Poyang and Dongting Lakes, Yangtze River: tributary lakes blocked by main-stem aggradation.

During its 6,300-km course from the Tibetan Plateau to the ocean, the Yangtze River is joined by two large lakes: Dongting Lake and Poyang Lake. We explain why these lakes exist. Deglaciation forced the ocean adjacent to the Yangtze mouth to rise ∼120 m. This forced a wave of rising water surface elevation and concomitant bed aggradation upstream. While aggradation attenuated upstream, the low bed slope of the Middle-Lower Yangtze River (∼2 × 10-5 near Wuhan) made it susceptible to sea level rise. The main stem, sourced at 5,054 m above sea level, had a substantial sediment load to "fight" against water surface level rise by means of bed aggradation. The tributaries of the Middle-Lower Yangtze have reliefs of approximately hundreds of meters, and did not have enough sediment supply to fill the tributary accommodation space created by main-stem aggradation. We show that the resulting tributary blockage likely gave rise to the lakes. We justify this using field data and numerical modeling, and derive a dimensionless number capturing the critical rate of water surface rise for blockage versus nonblockage.

Association between longitudinal changes in body composition and the risk of kidney outcomes in participants with overweight/obesity and type 2 diabetes mellitus.

AIMS: To assess the relationship of longitudinal changes in fat mass (FM), lean mass (LM) and waist circumference (WC) with incident kidney outcomes in people with overweight/obesity and type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A total of 3927 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 from the Look AHEAD (Action for Health in Diabetes) trial were included. The primary outcome was kidney outcomes, defined as a decrease in eGFR of at least 40% from baseline at follow-up visit, or end-stage kidney disease. RESULTS: During a median follow-up of 8.0 years, 450 kidney outcomes were documented after the first 1 year. In the intensive lifestyle intervention (ILI) group, reductions in FM (per 10% decrease, adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.94) and WC (per 10% decrease, adjusted HR 0.72, 95% CI 0.59-0.88) from baseline to 1-year follow-up were significantly associated with a lower risk of kidney outcomes. The change in LM was not significantly associated with risk of kidney outcomes (per 10% decrease, adjusted HR 0.78, 95% CI 0.58-1.06). In the diabetes support and education group (control group), no significant association was found between changes in body composition and kidney outcomes. Similar results were observed for the 4-year changes in body composition. CONCLUSIONS: In this post hoc analysis of the Look AHEAD trial, longitudinal declines in FM and WC were associated with a lower risk of kidney outcomes in the ILI group in participants with overweight/obesity and T2DM.

Tanshinone IIA regulates CCl4 induced liver fibrosis in C57BL/6J mice via the PI3K/Akt and Nrf2/HO-1 signaling pathways.

Chronic liver diseases caused by various factors may develop into liver fibrosis (LF). Early stage of LF could be reversible. Tanshinone IIA (Tan IIA), an extract from Salvia miltiorrhiza, has been reported to be hepatoprotective. However, the potential targets and mechanism of Tan IIA in the treatment of LF are still unclear. Our study aims at the anti-LF mechanism of Tan IIA through network pharmacological analysis combined with LF-related experiments. Serum biochemical indicators and histopathological examination showed that Tan IIA could ameliorate the process of LF in the CCl4 -induced mouse model. Western blot and immunohistochemical assays showed that Tan IIA decreased the expression of Kirsten rat sarcoma viral oncogene homolog (KRAS), phosphatidylinositide 3-kinases/protein kinase B (PI3K/Akt), and nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1). Compared with the model group, the Tan IIA groups increased the decreased superoxide dismutase activity and glutathione content, while decreasing the increased malondialdehyde content. These results indicate that Tan IIA may play an antioxidant role by inhibiting the expression of KRAS, PI3K/Akt, and Nrf2/HO-1 to ameliorate the progression of LF, which to some extent explains the pharmacological mechanism of Tan IIA in LF. In conclusion, our study demonstrates that Tan IIA could regulate LF via PI3K/Akt and Nrf2/HO-1 signaling pathways. It may be an effective therapeutic compound for the treatment of LF.

Study on Carbon Emission Influencing Factors and carbon emission reduction potential in China's food production industry.

Climate warming has become a global issue of close concern, and China, as a significant agricultural country, has an increasing demand for food, which requires China to increase carbon reduction in this industry. This paper accounts for carbon emissions from the food production industry (CEFI) using the input-output method, then screens the influencing factors of CEFI based on Random Forest (RF), analyzes the heterogeneous effects of the influencing factors on CEFI in different clusters through K-means-SHAP, and finally explores the potential of carbon emissions from this industry for the period 2024-2040. The study's findings are as follows: First, there are apparent inequalities in CEFI, especially between provinces, which are gradually increasing. Second, addressing people's consumption awareness and behaviors is not the fundamental solution to alleviate CEFI; instead, it should focus on sustainable agricultural production transformation and "food miles" in the transportation phase. In addition, attention needs to be paid to the impacts of fertilizer application, transport modes, and livestock management on the CEFI of each cluster. Finally, the study suggests that around 2028, 70% of China's provinces will be at the "carbon peak" and that less developed and more developed regions have more significant potential to reduce emissions. In this regard, this paper encourages a series of policies that are key to promoting the sustainable development of CEFI, such as reducing the volume and efficiency of traditional fertilizers, vigorously developing organic fertilizer inputs, strengthening technological innovation and R&D inputs in the transportation sector, and steadily supporting germplasm innovation in the livestock sector.

L-shaped association between dietary zinc intake and cognitive decline in Chinese older people.

BACKGROUND AND OBJECTIVE: The prospective association between dietary zinc (Zn) intake and cognitive decline remains uncertain. We aimed to assess the relationship of dietary Zn intake with the risk of cognitive decline in the Chinese older people, and examine the possible effect modifiers on this association. METHODS: A total of 3,106 older Chinese adults aged 55 years or older from China Health and Nutrition Survey were included. Dietary nutrients intake information was collected by combined 24-h dietary recalls with weighing food inventory. The cognitive decline was defined as the 5-year decline rate in global and composite cognitive scores, based on a subset of items from the Telephone Interview for Cognitive Status-modified. RESULTS: The median follow-up duration was 5.9 years. There was an L-shaped association between dietary Zn intake and the 5-year decline rates in global and composite cognitive scores, with an inflection point at 8.8 mg/day of dietary Zn. For the composite cognitive scores, compared with the first quantile (<7.9 mg/day) of dietary Zn intake, quantiles 2-6 (≥7.9 mg/day) had a significantly slower cognitive decline rate (ß: -0.24; 95% confidence interval: -0.40 to -0.07). Similar results were found for the global cognitive scores. Moreover, the inverse association between dietary Zn intake and cognitive decline in composite cognitive scores was significantly stronger in those with lower levels of physical activity (P-interactions = 0.041). CONCLUSION: Dietary Zn intake was negatively associated with cognitive decline in the older people. Maintaining appropriate dietary Zn levels may prevent cognitive decline.

Association Between Dietary Copper Intake and Cognitive Decline: A Perspective Cohort Study in Chinese Elderly.

OBJECTIVE: The association between dietary copper (Cu) intake and cognitive decline remains uncertain. We aim to investigate the longitudinal association of dietary Cu with cognitive decline in Chinese elderly. METHODS: A total of 3,106 Chinese adults aged older than or equal to 55 years from China Health and Nutrition Survey (CHNS) were included. Dietary nutrients information was collected by 24-hours dietary recalls in combination with a food-weighted method. The 5-year change rates in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified (TICS-m) was calculated as the last-survey score minus the baseline score, then divided by the follow-up time (unit, years) and multiplied by five. RESULTS: The median follow-up duration was 5.9 years. There was a nonlinear association of dietary Cu intake with the 5-year change rates in global or composite cognitive scores, with the inflection point at approximately 1.3 mg/day of dietary Cu intake. Accordingly, for the composite cognitive score, compared to the first quantile (<1.28 mg/day), those with dietary Cu in quantiles 2-8 (≥1.28 mg/day) had a significantly slower cognitive decline rate (B, 0.30; 95% CI, 0.13, 0.47). Similar results were found for the global cognitive score. Moreover, the inverse association between dietary Cu and cognitive decline was stronger in those with lower dietary fat intake and lower levels of physical activity (All p-interactions <0.05). CONCLUSION: There was a nonlinear inverse association of dietary Cu intake with cognitive decline in the elderly, with an inflection point at approximately 1.3 mg/day of dietary Cu intake.

Identification and analysis of anti-tumor effective substances in Yangzheng Mixture.

Yangzheng Mixture is a traditional Chinese medicine used in clinical practice as an adjuvant therapy for tumors. However, little is known about its active components in tumor treatment. The purpose of this study was to explore the potential anti-tumor components of Yangzheng Mixture to better promote its clinical application. Using LC-MS/MS, 43 components were detected in concentrated Yangzheng Mixture. Six components, comprising astragaloside, calycosin, formononetin, isoquercitrin, ononin, and calycosin-7-O-ß-D-glucoside, were identified in rat plasma. The cancer cell absorption assay showed that the intracellular concentration of four components, calycosin, calycosin-7-O-ß-D-glucoside, formononetin, and ononin, increased with extended incubation time and demonstrated potential anti-tumor effects. The MTT assay results confirmed that Yangzheng Mixture inhibited different tumor cells proliferation. Additionally, the colony formation assay, flow cytometry analysis and wound healing displayed that Yangzheng Mixture and a combination of four components could inhibit colony formation, arrest the cell cycle and impair cell migration of tumor cells, including HCT-116, MHCC-97L, MCF-7 and NCI-H1299. In summary, our study highlighted the plausible application of Yangzheng Mixture as a potential adjuvant treatment for tumors. Furthermore, it identified effective anti-tumor components and provided evidences for the further clinical application of Yangzheng Mixture.

Research Progress of Dihydroquercetin in the Treatment of Skin Diseases.

Skin is a barrier to maintaining the stability of the human environment and preventing the invasion of pathogens. When skin tissue is exposed to the external environment, it will inevitably develop defects due to trauma, injury, burns, ulcers, surgery, and chronic diseases. Rapid skin repair is the key to reducing infection, relieving pain, and improving quality of life. Dihydroquercetin is a kind of flavonoid that has a wide range of pharmacological activities and can improve skin repair, skin inflammation, skin cancer, and so on. In this paper, the application of dihydroquercetin in medical dressings and the research progress in the treatment of skin-related diseases are reviewed, so as to provide reference for further developing dihydroquercetin as a drug for the treatment of skin diseases.

Thebaine induces anaphylactic reactions via the MRGPRX2 receptor pathway on mast cells.

Morphine derivatives are clinically important anesthetic and sedative drugs, which often show anaphylactic side effects. Mas-related G-protein coupled receptor member X2 (MRGPRX2) triggers mast cell degranulation, which is important process in anaphylactic reactions. MRGPRX2-HEK293 and LAD2 cell membrane chromatographic (CMC) models were used to screen morphine derivatives binding to MRGPRX2. Furthermore, most morphine derivatives significantly enhanced Ca2+ mobilization. More importantly, thebaine was found to effectively promote histamine release. Thebaine induced the increased release of ß-hexosaminidase and high secretion level of cytokines, confirming that thebaine could further trigger anaphylactic reactions and promote subsequent inflammatory reactions. Moreover, the ability of thebaine inducing degranulation and the release of allergenic mediators in mast cells was significantly decreased after MRGPRX2 knockdown, which proved that MRGPRX2 is the key media for thebaine-induced anaphylactic reactions. Significant hind paw swelling and hypothermia in mice after injecting thebaine suggested that thebaine could trigger anaphylactic reactions in vivo.

[Technical system, strategy and development trend of excipient innovation research for pediatric preparations].

Under the background of the "14th Five-Year Plan" industry development, the pharmaceutical industry has ushered in a critical period of strategic transformation. Pharmaceutical excipients are a major categoryin drugs in addition tomedicinal substances, and the research and development of industrial technologies and innovative products play a decisive role in the development of high-quality drugs. The special drug for children is the focus ofthe pharmaceutical industry in the new era, and the application of standar-dized excipients is a key step indistinguishingbetween adult drugs and special drugs for children. In the context of the policy background in China, this paper reviewed the status quo of excipient industry, technical bottlenecks, application problems of pediatric excipients, and their development hotspots, interpreted the strategic layout of excipient innovation research and development suitable for pediatric preparations, and put forward prospects for their future development technicalroutes to lay a solid foundation for the industry transformation.

A microfluidic cytometer for white blood cell analysis.

Despite the wide use of cytometry for white blood cell classification, the performance of traditional cytometers in point-of-care testing remains to be improved. Microfluidic techniques have been shown with considerable potentials in the development of portable devices. Here we present a prototype of microfluidic cytometer which integrates a three-dimensional hydrodynamic focusing system and an on-chip optical system to count and classify white blood cells. By adjusting the flow speed of sheath flow and sample flow, the blood cells can be horizontally and vertically focused in the center of microchannel. Optical fibers and on-chip microlens are embedded for the excitation and detection of single-cell. The microfluidic chip was validated by classifying white blood cells from clinical blood samples.

All-atom structure ensembles of islet amyloid polypeptides determined by enhanced sampling and experiment data restraints.

Exploring the accurate structure ensembles are critical to understand the functions of intrinsically disordered proteins (IDPs). As a well-known IDP, islet amyloid polypeptide (IAPP) plays important roles in the development of human type II diabetes (T2D). The toxicity of human IAPP (hIAPP) is induced by the amyloidosis of the peptide, however, its aggregation mechanism remains ambiguous. The characterization of structure ensemble of hIAPP, as well as the differences between hIAPP and its non-amyloidogenic homologous such as rat IAPP (rIAPP), would greatly help to illuminate the amyloidosis mechanism of IAPP. In this study, the atomic structure ensembles of hIAPP and rIAPP were characterized by all-atom molecular dynamics (MD) simulations combined with enhanced sampling technology and experiment data restraints. The obtained structure ensembles were firstly compared with those determined by the conventional MD (cMD) and enhanced sampling without experiment data restraints. The results showed that the enhanced sampling and experiment data restraints would improve the simulation accuracy. The transient N-terminal α-helix structures were adopted by the sub-states of both hIAPP and rIAPP, however, the C-terminal helical structures were only present on hIAPP. The hydrophobic residues in the amyloid-core region of hIAPP are exposed to the solvent. The structure ensemble differences between hIAPP and rIAPP revealed in this work provide potential explain to the amyloidogenic mechanism and would be helpful for the design of drugs to combat T2D.

Incidence, risk and prognosis of second primary malignancy of patients with gastric adenocarcinoma.

Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Dauricine Inhibits Non-small Cell Lung Cancer Development by Regulating PTEN/AKT/mTOR and Ras/MEK1/2/ERK1/2 Pathways in a FLT4-dependent Manner.

OBJECTIVE: Non-small cell lung cancer (NSCLC) is still a solid tumor with high malignancy and poor prognosis. Vascular endothelial growth factor receptor 3 (FLT4, VEGFR3) is overexpressed in NSCLC cells, making it a potential target for NSCLC treatment. In this study, we aimed to explore the anti-cancer effects of dauricine on NSCLC cells and its mechanism targeting FLT4. METHODS: We found that dauricine inhibited the growth of NCI-H1299 cells by blocking the cycle in the G2/M phase through flow cytometry analysis. In addition, dauricine also inhibited the migration of NCI-H1299 cells by wound healing assay and transwell migration assay. More importantly, our empirical analysis found the anti-cancer effect of dauricine on NCI-H1299 cells and the protein level of FLT4 had a distinctly positive correlation, and this effect was weakened after FLT4 knockdown. RESULTS: It is suggested that dauricine suppressed the growth and migration of NCI-H1299 cells by targeting FLT4. Furthermore, dauricine inhibited FLT4 downstream pathways, such as PTEN/AKT/mTOR and Ras/MEK1/2/ERK1/2, thereby regulating cell migration-related molecule MMP3 and cell cycle-related molecules (CDK1, pCDK1-T161, and cyclin B1). CONCLUSION: Dauricine may be a promising FLT4 inhibitor for the treatment of NSCLC.

Pseudolaric Acid B Inhibits FLT4-induced Proliferation and Migration in Non-small Cell Lung Cancer.

OBJECTIVES: Non-Small Cell Lung Cancer (NSCLC) has attracted much attention on account of the high incidence and mortality of cancers. Vascular Endothelial Growth Factor Receptor 3 (VEGFR3/FLT4), which is a highly expressed receptor in NSCLC, greatly regulates cancer proliferation and migration. Pseudolaric Acid B (PAB) is a diterpenoid acid with antitumor activity isolated from Pseudolarix kaempferi. This study aimed to explore the inhibitory effect of PAB targeting FLT4 in NSCLC. METHODS: Cell membrane chromatography was used to evaluate the affinity of PAB binding on FLT4. NCIH1299 cells were used in this study, and an MTT assay was performed to determine the anti-proliferation effect of PAB. Cell cycle analysis was conducted to study the cycle arrest of PAB. Wound healing and Transwell assays assessed the rate of cell migration. Western blot analysis evaluated the expression of related proteins. RESULTS: PAB showed strong affinity to FLT4 with a KD value of 3.01 × 10- 6 M. Targeting FLT4 by PAB inactivated downstream P38MAPK and PI3K/AKT pathways, which inhibited the proliferation of NCI-H1299 cells. Meanwhile, PAB promoted G2/M phase arrest by influencing CyclinB1 and CDK1 complex formation to inhibit NCI-H1299 cell growth, but the effect was attenuated by knocking down the FLT4. Besides, PAB regulated MMP9 secretion through the Wnt/ß-catenin signaling pathway to inhibit NCI-H1299 cell migration. However, the ability of PAB to inhibit migration was significantly weakened by FLT4 knockdown in NCI-H1299 cells. CONCLUSION: PAB can inhibit the proliferation and migration of NSCLC cells through targeting FLT4 and is expected to be a promising FLT4 inhibitor for NSCLC treatment.

J-shaped association between dietary thiamine intake and the risk of cognitive decline in cognitively healthy, older Chinese individuals.

Background: The prospective association of dietary thiamine intake with the risk of cognitive decline among the general older adults remains uncertain. Aims: To investigate the association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals. Methods: The study included a total of 3106 participants capable of completing repeated cognitive function tests. Dietary nutrient intake information was collected through 3-day dietary recalls and using a 3-day food-weighed method to assess cooking oil and condiment consumption. Cognitive decline was defined as the 5-year decline rate in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified. Results: The median follow-up duration was 5.9 years. There was a J-shaped relationship between dietary thiamine intake and the 5-year decline rate in global and composite cognitive scores, with an inflection point of 0.68 mg/day (95% confidence interval (CI): 0.56 to 0.80) and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake. Before the inflection point, thiamine intake was not significantly associated with cognitive decline. Beyond the inflection point, each unit increase in thiamine intake (mg/day) was associated with a significant decrease of 4.24 (95% CI: 2.22 to 6.27) points in the global score and 0.49 (95% CI: 0.23 to 0.76) standard units in the composite score within 5 years. A stronger positive association between thiamine intake and cognitive decline was observed in those with hypertension, obesity and those who were non-smokers (all p<0.05). Conclusions: This study revealed a J-shaped association between dietary thiamine intake and cognitive decline in cognitively healthy, older Chinese individuals, with an inflection point at 0.68 mg/day and a minimal risk at 0.60-1.00 mg/day of dietary thiamine intake.

In vitro pharmacokinetic behavior in lung of harringtonine, an antagonist of SARS-CoV-2 associated proteins: New insights of inhalation therapy for COVID-19.

BACKGROUND: Recent studies have shown that harringtonine (HT) could specifically bind with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein and host cell transmembrane serine protease 2 (TMPRSS2) to block membrane fusion, which is an effective antagonist for SARS-CoV-2. PURPOSE: Our study focused on in-depth exploration of in vitro pharmacokinetic characteristics of HT in lung. METHODS: HPLC-fluorescence detection method was used to detect changes of HT content. Incubation systems of lung microsomes for phase I metabolism and UGT incubation systems for phase II metabolism were performed to elucidate metabolites and metabolic mechanisms of HT, and then the metabolic enzyme phenotypes for HT were clarified by chemical inhibition method and recombinant enzyme method. Through metabolomics, we comprehensively evaluated the physiological dynamic changes in SD rat and human lung microsomes, and revealed the relationship between metabolomics and pharmacological activity of HT. RESULTS: HPLC-fluorescence detection method showed strong specificity, high accuracy, and good stability for rapid quantification of HT. We confirmed that HT mainly underwent phase I metabolism, and the metabolites of HT in different species were all identified as 4'-demethyl HT, with metabolic pathway being hydrolysis reaction. CYP1A2 and CYP2E1 participated in HT metabolism, but as HT metabolism was not NADPH dependent, the esterase HCES1 in lung also played a role. The main KEGG pathways in SD rat and human lung microsomes were cortisol synthesis and secretion, steroid hormone biosynthesis and linoleic acid metabolism, respectively. The downregulated key biomarkers of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME suggested that HT could prevent immunosuppression and interfere with infection and replication of SARS-CoV-2. CONCLUSION: HT was mainly metabolized into 4'-demethyl HT through phase I reactions, which was mediated by CYP1A2, CYP2E1, and HCES1. The downregulation of 11-deoxycortisol, 21-deoxycortisol and 9(10)-EpOME were key ways of HT against SARS-CoV-2. Our study was of great significance for development and clinical application of HT in the treatment of COVID-19.

Expanding the cell quantity of CRISPR/Cas9 gene editing by continuous microfluidic electroporation chip.

CRISPR/Cas9-mediated gene editing offers promising and safe therapeutic options for a wide range of diseases. The technical difficulty of efficiently acquiring large quantities of gene-edited therapeutic cells in a short time period is now preventing the widespread clinical application of CRISPR/Cas9-mediated gene editing. Herein, a Large Volume Continuous Electroporation Chip (LaViE-Chip) has been developed to address the challenge of acquiring sufficient quantities of genetically edited cells for CRISPR/Cas9 gene editing. By connecting multiple relatively narrow microfluidic channels in parallel, a satisfactory balance between cell flow volume and electric field uniformity was achieved with two simple off-chip electrodes, which also isolated harmful effects around electrodes from target cells. Meanwhile, by carefully designing the curvature of the microfluidic channel, hydrodynamic controlled rotation of target cells has been realized to improve the transfection efficiency and cell viability. With these improvements, the LaViE-Chip realized 71.06 % electrotransfection efficiency, 84.3 % cell viability, and 107 cell/min cell processing speed. Moreover, the first successful incessant CRISPR gene editing by electroporation has been demonstrated, laying the technical foundation of therapeutic CRISPR gene editing.

HPLC-fluorescence detection for stability of harringtonine, and identification of degradation products by UPLC-Q-TOF-MS.

Harringtonine (HT) is an anticancer alkaloid early extracted and isolated from cephalotaxus fortunei Hook. f., also has various pharmacological activities such as antiviral, antibacterial, antimalarial, anti-inflammatory, antioxidant, herbicidal and insecticidal. However, the factors affecting the stability of HT, the main degradation sites and mechanisms involved in its disposal process in vivo have not yet been elucidated. This study utilized HPLC-fluorescence detection method to establish a simple quantitative detection method for HT with good accuracy, precision, and high sensitivity. Temperature and pH were the main factors affecting the stability of HT, which underwent significant degradation in high temperature and alkaline environments because of the occurrence of hydrolysis reactions. In isolated biological homogenates of SD rats, except gastrointestinal tract, HT was degraded in other sites, especially respiratory, mainly in airway and lungs, and systemic metabolism, mainly in livers, spleens, and kidneys. Through UPLC-Q-TOF-MS, three forced degradation products were identified as 4'-demethyl HT, cephalotaxine, and dehydrated HT, respectively. However, the degradation product in isolated biological homogenates of SD rats was only 4'-demethyl HT due to the relatively mild environment. Our findings contributed to a necessary study basis for HT in terms of structural optimization, dosage form selection, storage and transportation.

Six-year change in high-sensitivity cardiac troponin T with subsequent stroke risk in the general population.

BACKGROUND: The association between change in high-sensitivity cardiac troponin T (hs-cTnT) and stroke risk in the general population remains unknown. We aimed to assess the association of a 6-year change in hs-cTnT with incident stroke and its subtypes in the general American adult population. METHODS: 8675 middle-aged adults without prevalent cardiovascular disease from the Atherosclerosis Risk in Communities study were included. Hs-cTnT was measured at two time points (visits 2 and 4), 6 years apart. The relative percentage change of hs-cTnT was defined as hs-cTnT at visit 4 minus that at visit 2, divided by hs-cTnT at visit 2. The study outcome was incident stroke and its subtypes. All data were analysed in 2023. RESULTS: Over a median follow-up of 20.1 years, 682 incident strokes occurred, including 593 ischaemic and 89 haemorrhagic strokes. For absolute change, using low/low group as reference category, the low/high (adjusted HR 1.44, 95% CI 1.03 to 2.02) and high/high (adjusted HR 1.47, 95% CI 0.93 to 2.34) groups were associated with higher risk of stroke. Moreover, the relative percentage change in hs-cTnT with stroke followed an inverted L-shaped association, levelling off at about 75% increase in hs-cTnT (P for nonlinearity=0.009). Compared with those with ≤50% change in hs-cTnT, participants with >50% increase in hs-cTnT had a higher risk of stroke (adjusted HR 1.30, 95% CI 1.03 to 1.64). Similar results were found for ischaemic stroke. No significant association was found for haemorrhagic stroke. CONCLUSION: Temporal increase in hs-cTnT was associated with a higher risk of incident total and ischaemic stroke in the general population.