Chromone-deferiprone hybrids as novel MAO-B inhibitors and iron chelators for the treatment of Alzheimer's disease.

A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.

Carvedilol to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by liver stiffness: study protocol for a randomied, double-blind, placebo-controlled, multicentre trial in China.

INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

High-robustness autofocusing method in the microscope with laser-based arrayed spots.

Accurate and rapid autofocus technology plays a crucial role in various fields, including automatic optical inspection technology, bio-chips scanning, and semiconductor manufacturing. The current photoelectric autofocus methods have limitations because of detecting the focal plane solely at the center of the microscope field of view. In the application of Stereo-seq the risk of autofocus errors will be increased, which have reduced the robustness of the system, like when the surface of the tested samples are wrinkling and inconsistent thickness, or the detection spot is at the edge of the sample. To enhance the robustness of the autofocus system and mitigate the constraints of the photoelectric autofocus methods, the laser-based arrayed spots photoelectric autofocus method has been proposed. To achieve the uniform light splitting, a 2D-Dammann grating is incorporated into the optical path of the autofocus system, resulting in the formation of an n × n arrayed spots on the surface of the sample. Through experimental verification, it has been demonstrated that this method can achieve the autofocus range of ±100µm and the autofocus accuracy of ±1/4 DOF when applied to a microscope equipped with a 10× objective lens, thereby satisfying the requirements for microscopic focusing. The arrayed light autofocus method devised in this study presents what we believe is a novel research concept for active autofocus detection and holds significant application value.

Carbon-reinforced Ni3S2/Ti3C2Tx MXene composite as an anode for superior-performance lithium-ion capacitors.

Lithium ion capacitors (LICs) are a new generation of energy storage devices that combine the super energy storage capability of lithium ion batteries with the satisfactory power density of supercapacitors. The development of high-performance LICs still faces great challenges due to the unbalanced reaction kinetics at the anode and cathode. Therefore, it is an inevitable need to enhance the electron/ion transfer capability of the anode materials. In this paper, to obtain a superior-rate and high-capacity Ni3S2-based anode, highly conductive Ti3C2Tx MXene sheets were introduced to sever as the carrier of Ni3S2 nanoparticles and simultaneously an amorphous carbon layer which coats onto the surface of Ni3S2 nanoparticles was in-situ generated by the carbonization of dopamine reactant. The as-synthesized Ni3S2/Ti3C2Tx/C composite exhibits a high specific surface area (112.6 m2/g) because of the addition of Ti3C2Tx that can reduce the aggregation of Ni3S2 nanoparticles and the in-situ generated amorphous carbon layer that can suppress the growth of Ni3S2 nanoparticles. The Ni3S2/Ti3C2Tx/C anode possesses a remarkable reversible discharge specific capacity (626.0 mAh/g under 0.2 A/g current density), which increases to 1150.8 mAh/g after 400-cycle charge/discharge measurement at the same measurement condition indicating eminent cyclability, along with superior rate capability. To construct a superior-performance LIC device, a sterculiae lychnophorae derived porous carbon (SLPC) cathode with an average discharge specific capacity of 73.4 mAh/g@0.1A/g was prepared. The Ni3S2/Ti3C2Tx/C//SLPC LIC device with optimal cathode/anode mass ratio has a satisfactory energy density ranging from 32.8 to 119.1 Wh kg-1 at the corresponding power density of 8799.4 to 157.5 W kg-1, together with a prominent capacity retention (95.5 %@1 A/g after 10,000 cycles).

Impact of the COVID-19 pandemic on routine vaccination coverage under varying prevalence Conditions: A cohort study in Beijing, China.

BACKGROUND: The COVID-19 pandemic has experienced various phases including outbreaks, a global health crisis, and eventual de-escalation from a public health emergency of international concern, significantly affecting the delivery and utilization of healthcare services. This study aimed to evaluate the impact of the COVID-19 pandemic on the coverage rate of routine immunization in children under varying prevalence conditions. METHODS: We conducted a retrospective, population-based cohort study in Beijing, China, utilizing stratified random sampling by birthdate to obtain a sample of 29,811 participants. Subjects were categorized into four cohorts based on when they became eligible for vaccination: the Pre-COVID Period cohort, the COVID-19 Low Epidemic Period cohort, the COVID-19 Surging Period cohort, and the COVID-19 Slowing Down Period cohort. A one-month follow-up was conducted. Cox proportional hazards model was employed to examine associations between the COVID-19 epidemic status and timely vaccination. RESULTS: Participants age-eligible for vaccination during the COVID-19 Low Epidemic Period demonstrated higher rates of timely vaccination (HR 1.18, 95% CI 1.15-1.22) compared to those eligible during the Pre-COVID Period. Conversely, those eligible during the COVID-19 Surging Period displayed lower rates (HR 0.73, 95% CI 0.66-0.82). No significant difference in vaccination timeliness was observed for those eligible during the COVID-19 Slowing Down Period in comparison to the Pre-COVID Period (HR 0.99, 95% CI 0.91-1.09). By the end of May 2023, DTP3 rate among eligible children during the COVID-19 Surging Period had surpassed 90%. CONCLUSIONS: Significantly declining rates of timely vaccination were observed during the COVID-19 Surging Period, which lasted two months, but not during the nearly three-year-long COVID-19 Low Epidemic Period. An upward trend in vaccination timeliness followed, culminating in a return to baseline levels over the subsequent 3-4 months. Our findings suggested that the pandemic exerted a decreasing and recoverable impact on the coverage rate of routine immunizations in China.

Mesenchymal stem cells paracrine proteins from three-dimensional dynamic culture system promoted wound healing in third-degree burn models.

Recovery of skin function remains a significant clinical challenge for deep burns owing to the severe scar formation and poor appendage regeneration, and stem cell therapy has shown great potential for injured tissue regeneration. Here, a cell-free therapy system for deep burn skin was explored using mesenchymal stem cell paracrine proteins (MSC-PP) and polyethylene glycol (PEG) temperature-sensitive hydrogels. A three-dimensional (3D) dynamic culture system for MSCs' large-scale expansion was established using a porous gelatin microcarrier crosslinked with hyaluronic acid (PGM-HA), and the purified MSC-PP from culture supernatant was characterized by mass spectrometric analysis. The results showed the 3D dynamic culture system regulated MSCs cell cycle, reduced apoptosis, and decreased lactic acid content, and the MSC-PP produced in 3D group can promote cell proliferation, migration, and adhesion. The MSC-PP + PEG system maintained stable release in 28 days of observation in vitro. The in vivo therapeutic efficacy was investigated in the rabbit's third-degree burn model, and saline, PEG, MSC-PP, and MSC-PP + PEG treatments groups were set. The in vivo results showed that the MSC-PP + PEG group significantly improved wound healing, inhibited scar formation, and facilitated skin appendage regeneration. In conclusion, the MSC-PP + PEG sustained-release system provides a potentially effective treatment for deep burn skin healing.

Vaccination coverage survey of children aged 1-3 years in Beijing, China, 2005-2021.

BACKGROUND: The routine immunization program for children is a primary strategy and a core part of vaccination. Achieving and maintaining high level of vaccination coverage are important to reduce morbidity and mortality caused by vaccine-preventable diseases. In Beijing, annual coverage surveys have been conducted since 2005. It is necessary and possible to assess the level and trend of routine vaccination coverage of children in Beijing as well as the disruption of coronavirus disease 2019 (COVID-19) pandemic and provide the reference for the further improve the vaccination coverage. METHODS: The data of 61,521 children aged 1-3 years in the vaccination coverage surveys during 2005-2021 were analyzed by Beijing Center for Disease Control and Prevention. Descriptive epidemiological method was used to analyze the data and the difference of vaccination coverage within the time period. RESULTS: More than 99 % of participants had immunization cards and electronic immunization records. The concordance rate of both records were also over 99 %. During 2011-2019, the rates of on-time and in-time vaccination of each routine vaccine reached 96 % or more and increased significantly (all P values <0.05), compared with that of 2005-2010. All rates of the investigated vaccine, except for Bacillus Calmette-Guérin vaccine (BCG) and the first dose of hepatitis B vaccine (HepB), decreased in 2020-2021 significantly (all P values <0.05). For the causes of failing to vaccinate on time, delayed vaccination accounted for 47.82 %. The top two vaccines to be missed were the first dose of hepatitis A vaccine and the 4th dose of diphtheria-tetanus-acellular pertussis vaccine, accounting for 21.41 % and 20.79 %, respectively. The main reason for zero-dose/drop-out vaccination was "Guardians regarded the immunization service time as inappropriate", accounting for 72.27 %. CONCLUSION: The coverage level and service quality of routine immunization in Beijing were relatively high. However, as influenced by COVID-19 epidemics, both on-time and in-time vaccination rates decreased significantly, except for BCG and HepB. Under the background of COVID-19 pandemic, the keys to maintain high level of vaccination coverage include flexible immunization service time to ensure the guardians bringing their children for vaccination timely, and more attention from providers to the doses after children's first birthday.

Efficacy evaluation of direct antiviral drugs against hepatitis B virus in improving the degree of liver fibrosis.

Introduction: The aim of the study was to find an ideal index reflecting inflammation and fibrosis for patients after antiviral treatment, and compare it with imaging examination (liver stiffness measurement - LSM) and traditional liver fibrosis models (APRI and FIB-4). Material and methods: A total of 77 chronic hepatitis B (CHB) patients who achieved a sustained virological response (SVR) after entecavir (ETV) treatment were included, and the changes of various clinical indicators before and after treatment were compared. Results: After 78 weeks of ETV treatment, WBC and PLT of 77 patients were significantly increased, while ALT, AST and total bilirubin were significantly decreased (p < 0.05). There was no significant difference in serum creatinine (Cr) or blood urea nitrogen (BUN) compared to the values before treatment (p > 0.05). The three non-invasive liver fibrosis indexes, namely, LSM, APRI and FIB-4, were significantly decreased in 77 patients compared to the values before treatment (p < 0.001). Conclusions: Acoustic radiation force impulse (ARFI), fibrosis-4 (FIB-4), aspartate aminotransferase-to-platelet ratio index (APRI) have a high consistency with the grading of liver fibrosis, and can be used to evaluate the severity of liver fibrosis. Among them, ARFI has good diagnostic value for the classification of different degrees of liver fibrosis and the best diagnostic accuracy.

Molecular characterization and antimicrobial activity of NK-lysin in black scraper (Thamnaconus modestus).

NK-lysin (NKL) is a positively charged antimicrobial peptide with broad-spectrum bactericidal activities. In this study, the cDNA sequence of NKL (TmNKL) from black scraper (Thamnaconus modestus) was cloned, which encodes a predicted polypeptide of 150 amino acids that contains a surfactant protein B domain with three disulfide bonds. Phylogenetically, TmNKL was most closely related to its teleost counterpart from tiger puffer (Takifugu rubripes). Expression analysis demonstrated that TmNKL transcripts were constitutively expressed in all tested tissues, with the highest expression levels in the gills. Its expression was significantly upregulated in the gills, head kidney, and spleen after infection with Vibrio parahaemolyticus. A linear peptide (TmNKLP40L) and a disulfide-type peptide (TmNKLP40O) were further synthesized and results showed that disulfide bonds are not essential for bactericidal activities of TmNKL, and that both forms of TmNKL exhibited potent bactericidal activities against 4 gram- negative bacteria, including V. parahaemolyticus, V. alginolyticus, Edwardsiella tarda, and V. harveyi. Observed antimicrobial activities are likely due to the effects of TmNKLP40L and TmNKLP40O treatment on disrupting the integrity of both inner and outer membrane of V. parahaemolyticus, resulting in hydrolysis of bacterial genomic DNA. Damaged cell membranes and leakage of intracellular contents were further confirmed using scanning and transmission microscopy. Moreover, administration of 1.0 µg/g TmNKLP40L or TmNKLP40O significantly decreased bacterial load in tissues and thus, pronouncedly enhanced the survival of V. parahaemolyticus-infected fish. Overall, our results demonstrated that TmNKL is a potent innate effector and provides protective effects against bacterial infection.

Effect of copper sulphate on Cryptocaryon irritans based on metabolome analysis.

Cryptocaryon irritans is one of the most harmful marine parasites in mariculture. Copper sulphate is often used to kill parasites and the influence of copper sulphate on the tomont stage of C. irritans was explored in this study. The results showed that excystment rate was not significantly affected when tomonts were exposed to 5 mg/L (76.7%) and 10 mg/L (78.9%) of copper sulphate for 3 h. However, excystment rate was significantly inhibited when exposed to 15 mg/L (33.3%) for 3 h and 5 mg/L (28.9%), 10 mg/L (33.3%) and 15 mg/L (33.3%) for 6 h. After treatment with high concentrations of copper sulphate, the interior of the tomonts was fuzzy under the microscope, and the division process could not be observed. Metabolomic results combined with preliminary transcriptome analysis results showed that the tomonts were induced to produce linoleate, riboflavin, inositol and other substances under the stress of Cu2+ , which affected the antioxidant mechanism of the body. Using MDA content determination and antioxidant enzyme activity analysis, copper sulphate was found to cause oxidative damage to tomonts by affecting the generation of metabolites, leading to the death of tomonts.

Therapeutic efficacy of novel memantine nitrate MN-08 in animal models of Alzheimer's disease and vascular dementia / 中国药理学与毒理学杂志

OBJECTIVE Alzheimer's disease(AD)and vascular dementia(VD)are the primary causes of dementia in elderly individuals,and therapeutic options for both conditions are limited.Overactivation of N-methyl-D-aspartate(NMDA)receptors,decreased cerebral blood flow,and subsequent pathological events,play signifi-cant roles in the progression of AD and VD.METHODS In this study,we investigated the therapeutic effects and underlying mechanisms of MN-08,a novel memantine nitrate,in mouse models of AD and rats with VD.RESULTS MN-08 was found to inhibit Aβ accumulation,prevent neuronal and dendritic spine loss,and attenuate cognitive deficits in 2-month-old APP/PS1 transgenic mice(following a 6-month preventative course)and in 8-month-old triple-transgenic(3×Tg-AD)mice(following a 4-month therapeutic course),as well as in rat models of VD with preventive and therapeutic treatments.In vitro,MN-08 was shown to bind to and antagonize NMDA receptors,inhibit calcium influx,and reverse dysregula-tions of the ERK and PI3K/Akt/GSK3β pathway,subse-quently preventing glutamate-induced neuronal loss.Additionally,MN-08 exhibited favorable pharmacokinet-ics,blood-brain barrier penetration,and safety profiles in rats and beagle dogs.CONCLUSION These findings suggest that the novel memantine nitrate MN-08 may be a useful therapeutic agent for AD and VD.

Monoterpenoids from Paeoniae Radix Rubra based on UPLC-Q-TOF-MS / 中国中药杂志

The ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used to conduct the qualitative analysis of the monoterpene chemical components from Paeoniae Radix Rubra. Gradient elution was performed on C_(18) HD(2.1 mm×100 mm, 2.5 μm) column with a mobile phase of 0.1% formic acid(A) and acetonitrile(B). The flow rate was 0.4 mL·min~(-1) and the column temperature was 30 ℃. MS analysis was conducted in both positive and negative ionization modes using electrospray ionization(ESI) source. Qualitative Analysis 10.0 was used for data processing. The identification of chemical components was realized by the combination of standard compounds, fragmentation patterns, and mass spectra data reported in the literature. Forty-one monoterpenoids in Paeoniae Radix Rubra extract were identified. Among them, 8 compounds were reported in Paeoniae Radix Rubra for the first time and 1 was presumed to be the new compound 5″-O-methyl-galloylpaeoniflorin or its positional isomer. The method in this study realizes the rapid identification of monoterpenoids from Paeoniae Radix Rubra and provides a material and scientific basis for quality control and further study on the pharmaceutical effect of Paeoniae Radix Rubra.

Current status and development prospects of aquatic vaccines.

Diseases are a significant impediment to aquaculture's sustainable and healthy growth. The aquaculture industry is suffering significant financial losses as a result of the worsening water quality and increasing frequency of aquatic disease outbreaks caused by the expansion of aquaculture. Drug control, immunoprophylaxis, ecologically integrated control, etc. are the principal control strategies for fish infections. For a long time, the prevention and control of aquatic diseases have mainly relied on the use of various antibiotics and chemical drugs. However, long-term use of chemical inputs not only increases pathogenic bacteria resistance but also damages the fish and aquaculture environments, resulting in drug residues in aquatic products, severely impeding the development of the aquaculture industry. The development and use of aquatic vaccines are the safest and most effective ways to prevent aquatic animal diseases and preserve the health and sustainability of aquaculture. To give references for the development and implementation of aquatic vaccines, this study reviews the development history, types, inoculation techniques, mechanisms of action, development prospects, and challenges encountered with aquatic vaccines.

Diagnostic Potential of the Serum lncRNAs HOTAIR, BRM and ICR for Hepatocellular Carcinoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) are closely associated with the initiation, progression, metastasis, and recurrence of hepatocellular carcinoma (HCC). They could therefore serve as markers for the early diagnosis and for the prognosis of HCC patients. METHODS: This was an observational prospective cohort study. A total of 101 participants were included, comprising patients with HCC (n = 61), liver cirrhosis (LC) (n = 20), or healthy controls (HC) (n = 20). The baseline characteristics of participants in each group were compared. Serum levels of the lncRNAs HOTAIR, BRM and ICR were determined in each group by reverse transcription and quantitative real-time polymerase chain reaction (qRT-PCR). Correlations between the serum levels of the three lncRNAs and multiple clinical parameters were analysed. The receiver operating characteristic (ROC) curve was used to assess the diagnostic potential for HCC of each lncRNA individually, or in combination with AFP. Multivariate Cox regression analysis was used to evaluate the accuracy of these lncRNAs for predicting the outcome and survival of HCC patients. RESULTS: The serum levels of HOTAIR, BRM and ICR were significantly higher in HCC patients compared to LC patients and healthy subjects. The HOTAIR level was positively correlated to tumour-node metastasis (TNM), Barcelona Clinic Liver Cancer (BCLC) stage, extrahepatic metastasis, vascular invasion, portal vein tumour thrombus (PVTT), and tumour size. The BRM level was positively associated with TNM stage, BCLC stage, vascular invasion, PVTT, and tumour size, while the ICR level was positively correlated with PVTT. A combination of the three lncRNAs and AFP showed the highest diagnostic accuracy for HCC, with an AUC of 0.998, sensitivity of 98.4%, and specificity of 100.0%. This combination showed a better diagnostic accuracy than the individual lncRNAs or AFP alone. Serum levels of the HOTAIR and ICR lncRNAs decreased significantly following surgery. CONCLUSIONS: Serum levels of the HOTAIR, BRM and ICR lncRNAs are potential prognostic markers for HCC. Upregulation of HOTAIR, BRM and ICR may facilitate early diagnosis and indicate poor prognosis for HCC. These lncRNAs could potentially serve as therapeutic targets for HCC. Combination of the three lncRNAs with AFP may increase the diagnostic accuracy for HCC. Further studies in larger cohorts of patients are needed to validate these findings.

Determinants and Incidence of Chronic Kidney Disease with Tenofovir- Based Antiretroviral Therapy Regimens: A Cohort Study in HIV-Infected Adults in South China.

BACKGROUND: The data of the impact of tenofovir (TDF) on kidney damage in Chinese HIV-1 infected patients are limited. OBJECTIVE: The study aims to evaluate the incidence and risk factors of stage 3 chronic kidney disease (CKD) and rapid kidney function decline (RKFD) among Chinese HIV-1 infected patients starting with a TDF-based regimen. METHODS: We enrolled 797 TDF-initiated HIV-1-infected patients in a Chinese cohort. Kidney dysfunctions were defined as stage 3 CKD (eGFR < 60 mL/min/1.73 m2 during follow-up) and RKFD (eGFR decline > 10 mL/min/1.73 m2/year). A linear mixed-effects model was used to quantify the average eGFR change per 48 weeks. A generalized estimating equation regression analysis was conducted to determine the risk factors associated with renal dysfunction. The method of multiple imputations was used to reduce the bias caused by missing data. RESULTS: In this retrospective study, 14 (2%) patients experienced stage 3 CKD, and 272 (34%) individuals experienced RKFD during a median of 26 (IQR, 4-78; maximum 325) weeks follow-up period. The mean loss in eGFR per 48 weeks increased consistently over time, from -2.59 mL/min/1.73 m2 before 48 weeks to -17.61 mL/min/1.73 m2 after 288 weeks. For every 10 mL/min/1.73 m2 increase of eGFR, the risk of RKFD increased by 29% (95%CI: 18%, 40%). Each 10 years older and every 10 mL/min/1.73 m2 higher in baseline eGFR, the risk of stage 3 CKD increased to 1.56 (95% CI: 1.00, 2.43) and decreased by 65% (95% CI: 48%, 76%), respectively. Anemia and higher viral load were significantly associated with RKFD. The results were robust across a range of multiple imputation analyses. CONCLUSION: TDF-associated CKD is rare in HIV-1 infected Chinese adults. Longer TDF-exposed patients are more likely to have renal dysfunction, especially those with older age, anemia, lower baseline eGFR, and higher viral load.

The Associations of Lymphocyte Ratio and Neutrophil Ratio on Liver Dysfunction in COVID-19 Patients.

Data on the impact of lymphocytes and neutrophils on the incidence of liver dysfunction in COVID-19 patients are limited. This study aimed to investigate the lateral and longitudinal associations of lymphocyte ratio (LR) and neutrophil ratio (NR) on liver dysfunction in COVID-19 patients. We tested 1,409 blood samples from 245 COVID-19 patients in China between January 2020 and June 2021. The lateral U-shaped relationships, determined by smooth curve fitting and the piecewise-linear mixed-effect model, were observed between LR, NR, and AST and the incidence of AST-linked liver dysfunction, with the threshold cutoffs of 26.1 and 62.0, respectively. Over the 1,409 tests, the LR ≤ 26.1 and NR ≥ 62.0 related to the occurrence of mild liver dysfunction (HR: 1.36; 95% CI: 1.01, 1.82), moderate liver dysfunction (HR: 1.37; 95% CI: 1.01, 1.85), and severe liver dysfunction (HR: 1.72; 95% CI: 1.02, 2.90). For the patients with preexisting AST ≥ 35 U/L, the baseline LR ≤ 26.1 and NR ≥ 62.0 (b.LLCHN) groups had a fully adjusted 8.85-, 7.88-, and 5.97-fold increased risk of mild and moderate liver dysfunction after being hospitalized of 3, 6, and 9 days compared to the baseline LR > 26.1 and NR < 62.0 (b.normal) groups. Severe liver dysfunction only presents significant differences after being adjusted for age, sex, and BMI. Consistently, Kaplan-Meier analyses showed that b.LLCHN reflects a better predictive value for different subsequent magnitude liver dysfunctions after admission of 3 and 6 days. To improve liver function in patients with preexisting AST ≥35 U/L, future management strategies should pay more attention to baseline LR ≤ 26.1 and NR ≥ 62.0 patients.

Pharmacological inhibition of KDM5A for cancer treatment.

Lysine-specific demethylase 5A (KDM5A, also named RBP2 or JARID1A) is a demethylase that can remove methyl groups from histones H3K4me1/2/3. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, drug resistance, and is associated with poor prognosis. Pharmacological inhibition of KDM5A has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of KDM5A, its role in carcinogenesis, a comparison of currently available approaches for screening KDM5A inhibitors, a classification of KDM5A inhibitors, and its potential as a drug target in cancer therapy.

Ketoplatin in triple-negative breast cancer cells MDA-MB-231: High efficacy and low toxicity, and positive impact on inflammatory microenvironment.

Triple-negative breast cancer (TNBC) shares the molecular features facilitating epithelial-to-mesenchymal transition (EMT), which contributed to tumor invasion and metastasis. A platinum(IV) conjugate ketoplatin deriving from FDA-approved drugs cisplatin and ketoprofen was designed and prepared to enhance antitumor activity and suppress EMT in TNBC via positive impact on inflammatory microenvironment by modulating COX-2 signal. As a prodrug, ketoplatin afforded 50.26-fold higher cytotoxicity than cisplatin against TNBC mesenchymal-stem cell-like MDA-MB-231 cells, partly attributing to its dramatic increase of cellular uptake and DNA damage. More importantly, EMT progress in MDA-MB-231 was markedly restrained by ketoplatin, resulting from the suppression of vimentin and N-cadherin mediated by down-regulated COX-2. Further in vivo investigation exhibited that ketoplatin effectively inhibited tumor growth and reduced systemic toxicity compared to cisplatin. Overall, ketoplatin possessed high antitumor activity and low toxicity against TNBC MDA-MB-231 in vitro and in vivo.

Comprehensive profiling and characterization of the absorbed components and metabolites in mice serum and tissues following oral administration of Qing-Fei-Pai-Du decoction by UHPLC-Q-Exactive-Orbitrap HRMS / 中国天然药物

Qing-Fei-Pai-Du decoction (QFPDD) is a Chinese medicine compound formula recommended for combating corona virus disease 2019 (COVID-19) by National Health Commission of the People's Republic of China. The latest clinical study showed that early treatment with QFPDD was associated with favorable outcomes for patient recovery, viral shedding, hospital stay, and course of the disease. However, the effective constituents of QFPDD remain unclear. In this study, an UHPLC-Q-Orbitrap HRMS based method was developed to identify the chemical constituents in QFPDD and the absorbed prototypes as well as the metabolites in mice serum and tissues following oral administration of QFPDD. A total of 405 chemicals, including 40 kinds of alkaloids, 162 kinds of flavonoids, 44 kinds of organic acids, 71 kinds of triterpene saponins and 88 kinds of other compounds in the water extract of QFPDD were tentatively identified via comparison with the retention times and MS/MS spectra of the standards or refereed by literature. With the help of the standards and in vitro metabolites, 195 chemical components (including 104 prototypes and 91 metabolites) were identified in mice serum after oral administration of QFPDD. In addition, 165, 177, 112, 120, 44, 53 constituents were identified in the lung, liver, heart, kidney, brain, and spleen of QFPDD-treated mice, respectively. These findings provided key information and guidance for further investigation on the pharmacologically active substances and clinical applications of QFPDD.

[UPLC quantitative fingerprint research on Gardeniae Fructus based on chemical pattern recognition technology].

Twenty-six batches of Gardeniae Fructus from different producing area were collected for the development of the fingerprint, and the main components of Gardeniae Fructus were identified by liquid chromatography-mass spectrometry. The producing areas of Gardeniae Fructus were distinguished by chemical pattern recognition technology, and the index components of Gardeniae Fructus were quantitated. An UPLC wavelength switching method was adopted, and the separation was carried out on a Waters Acquity UPLC HASS C_(18)(2.1 mm×100 mm, 1.7 µm) column using the mobile phase of acetonitrile-0.5% formic acid water for gradient elution. Principal component analysis(PCA) and orthogonal partial least square discriminant analysis(OPLS-DA) were used for the data ana-lysis. The results showed that the similarity of 26 batches of Gardeniae Fructus was more than 0.89, and ten common peaks were defined. Sixteen compounds including monoterpenes, iridoids and diterpenoids were identified by reference identification, literature comparison and high-resolution mass spectrometry data analysis. The distinguishment of origin of Gardeniae Fructus was realized by PCA and OPLS-DA analysis, and two quality differential markers were screened as geniposide and crocin Ⅰ. The contents of crocin Ⅰ, crocin Ⅱ and geniposide in Gardeniae Fructus from different places were different. These results will provide reference for the geographical origin traceability of Gardeniae Fructus.