Evaluation of the liver targeting and anti­liver cancer activity of artesunate­loaded and glycyrrhetinic acid­coated nanoparticles.

Globally, liver cancer ranks among the most lethal cancers, with chemotherapy being one of its primary treatments. However, poor selectivity, systemic toxicity, a narrow treatment window, low response rate and multidrug resistance limit its clinical application. Liver-targeted nanoparticles (NPs) exhibit excellent targeted delivery ability and promising effectivity in treating liver cancer. The present study aimed to investigate the liver-targeting and anti-liver cancer effect of artesunate (ART)-loaded and glycyrrhetinic acid (GA)-decorated polyethylene glycol (PEG)-poly (lactic-co-glycolic acid) (PLGA) (ART/GA-PEG-PLGA) NPs. GA-coated NPs significantly increased hepatoma-targeted cellular uptake, with micropinocytosis and caveolae-mediated endocytosis as its chief internalization pathways. Moreover, ART/GA-PEG-PLGA NPs exhibited pro-apoptotic effects on HepG2 cells, mainly via the induction of a high level of reactive oxygen species, decline in mitochondrial membrane potential and induction of cell cycle arrest. Additionally, ART/GA-PEG-PLGA NPs induced internal apoptosis pathways by upregulating the activity of cleaved caspase-3/7 and expression of cleaved poly (ADP-Ribose)-polymerase and Phos-p38 mitogen-activated protein kinase in HepG2 cells. Furthermore, ART/GA-PEG-PLGA NPs exhibited higher liver accumulation and longer mean retention time, resulting in increased bioavailability. Finally, ART/GA-PEG-PLGA NPs promoted the liver-targeting distribution of ART, increased the retention time and promoted its antitumour effects in vivo. Therefore, ART/GA-PEG-PLGA NPs afforded excellent hepatoma-targeted delivery and anti-liver cancer efficacy, and thus, they may be a promising strategy for treating liver cancer.

Design, Synthesis and Biological Evaluation of Glycosylated Derivatives of Silibinin as Potential Anti-Tumor Agents.

Objective: Silibinin, a natural product extracted from the seeds of the Silybum marianum, is versatile with various pharmacological effects. However, its clinical application was strongly hampered by its low bioavailability and poor water solubility. Herein, a series of glycosylated silibinin derivatives were identified as novel anti-tumor agents. Materials and Methods: The cell viability was evaluated by CCK8 assay. Furthermore, cell apoptosis and cell cycle progression were tested by flow cytometry. In addition, the pharmacokinetic assessment of compound 15 and silibinin through intravenous administration (i.v., 2 mg/kg) to ICR mice were performed. Results: The synthesized compounds showed better water solubilities than silibinin. Among them, compound 15 exhibited inhibitory activity against DU145 cells with IC50 value of 1.37 ± 0.140 µM. Moreover, it arrested cell cycle at G2/M phase and induced apoptosis in DU145 cells. Additionally, compound 15 also displayed longer half-life (T1/2 = 128.3 min) in liver microsomes than that of silibinin (T1/2 = 82.5 min) and appropriate pharmacokinetic parameters in mice. Conclusion: Overall, glycosylation of silibinin would be a valid strategy for the development of silibinin derivatives as anti-tumor agents.

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.

Repeated COVID-19 relapse during post-discharge surveillance with viral shedding lasting for 67 days in a recovered patient infected with SARS-CoV-2.

A case who revealed the longest duration of viral shedding (67 days) in current reports, presented complicated characteristic on the relapse of COVID-19 due to the inconsistent performance of chest radiography and SARS-CoV-2-RNA detection after discharge. Lopinavir-interferon α2b boosted ribavirin following with lopinavir boosted budesonide might be a potent treatment for viral clearance.

Positive SARS-CoV-2 RNA recurs repeatedly in a case recovered from COVID-19: dynamic results from 108 days of follow-up.

The evidence of long-term clinical dynamic on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) RNA re-positive case are less. We performed a 108 days follow-up on dynamic clinical presentations in a case, who hospitalized three times due to the positive recurrence of SARS-CoV-2 RNA after discharge, to understand the prognosis of the 2019-Coronavirus disease (COVID-19). In this case, positive SARS-CoV-2 recurred even after apparent recovery (normal CT imaging, no clinical symptoms, negative SARS-CoV-2 on stool sample and negative serum IgM test) from COVID-19, viral shedding duration lasted for 65 days, the time from symptom onset to disappearance was up to 95 days. Erythrocyte-associated indicators, liver function and serum lipid metabolism presented abnormal throughout during the observation period. Awareness of atypical presentations such as this one is important to prompt the improvement of the management of COVID-19.

Acetaminophen-induced acute pancreatitis: A case report and literature review.

Acute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-year-old woman presented with nausea and vomiting for 12 h, but no abdominal pain following an overdose of eight Tylenol tablets containing acetaminophen (325 mg acetaminophen per tablet). Laboratory results on admission showed abnormal amylase and lipase levels but completely normal liver function. Magnetic resonance cholangiopancreatography revealed mild swelling of the pancreas without fluid collection around the pancreas. The patient complained of severe abdominal pain five days after admission when attempting to drink water and liquids. Eight days after admission, fluid around the pancreas was observed by computed tomography. The patient was subsequently diagnosed with acetaminophen-induced acute pancreatitis after exclusion of common causes. Routine treatment for pancreatitis and N-acetylcysteine were administered to prevent disease progression. The patient was discharged in good condition.

[Early surgical outcomes of coronary heart disease with severe ischemic mitral regurgitation].

OBJECTIVE: To summarize the experience with surgical treatment of coronary artery disease with severe ischemic mitral valve regurgitation (IMR). METHODS: From January 2006 to December 2009, 45 patients (35 males, 10 females aged 32-74 years) with the diagnosis of coronary artery disease complicated by IMR underwent coronary artery bypass grafting (CABG) combined with mitral valve plasty (MVP, 24 cases) or mitral valve replacement (MVR, 21 cases). RESULTS: Perioperative deaths occurred in 2 cases due to multiple organ failure (MOF). Echocardiography showed a significant reduction of the mitral regurgitation area (from 11.80∓2.45 cm(2) to 2.83∓0.98 cm(2), t=22.80, P=0.00) after CABG combined with mitral valve surgery, with also significantly reduced postoperative left ventricular end diastolic diameter (LVEDD) (from 57.61∓10.06 mm to 51.84∓8.98 mm, t=2.85, P=0.005). No significant difference was detected in the left ventricular ejection fraction after the operation [(52.7∓15.4)% vs (53.2∓13.2)%, t=0.16, P=0.87)]. CONCLUSIONS: CABG combined with mitral valve surgery can improve early postoperative left ventricular function in patients with ischemic coronary heart disease complicated by severe mitral regurgitation, but further follow-up study is still needed for evaluation of the long-term results.

[Surgical treatment of 128 cases of constrictive pericarditis].

OBJECTIVE: To summarize the experience with surgical treatment of constrictive pericarditis. METHODS: A retrospective analysis of the post-operative clinical data was conducted in 128 surgical patients with chronic constrictive pericarditis. RESULTS: Two early postoperative death occurred in this group due to severe low cardiac output syndrome, with the mortality rate of 1.57%. The postoperative complications included low cardiac output syndrome (13.2%), arrhythmia (7.02%), acute renal insufficiency (3.9%), respiratory insufficiency (3.1%), wound infection (2.3%), postoperative chest bleeding (1.6%) and cerebral infarction (0.78%). Relapse occurred in one case because of incomplete pericardial resection. CONCLUSIONS: Constrictive pericarditis should be confirmed as soon as possible with actively surgery, and the extent of pericardial resection should be decided according to the individual conditions. Complete untethering of the diseased pericardium should be performed with active prevention of postoperative complications.

[Combined slower plasma exchange and continuous veno-venous hemofiltration with a parallel circuit in the treatment of chronic severe viral hepatitis B patients.].

OBJECTIVE: To explore the clinical effects of combined slower plasma exchange (PE) and continuous veno-venous hemofiltration (CVVH) with a parallel circuit in the treatment of chronic severe viral hepatitis B patients. METHODS: 104 patients with chronic severe viral hepatitis B were divided into three groups: 44 patients were treated with a parallel circuit of combined slower plasma exchange and continuous veno-venous hemofiltration (group A), 30 patients were treated with plasma exchange (group B), and 30 patients received routine treatment (group C). Efficacy of treatment and survival rate in three groups were investigated. The levels of cytokine, plasma sodium concentration and pH value were examined before and after artificial liver support system treatment. RESULTS: In group A, 7 of 9 patients in coma regained normal consciousness, 6 of 9 patients with hepatorenal syndrome restored renal function, hyponatremia was improved, the balance of pH value was corrected, tumor necrosis factor (TNF)-alpha level was decreased, and the total survival rate was 56.82%. In group B, 2 of 7 patients in coma regained normal consciousness, 1 of 5 patients with hepatorenal syndrome restored renal function. Hyponatremia, pH value and TNF-alpha level were not changed; the total survival rate was 33.33%. Both IL-1 and IL-6 levels were significantly decreased after treatment in group A. IL-10 level was increased in both group A and group B. In group C, 1 of 6 patients regained normal consciousness from coma, none of them restored renal function, and the total survival rate was 16.67%. CONCLUSIONS: Combined slower PE and CVVH with a parallel circuit is a new, safe and effective non-biological artificial liver in the treatment for chronic severe viral hepatitis B patients.

[Prospective study of cystatin C for diagnosis of acute kidney injury after cardiac surgery].

OBJECTIVE: To prospectively study the value of cystatin C in diagnosis of acute kidney injury (AKI) in patients after cardiac surgery. METHODS: A total of 132 patients undergoing cardiopulmonary bypass were enrolled in this prospectively study. From each patient, blood samples were collected everyday before and after operation to detect the serum creatinine (Scr) and cystatin C levels by enzymatic method and particle-enhanced turbidimetric immunoassay (PETIA), respectively, and the glomerular filtration rate (eGFR) was estimated using MDRD equation. AKI diagnosis was made according to the RIFLE criteria of the Acute Dialysis Quality Initiative (ADQI) (R: Scr increased by > or =50%; I: Scr increased by > or =100%; F: Scr increased by > or =200%; L: Loss of kidney function; E: End-stage renal disease). Another AKI diagnostic criterion was also adopted according to the levels of cystatin C increment, namely an increase by > or =50%, > or =100%, and > or =200%. RESULTS: Twenty-nine patients (21.9%) developed AKI of varied severities, including 10 meeting the R-criteria, 12 the I-criteria, 7 the F-criteria, with the other 103 patients without AKI serving as the control group. Cystatin C of the 29 AKI patients was drastically increased in comparison with that of the control group (P<0.001). Significant linear correlation was found between cystatin C and Scr (r=0.732, P<0.001) and between [cystatin C]-1 and estimated GFR (R=0.803, P<0.001). By the two diagnostic criteria based on cystatin C and Scr levels, respectively, the median diagnostic time of AKI was 2 days (range 1-4 days) and 3 days (range 2-5 days) for R criteria (10 patients, P=0.014), 3.5 days (range 1-6 days) and 5 days (range 2-8 days) for I criteria (12 patients, P=0.008), and 5 days (range 3-7 days) and 6.5 days (range 4-9 days) for F criteria (7 patients, P=0.02), respectively. ROC analysis confirmed excellent accuracy of cystatin C in AKI diagnosis (AUC=0.992). With the cut-off value of cystatin C increment by > or =50%, the diagnostic sensitivity and specificity of AKI was 92% and 95%, respectively. CONCLUSION: Cystatin C can serve as a good indicator for AKI diagnosis to allow earlier detection of AKI than Scr-based diagnosis in patients after cardiac surgery.

[Transepicardial autologous transplantation of bone marrow mononuclear cells for acute myocardial infarction].

OBJECTIVE: To test the effect of intramyocardial injection of autologous bone marrow mononuclear cells (MNCs) in improving the cardiac function and myocardial revascularization in miniswine models of myocardial infarction. METHODS: The miniswine models of myocardial infarction established by ligation of the anterior descending coronary artery were divided into 3 groups including a control and two MNC injection groups. Autologous bone marrow MNCs were injected via the epicardium into the infarcted area in the latter two groups at 1 and 2 weeks after the infarction, respectively. The ventricular segmental wall motion was evaluated after the treatment, and the infarcted myocardium observed with immunohistochemistry on frozen sections. RESULTS: The left ventricular segmental wall motion differed significantly between the control and the MNC injection groups at 1 and 2 months after the treatment. CM-DiI-positive cells were detected in the infarcted myocardium where MNCs were implanted. CONCLUSION: Intramyocardial injection of autologous bone marrow MNCs improves the infarcted ventricular segmental wall motion, and significantly increases the number of blood vessels in the infracted area. The transplanted cells can be integrated into the vascular walls of the capillaries and arterioles and differentiate into cardiomyocytes.

Explorative study on the expression of neuregulin-1 gene in peripheral blood of schizophrenia.

Neuregulin-1 (Nrg-1)(1) gene has been considered as a schizophrenia susceptibility gene. In order to observe the association of Nrg-1 gene with schizophrenia, the study was designed to investigate the effect of anti-psychotic treatment on the Nrg-1 mRNA expression in peripheral blood lymphocytes of the patients with a diagnosis of schizophrenia. The Nrg-1 mRNA expression in peripheral blood lymphocytes (PBLs) was measured by using semi-quantitative RT-PCR in 31 first-onset schizophrenia patients, 16 sibling controls and 31 no-sibship controls. Results showed that Nrg-1 mRNA expression in PBLs of patients was lower than that in other two control groups (F=6.722, P=0.002). However, as follow-up time extended, from the second week, Nrg-1 mRNA expression of PBLs in antipsychotic treated patients gradually increased and has obvious statistical significance compared the efficacy of taking anti-psychotic before and after therapy. These results demonstrated that Nrg-1 gene has association with schizophrenia. It is possible to select Nrg-1 mRNA expression of PBLs in schizophrenia patients as a potential therapeutic marker.

5-HT2A receptor gene polymorphism and negative symptoms in first episode (drug-naive) Chinese Han nationality individuals with schizophrenia.

OBJECTIVE: To investigate whether the 5-hydroxytryptamine 2A receptor (5-HT2A) gene T102C polymorphism is associated with the severity symptoms and negative symptoms in the first episode Chinese Han nationality patients with schizophrenia. METHODS: Altogether 201 first episode Chinese Han nationality patients with schizophrenia were enrolled in this study. Genotyping of 5-HT2A gene T102C polymorphism was performed by PCR-RFLP technique. The positive and negative Symptom Scale (PANSS) was used for the evaluation of the severity of psychotic symptoms before any drug treatment. RESULTS: 5-HT2A receptor 102-T/T genotype was significantly associated with both the PANSS total and negative symptom subscale baseline scores before the treatment, but not with the positive and general psychopathology subscales. CONCLUSION: 5-HT2A T102C functional polymorphism may play a role in negative symptoms and prognosis of Chinese Han nationality people with schizophrenia.

[Indigenous and imported low molecular weight heparin in the treatment of chronic hepatitis B and cirrhosis with hepatitis B virus: a prospective randomized controlled clinical study].

OBJECTIVE: To evaluate the effect of indigenous and imported low molecular weight heparin (LMWH) in the treatment of chronic hepatitis and hepatic cirrhosis aiming at seeking a safe and effective anti-fibrosis therapy. METHODS: A prospective randomized controlled clinical study of the treatment of patients with chronic hepatitis B using indigenous and imported LMWH was performed. Seventy-five patients were randomly divided into three groups: conventional treatment group (n=15), conventional treatment plus imported LMWH treatment group (n=30) and conventional treatment plus indigenous LMWH treatment group (n=30). The clinical parameters and treatment results in three groups were compared. RESULTS: Three weeks after treatment, Child-Pugh scores in LMWH treatment groups were significantly lower than that in conventional treatment group (all P<0.05), hepatic function, serum PIII P and type IV collagen levels and portal vein blood flow velocity were much better (all P<0.05), levels of serum prealbumin were significantly elevated (all P<0.05). There were no significant differences between two groups with LMWH treatment. Subcutaneous hemorrhage, incidence of hematoma was lower (10.0% vs. 33.3%, P<0.05), area of ecchymosis was smaller [(0.004 2+/-0.012 7) cm(2) vs. (0.01 64+/-0.027 8) cm(2), P<0.05], and pain was released (8.3% vs. 81.0%, P<0.05) in conventional treatment plus indigenous LMWH treatment group than in conventional treatment plus imported LMWH treatment group. CONCLUSION: LMWH in combination with conventional treatment for patients with cirrhosis of liver, significantly improves the outcome, indigenous LMWH calcium is a safe and effective anti-fibrosis drug as imported LMWH, also the price is lower and pain is less intense during injection than the latter.

The TKTL1 gene influences total transketolase activity and cell proliferation in human colon cancer LoVo cells.

A plasmid carrying DNA to be transcribed into a small interfering RNA against transketolase-like-1 mRNA was constructed and transfected into a human colon cancer cell line. The mRNA expression of transketolase gene family in the human colon cell line was determined by real-time polymerase chain reaction. The effect of anti-transketolase-like-1 small interfering RNA on cell proliferation and cell cycle in the human colon cancer cell line cells was detected by flow cytometry and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide. The transketolase-like-1 gene was significantly downregulated in human colon cancer cell line cells transfected with small interfering RNA transketolase-like-1 constructs compared with the cells transfected with control vector and the cells without transfection. In addition, the anti-transketolase-like-1 small interfering RNA construct significantly decreased the level of transketolase in the transfected human colon cancer cell line cells, arrested them in G0/G1 phase and substantially inhibited cell proliferation. No significant difference was found in the other two genes (transketolase and transketolase-like-2 genes) between the transfected human colon cancer cell line cells and the controls (P>0.05). Our data demonstrated that the transketolase-like-1 gene plays an important role in total transketolase activity and in the cell proliferation of human colon cancer. Transketolase-like-1 may serve as a target for novel anticancer therapies.

[Combined non-biological artificial liver in treatment of late stage chronic severe hepatitis].

OBJECTIVE: To explore the clinical effects of combined non-biological artificial liver in the treatment of late stage chronic severe hepatitis and especially to observe their effects on hepatic encephalopathy, hepatorenal syndrome and disturbance of electrolytes. METHODS: 103 chronic severe hepatitis patients were treated with the same medical measures, including plasma exchange. Among them, 63 patients were also treated with combinations of non-biological artificial liver (treatment group), and the other 40 patients served as controls (control group). The efficacy of the treatments and survival rates of the two groups were compared. RESULTS: In the treatment group, the rate of regaining normal consciousness was 72.7%, the rate of electrolyte disorder being rectified was 89.5%, the rate of restoring renal function was 66.7% and the total survival rate was 47.6%. In comparison, in the control group the rate of regaining normal consciousness was 16.7%, the rate of electrolyte disorder being rectified was 42.3%, none of their renal functions were restored and the total survival rate was 22.5%. The differences between the two groups were significant (chi2=6.56, P less than 0.05). CONCLUSION: With other medical treatment, combined non-biological artificial liver can improve the survival rate of severe hepatitis patients.