced cell apoptosis. In addition, upon H2O2 exposure, silencing of FOXO4 reduced SOD and CAT activities, as well as increased intracellular MDA and ROS levels. FOXO4 silencing also inhibited Nrf2 nuclear translocation, followed by reducing the expressions of Nrf2-governed antioxidant genes HO-1 and NOQ-1. Exogenous overexpression of FOXO4 was also involved in this study and exhibited opposite effects of FOXO4-silencing. Mechanistically, FOXO4 directly bound the promoter of TRIM25 and regulated its transcription, thereby activating the Nrf2 signaling. Taken together, in the condition of oxidative stress, the expression of FOXO4 showed a compensatory upregulation and it exhibited an anti-oxidative effect by modulating the transcription of TRIM25, thus activating the Nrf2 signaling. The FOXO4/TRIM25/Nrf2 axis may be associated with the pathological mechanisms of cataract.

Design, synthesis and anticancer evaluation of novel oncolytic peptide-chlorambucil conjugates.

Nitrogen mustards (NMs) are an important class of chemotherapeutic drugs and have been widely employed for the treatment of various cancers. However, due to the high reactivity of nitrogen mustard, most NMs react with proteins and phospholipids within the cell membrane. Therefore, only a very small fraction of NMs can reach the reach nucleus, alkylating and cross-linking DNA. To efficiently penetrate the cell membrane barrier, the hybridization of NMs with a membranolytic agent may be an effective strategy. Herein, the chlorambucil (CLB, a kind of NM) hybrids were first designed by conjugation with membranolytic peptide LTX-315. However, although LTX-315 could help large amounts of CLB penetrate the cytomembrane and enter the cytoplasm, CLB still did not readily reach the nucleus. Our previous work demonstrated that the hybrid peptide NTP-385 obtained by covalent conjugation of rhodamine B with LTX-315 could accumulate in the nucleus. Hence, the NTP-385-CLB conjugate, named FXY-3, was then designed and systematically evaluated both in vitro and in vivo. FXY-3 displayed prominent localization in the cancer cell nucleus and induced severe DNA double-strand breaks (DSBs) to trigger cell apoptosis. Especially, compared with CLB and LTX-315, FXY-3 exhibited significantly increased in vitro cytotoxicity against a panel of cancer cell lines. Moreover, FXY-3 showed superior in vivo anticancer efficiency in the mouse cancer model. Collectively, this study established an effective strategy to increase the anticancer activity and the nuclear accumulation of NMs, which will provide a valuable reference for future nucleus-targeting modification of nitrogen mustards.

Efficient synthesis and anticancer evaluation of spider toxin peptide LVTX-8-based analogues with enhanced stability.

Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata, exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro, which was better than or comparable to that of natural LVTX-8. In particular, both N-acetyl and C-hydrazide modified LVTX-8 (825) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (827) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides.

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus.

The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells. Thus, four hybrid peptides, NTP-212, NTP-217, NTP-223 and NTP-385, were synthesized. These hybrid peptides enhanced the anticancer activity of LTX-315 in a panel of adherent cancer cell lines by 2.4- to 37.5-fold. In model mice bearing B16-F10 melanoma xenografts, injection of NTP-385 (0.5 mg per mouse for 3 consecutive days) induced almost complete regression of melanoma, prolonged the median survival time and increased the overall survival. Notably, the administered dose of NTP-385 was only half the effective dose of LTX-315. We further revealed that unlike LTX-315, which targets the mitochondria, NTP-385 disrupted the nuclear membrane and accumulated in the nucleus, resulting in the transfer of a substantial amount of reactive oxygen species (ROS) from the cytoplasm to the nucleus through the fragmented nuclear membrane. This ultimately led to DNA double-strand break (DSB)-mediated intrinsic apoptosis. In conclusion, this study demonstrates that hybrid peptides obtained from the fusion of LTX-315 and rhodamine B enhance anti-adherent cancer cell activity by targeting the nucleus and triggering DNA DSB-mediated intrinsic apoptosis. This study also provides an advantageous reference for nucleus-targeting peptide modification.

Shift in prevalence and systemic inflammation levels from NAFLD to MAFLD: a population-based cross-sectional study.

BACKGROUND: Variations in the prevalence and systemic inflammatory (SI) status between non-alcoholic fatty liver disease (NAFLD) and newly defined metabolic dysfunction-associated fatty liver disease (MAFLD) have only been reported by few studies. Hence, this study aimed to compile data on the prevalence and the systemic inflammation levels of MAFLD and NAFLD in a general population from Southeast China was summarized to explore the potential effect of the transformation of disease definition. METHODS: A total of 6718 general population participants aged 35-75 were enrolled. Logistic regression and restricted cubic spline (RCS) models were used to examine the relationship between 15 SI indicators and NAFLD and MAFLD. The predicted values of MAFLD and NAFLD were analyzed using the receiver operating characteristic (ROC) curve. RESULTS: The prevalence of MAFLD and NAFLD was 34.7% and 32.4%, respectively. Their overlapping rate was 89.7%, while only 8.3% and 1.9% of participants were MAFLD-only and NAFLD-only. Among three FLD groups, the MAFLD-only group had the highest levels of 8 SI indicators, including CRP, WBC, LYMPH, NEUT, MONO, ALB, NLR, and SIRI. The non-FLD group had the lower levels of all 15 SI indicators compared with all FLD subgroups. The odds ratios (ORs) of 10 SI indicators were significant in both multivariable-adjusted logistic regression and RCS analyses of MAFLD or NAFLD, including CRP, WBC, LYMPH, NEUT, MONO, ALB, PLR, LMR, ALI and CA. ROC analysis showed that the AUC values of all SI were lower than 0.7 in both MAFLD and NAFLD. CONCLUSIONS: MAFLD could cover more FLD than NAFLD, and the MAFLD-only group had a more severe inflammation status, whereas the NAFLD-only exhibited lower levels. Moreover, there was not a high AUC and a high sensitivity of SI indicators, suggesting that SI indicators are not good indicators to diagnose NAFLD/MAFLD.

Behavioral deviations: healthcare-seeking behavior of chronic disease patients with intention to visit primary health care institutions.

BACKGROUND: Although primary health care (PHC) has been proven to be effective in preventing and treating chronic diseases, the visits rate of PHC institutions is still not ideal. Some patients initially express a willingness to visit PHC institutions but end up seeking health services at non-PHC institutions, and the reasons for this behavior remain unclear. Therefore, the objective of this study is to analyze the factors that contribute to behavioral deviations among chronic disease patients who originally intended to visit PHC institutions. METHODS: Data were collected from a cross-sectional survey among chronic disease patients with original intention to visit PHC institutions in Fuqing City, China. The analysis framework was guided by Andersen's behavioral model. Logistic regression models were employed to analyze the factors affecting the behavioral deviations among chronic disease patients with a willingness to visit PHC institutions. RESULTS: A total of 1,048 individuals were finally included and about 40% of the participants with the original willingness to seek care from PHC institutions finally chose non-PHC institutions in their subsequent visits. The results of logistic regression analyses indicated that at the predisposition factor level, older participants (aOR60-69 = 0.602, P < 0.01; aOR70-75 = 0.475, P < 0.01) were less likely to have behavioral deviations. At the enabling factor level, compared to those covered by Urban Employee Basic Medical Insurance (UEBMI) and not reimbursed, those covered by Urban-Rural Resident Basic Medical Insurance (URRBMI) (aOR = 0.297, P < 0.01), and those answering that reimbursement from medical institutions was convenient (aOR = 0.501, P < 0.01) or very convenient (aOR = 0.358, P < 0.001) were less likely to have behavioral deviations. At the need factor level, participants who visited PHC institutions due to illness last year (aOR = 0.348, P < 0.001) and with polypharmacy (aOR = 0.546, P < 0.01) were less likely to have behavioral deviations compared to those without the visit of PHC institutions and not taking polypharmacy, respectively. CONCLUSIONS: The deviations between the original willingness of PHC institution visits and subsequent behavior among chronic disease patients were associated with a number of predisposing, enabling, and need factors. Developing the health insurance system, strengthening the technical capacity of PHC institutions, and steadily developing a new concept of orderly healthcare-seeking behavior among chronic disease patients, will help promote their access to PHC institutions as well as improve the effectiveness of the tiered medical system for chronic disease care.