Serum extracellular vesicle-derived ASS1 is a promising predictor for the occurrence of HEV-ALF.

Development of biomarkers for predicting the occurrence of hepatitis E virus related-acute liver failure (HEV-ALF) is conducive to prevention and early intervention. Serum samples from 250 HEV-ALF patients, 250 patients with acute hepatitis E (AHE) and 250 health controls (HCs) were collected. We assessed the predictive ability of extracellular vesicle (EV)-derived argininosuccinate synthase 1 (ASS1) levels for HEV-ALF occurrence. Serum EVs were successfully isolated. EV-derived ASS1 levels in the HEV-ALF patients were significantly higher than those in the AHE patients and HCs. In HEV-ALF patients, EV-derived ASS1 levels were positively correlated with the number of failed organs and disease progression. The logistical regression showed that EV-derived ASS1 level is an independent risk factor for HEV-ALF, and orthogonal partial least squares discriminant analysis (OPLS-DA) also suggested that EV-derived ASS1 level has high predictive capability. Besides, the area under the curve (AUC) of EV-derived ASS1 level to predict HEV-ALF occurrence was 0.728 (0.684-0.772) with the sensitivity and specificity being 72.80% and 64.80%, which had a high decision-making ability. Furthermore, there existed no significant difference between the age ≥60 and age <60 groups in EV-derived ASS1 levels. Serum EV-derived ASS1 level is a promising predictor for the occurrence of HEV-ALF.

Citrullus colocynthis (L.) Schrad.: A Promising Pharmaceutical Resource for Multiple Diseases.

Citrullus colocynthis (L.) Schrad. (Cucurbitaceae) is widely distributed in the desert areas of the world. The fruit bodies of C. colocynthis are recognized for their wide range of nutraceutical potential, as well as medicinal and pharmaceutical uses. The plant has been reported for various uses, such as asthma, bronchitis, cancer, colic, common cold, cough, diabetes, dysentery, and jaundice. The fruit has been extensively studied for its biological activities, which include insecticide, antitumor, and antidiabetic effects. Numerous bioactive compounds have been reported in its fruit bodies, such as essential oils, fatty acids, glycosides, alkaloids, and flavonoids. Of these, flavonoids or caffeic acid derivatives are the constituents associated with the inhibition of fungal or bacterial growth, whereas eudesmane sesquiterpenes or sesquiterpene lactones are most active against insects, mites, and nematodes. In this review, the scientific evidence for the biological activity of C. colocynthis against insecticide, cytotoxic, and antidiabetic effects is summarized.

Biotransformation of Ursonic Acid by Aspergillus ochraceus and Aspergillus oryzae to Discover Anti-Neuroinflammatory Derivatives.

Biotransformation of ursonic acid (1) by two fungal strains Aspergillus ochraceus CGMCC 3.5324 and Aspergillus oryzae CGMCC 3.407 yielded thirteen new compounds (4, 5, 7-10, and 13-19), along with five recognized ones. The structural details of new compounds were determined through spectroscopic examination (NMR, IR, and HR-MS) and X-ray crystallography. Various modifications, including hydroxylation, epoxidation, lactonization, oxygen introduction, and transmethylation, were identified on the ursane core. Additionally, the anti-neuroinflammatory efficacy of these derivatives was assessed on BV-2 cells affected by lipopolysaccharides. It was observed that certain methoxylated and epoxylated derivatives (10, 16, and 19) showcased enhanced suppressive capabilities, boasting IC50 values of 8.2, 6.9, and 5.3 µM. Such ursonic acid derivatives might emerge as potential primary molecules in addressing neurodegenerative diseases.

Design, synthesis, and biological evaluation of novel FXR agonists based on auraptene.

Farnesoid X receptor (FXR) has been considered as an attractive target for metabolic disorder and liver injury, while many current FXR agonists suffer from undesirable side effects, such as pruritus. Therefore, it is urgent to develop new structure types different from current FXR agonists. In this study, a series of structural optimizations were introduced to displace the unstable coumarin and geraniol scaffolds of auraptene (AUR), a novel and safe FXR agonist. All of these efforts led to the identification of compound 14, a potent FXR agonist with nearly fourfold higher activity than AUR. Molecular modeling study suggested that compound 14 fitted well with binding pocket, and formed the key ionic bond with His291 and Arg328. In acetaminophen-induced acute liver injury model, compound 14 exerts better therapeutic effect than that of AUR, which highlighting its pharmacological potential in the treatment of drug-induced liver injury.

Recent Advances in Enhancement of Dissolution and Supersaturation of Poorly Water-Soluble Drug in Amorphous Pharmaceutical Solids: A Review.

Amorphization is one of the most effective pharmaceutical approaches to enhance the dissolution and oral bioavailability of poorly water-soluble drugs. In recent years, amorphous formulations have been experiencing rapid development both in theoretical and practical application. Based on using different types of stabilizing agents, amorphous formulations can be mainly classified as polymer-based amorphous solid dispersion, coamorphous formulation, mesoporous silica-based amorphous formulation, etc. This paper summarizes recent advances in the dissolution and supersaturation of these amorphous formulations. Moreover, we also highlight the roles of stabilizing agents such as polymers, low molecular weight co-formers, and mesoporous silica. Maintaining supersaturation in solution is a key factor for the enhancement of dissolution profile and oral bioavailability, and thus, the strategies and challenges for maintaining supersaturation are also discussed. With an in-depth understanding of the inherent mechanisms of dissolution behaviors, the design of amorphous pharmaceutical formulations will become more scientific and reasonable, leading to vigorous development of commercial amorphous drug products.

Regulation of hematopoietic stem cells differentiation, self-renewal, and quiescence through the mTOR signaling pathway.

Hematopoietic stem cells (HSCs) are important for the hematopoietic system because they can self-renew to increase their number and differentiate into all the blood cells. At a steady state, most of the HSCs remain in quiescence to preserve their capacities and protect themselves from damage and exhaustive stress. However, when there are some emergencies, HSCs are activated to start their self-renewal and differentiation. The mTOR signaling pathway has been shown as an important signaling pathway that can regulate the differentiation, self-renewal, and quiescence of HSCs, and many types of molecules can regulate HSCs' these three potentials by influencing the mTOR signaling pathway. Here we review how mTOR signaling pathway regulates HSCs three potentials, and introduce some molecules that can work as the regulator of HSCs' these potentials through the mTOR signaling. Finally, we outline the clinical significance of studying the regulation of HSCs three potentials through the mTOR signaling pathway and make some predictions.

Genotype 4 HEV infection triggers the initiation and development of acute pancreatitis.

The role of HEV infection in AP remains unclear. 1000 patients with AP and 1000 HCs were enrolled, and pancreatitis was evaluated in HEV-infected rhesus macaques. The positive rates of anti-HEV IgG, IgM, and HEV RNA in the AP patients were significantly higher than HCs. With the increase in the severity of AP, the percentage of HEV infection increased. AP patients were divided into AP- and AP + AHE groups. The percentage of severe AP in the AP + AHE group was significantly higher than in the AP- group. HEV infection was one of the main independent risk factors and had high predictive power for AP outcomes. A high level of HEV titer would prolong the recovery time and increase the risk of recurrent AP. Moreover, AP + AHE patients receiving conservative treatment showed a better prognosis. Furthermore, HEV can replicate in the pancreas of rhesus macaques. The pancreatic islet structure was damaged, the tissue was loose after 272 dpi, and a large amount of hyperemia appeared after 770 dpi. HEV infection also caused a large number of inflammatory cells in the pancreas. The pancreas and liver had a comparable viral load. HEV infection affects AP's occurrence, development, and prognosis.

Advances in the application of proteomics in lung cancer.

Although the incidence and mortality of lung cancer have decreased significantly in the past decade, it is still one of the leading causes of death, which greatly impairs people's life and health. Proteomics is an emerging technology that involves the application of techniques for identifying and quantifying the overall proteins in cells, tissues and organisms, and can be combined with genomics, transcriptomics to form a multi-omics research model. By comparing the content of proteins between normal and tumor tissues, proteomics can be applied to different clinical aspects like diagnosis, treatment, and prognosis, especially the exploration of disease biomarkers and therapeutic targets. The applications of proteomics have promoted the research on lung cancer. To figure out potential applications of proteomics associated with lung cancer, we summarized the role of proteomics in studies about tumorigenesis, diagnosis, prognosis, treatment and resistance of lung cancer in this review, which will provide guidance for more rational application of proteomics and potential therapeutic strategies of lung cancer.

Plasma Exosome-Derived SENP1 May Be a Potential Prognostic Predictor for Melanoma.

OBJECTIVE: To evaluate plasma exosome-derived SUMO-specific protease (SENP)1 levels and assess their prognostic value in melanoma. PATIENTS AND METHODS: We extracted exosomes from the plasma of 126 melanoma patients, and identified them with transmission electron microscopy, nanoparticle tracking analysis and western blotting. The plasma exosome-derived SENP1 levels of melanoma patients and healthy controls were detected with ELISA. RESULTS: Plasma exosome-derived SENP1 levels in melanoma patients were significantly upregulated than in healthy controls (P < 0.001). Plasma exosome-derived SENP1 levels in melanoma patients with tumor size >10 cm, located in the mucosa or viscera, with Clark level IV/V, with lymph node metastasis, and TNM stages IIb-IV were significantly higher than in patients in with tumor size <10 cm, located in the skin, with Clark level I-III, without lymph node metastasis, and TNM stages IIb-IV (all P < 0.05). Disease-free survival (DFS) and overall survival (OS) were worse in melanoma patients who had higher plasma exosome-derived SENP1 levels than lower plasma exosome-derived SENP1 levels (both P < 0.001). Area under the receiver operating characteristic curve (AUROC) of plasma exosome-derived SENP1 for predicting 3-year DFS of melanoma patients was 0.82 [95% confidence interval (CI): 0.74-0.88], with a sensitivity of 81.2% (95% CI: 69.9-89.6%) and specificity of 75.4% (95% CI: 62.2-85.9%). The AUROC of plasma exosome-derived SENP1 for predicting 3-year OS of melanoma patients was 0.76 (95% CI: 0.67-0.83), with a sensitivity of 95.7% (95% CI: 85.5-99.5%) and specificity of 62.0% (95% CI: 50.4-72.7%). CONCLUSIONS: Melanoma patients with higher plasma exosome-derived SENP1 levels had worse DFS and OS. The plasma exosome-derived SENP1 levels may be a potential prognostic predictor for 3-year DFS and 3-year OS of melanoma.

Immunological Manifestations of Hepatitis E-Associated Acute and Chronic Liver Failure and Its Regulatory Mechanisms.

Hepatitis E virus (HEV) is a common cause of viral hepatitis in developing countries, most commonly transmitted through the fecal-oral route. The virus is mainly of genotypes (GT) 1 and GT2 genotypes, and patients usually show symptoms of acute hepatitis. Due to the rising trend of HEV serological prevalence in global population, HEV has become an important public health problem in developed countries. Severe hepatitis caused by HEV includes acute and chronic liver failure (ACLF). ACLF frequently occurs in developed countries and is caused by overlapping chronic liver diseases of HEV with genotypes GT3 and GT4. Because the onset of hepatitis E is closely associated with immunity, it is critical to understand the immunological mechanism of hepatitis E associated with acute and chronic liver failure (HEV-ACLF). This review discusses the immunological manifestations and mechanisms of HEV-ACLF, intrahepatic immune microenvironment and treatment, and raises outstanding questions about the immunological mechanism and treatment of the disease.

[Effects of endostatin on the growth and lymphangiogenesis of Lewis lung carcinoma xenograft in mice].

OBJECTIVE: to investigate the effects of endostar, a recombined humanized endostatin, on the growth, lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenograft in mice. METHODS: lewis lung carcinoma (LLC) xenograft were established in C57 mice by intravenous transplantation of 1 × 10(6) cells. Then tumor-bearing mice were assigned into two groups: control group received caudal vein injections of 0.2 ml of 0.9% sodium chloride for 15 days, and treatment group received 500 µg endostar daily. Six weeks after LLC cell injection mice were sacrificed, and then tumor numbers and size were recorded. The expression of vascular endothelial growth factor-c (VEGF-C) and microlymphatic vessel density (MLVD) were observed by immunohistochemical staining. RESULTS: tumor number and size of control group were significantly higher than those of treatment group. The microlymphatic vessel density (MLVD) was 5.7 ± 1.6 in the treatment group, which was markedly lower than in the control mice (7.8 ± 1.6). Two lymph node metastases were observed in treatment group, and eight in control group. Lymphatic metastases were more frequent in control group than in treatment group. Expression of VEGF-C in control group was significantly higher than that in treatment group. CONCLUSION: endostar significantly inhibits the growth, lymphangiogenesis and lymphatic metastasis of Lewis lung carcinoma xenografts, and the inhibitory effect is due to its ability to regulate the expression of VEGF-C of tumors in part.

Clinical significance of ring finger protein 2 high expression in skin squamous cell carcinoma.

Although ring finger protein 2 (RNF2) serves an important role in the occurrence, development and regulation of various types of cancer, RNF2 expression in skin squamous cell carcinoma (SCC) remains unknown. The aim of the present study was to investigate the role of RNF2 expression in SCC and adjacent tissues from patients. The protein and gene expression levels of RNF2 in SCC and adjacent tissues were detected by immunohistochemistry (IHC), western blot analysis and semi-quantitative reverse transcription (RT) PCR. Single factor analysis was used to study the association between RNF2 expression level and the clinicopathological characteristics of patients with SCC. Multifactor Cox survival analysis was used to examine the association between RNF2 expression and the overall survival rate of postoperative patients with SCC. The results from IHC staining demonstrated that the positive expression rate of RNF2 was 84.68% (210/248) and 56.05% (139/248) in SCC and in adjacent tissues, respectively. Furthermore, results from western blot analysis demonstrated that RNF2 protein expression in SCC tissues was significantly higher compared with that in the adjacent tissues (P<0.05). The positive rate of RNF2 mRNA in SCC was 81.05% (201/248), which was significantly higher compared with that in the adjacent tissues 54.44% (135/248; P<0.05). Furthermore, RNF2 protein and gene expression levels were associated with tumor diameter, tumor stage, tumor metastasis and the degree of tumor differentiation in patients with SCC. Patients exhibiting higher RNF2 protein expression in SCC tissues had a significantly shorter disease-specific survival rate compared with patients with low RNF2 expression. In addition, RNF2 protein expression, tumor diameter, tumors site and tumor stage were independent factors affecting the overall survival rate of postoperative patients. High protein and gene expression levels of RNF2 in SCC tissues may be associated with the occurrence and development of SCC and prognosis of patients. The results form this study may serve the development of novel therapeutic options and diagnostic strategies for patients with SCC.

Case report: severe myoclonus associated with oral midodrine treatment for hypotension.

RATIONALE: Midodrine is widely used in the treatment of hypotensive states, there have been no reports of myoclonus associated with midodrine use in hypotension with chronic kidney disease. PATIENT CONCERNS: We report a 58-year-old female patient with chronic kidney disease (CKD) presenting with involuntary tremor 2 h after taking midodrine, which became more frequent after 6 h. Brain CT and neurological examination did not yield findings of note. Blood chemistry showed serum albumin of 3.1 g/L, ALT of 19 U/L, AST of 22 U/L, SCr of 273.9 µmol/L, K of 2.94 mmol/L, Ca of 1.63 mmol/L, and Mg of 0.46 mmol/L. Her BP was maintained at 83-110/56-75 mmHg. Her urine volume was 600-1000 mL/d, and her heart rate was within a range of 90-100 beats/min. DIAGNOSIS: Chronic kidney disease (CKD), hypotension, metabolic acidosis, hypocalcemia, hypokalemia, and hypomagnesemia. INTERVENTIONS: Midodrine treatment was stopped and the patient was treated with intravascular rehydration and furosemide. Myoclonus ceased one day after midodrine withdrawal. LESSONS: Oral midodrine is widely used in the treatment of orthostatic hypotension, recurrent reflex syncope and dialysis-associated hypotension and the adverse effects are mostly mild. However, clinicians should be alert for midodrine-induced myoclonus, especially in patients with CKD.

Clinical significance of high expression of proliferating cell nuclear antigen in non-small cell lung cancer.

Although proliferating cell nuclear antigen (PCNA) plays an important role in tumor proliferation and its expression level is closely related to the biological activity of tumor cells, PCNA expression in non-small cell lung cancer (NSCLC) has been seldom reported. In this study, we aimed to investigate the significance of PCNA expression in NSCLC tissues. PCNA expression in NSCLC and adjacent tissues were assessed by immunohistochemistry (IHC), western blotting, and reverse transcription polymerase chain reaction. Single factor analysis was used to study the relationship between the expression of PCNA and clinicopathological features of NSCLC. Multi-factor Cox survival analysis was used to evaluate the relationship between the expression of PCNA and overall survival of postoperative NSCLC patients. The areas under the receiver operating characteristics were calculated to evaluate the value of PCNA expression level in predicting the 3-year survival of NSCLC patients. IHC analysis showed that the positive expression rates of PCNA protein in NSCLC and adjacent tissues were 91.79% (257/280) and 25.83% (31/120), respectively. Western blotting confirmed that PCNA protein level was significantly higher in NSCLC tissues than in the adjacent tissues (P < .05). Reverse transcription polymerase chain reaction showed that the positive rate of PCNA mRNA in NSCLC was 88.93% (249/280), which was significantly higher than that in adjacent tissues 29.17% (35/120) (P < .05). Both PCNA mRNA and protein levels were correlated with tumor differentiation, size, metastasis, and stage in NSCLC. Patients exhibiting higher PCNA protein expression had a significantly shorter disease-specific survival rate than the other patients. PCNA protein level and tumor pathological type, metastasis, differentiation degree, and stage were independent factors affecting the overall survival of postoperative patients. The areas under the receiver operating characteristics of PCNA mRNA for predicting the 3-year survival of NSCLC patients was 0.89 (0.79-0.98), with a sensitivity and specificity of 0.84 and 0.76, respectively. In conclusion, high PCNA protein and mRNA levels may be associated with the occurrence, development, and prognosis of NSCLC.