Paraptosis: a non-classical paradigm of cell death for cancer therapy.

Due to the sustained proliferative potential of cancer cells, inducing cell death is a potential strategy for cancer therapy. Paraptosis is a mode of cell death characterized by endoplasmic reticulum (ER) and/or mitochondrial swelling and cytoplasmic vacuolization, which is less investigated. Considerable evidence shows that paraptosis can be triggered by various chemical compounds, particularly in cancer cells, thus highlighting the potential application of this non-classical mode of cell death in cancer therapy. Despite these findings, there remain significant gaps in our understanding of the role of paraptosis in cancer. In this review, we summarize the current knowledge on chemical compound-induced paraptosis. The ER and mitochondria are the two major responding organelles in chemical compound-induced paraptosis, which can be triggered by the reduction of protein degradation, disruption of sulfhydryl homeostasis, overload of mitochondrial Ca2+, and increased generation of reactive oxygen species. We also discuss the stumbling blocks to the development of this field and the direction for further research. The rational use of paraptosis might help us develop a new paradigm for cancer therapy.

Development and validation of a nomogram to predict overall survival for cervical adenocarcinoma: A population-based study.

This study aimed to develop and validate a nomogram for predicting the overall survival of cervical adenocarcinoma (CAC) patients using a large database comprising patients with different ethnicities. We enrolled primary CAC cases with complete clinicopathological and survival data from the Surveillance, Epidemiology, and End Results program during 2004 to 2015. For training set samples, this work applied the Cox regression model to obtain factors independently associated with patient prognosis, which could be incorporated in constructing the nomogram. Altogether 3096 qualified cases were enrolled, their survival ranged from 0 to 155 (median, 45.5) months. As revealed by multivariate regression, age, marital status, tumor size, grade, International Federation of Gynecology and Obstetrics (FIGO) classification, pelvic lymph node metastasis, surgery, and chemotherapy served as the factors to independently predict CAC (all P < .05). We later incorporated these factors for constructing the nomogram. According to the concordance index determined, this nomogram had superior discrimination over FIGO classification system (all P < .001). Based on calibration plot, the predicted value was consistent with actual measurement. As revealed by time-independent area under the curves, our constructed nomogram had superior 5-year overall survival over FIGO system. Additionally, according to decision curve analysis, our constructed nomogram showed high clinical usefulness as well as favorable discrimination. Our constructed nomogram attains favorable performances, indicating that it may be applied in predicting survival for CAC patients.

Construction and functional verification of size-reduced plasmids based on TMP resistance gene dfrB10.

IMPORTANCE: Plasmid size is one of the factors affecting transfection efficacy in most of the molecular genetic research studies. One effective approach for reducing plasmid size is to replace relatively large, conventional antibiotic resistance genes with the short-size dfrB10 gene. The successful construct of a series of dfrB10-based tool plasmids and their functional validation, via comparison with original plasmids, suggest that dfrB10 is a potent drug resistance selection marker. The antibiotic trimethoprim offers convenient usage comparable to that of ampicillin or kanamycin. Additionally, fluorescence analysis has demonstrated the compatibility of TMP with protein expression in various host cells. Based on these findings, TMP-dfrB10 could be an alternative choice for future use in molecular genetic research studies that require miniature plasmids to achieve optimal results.

Current Progress and Outlook for Agrimonolide: A Promising Bioactive Compound from Agrimonia pilosa Ledeb.

Agrimonolide (AM), which is a derivative of isocoumarins, is found mainly in the herb Agrimonia pilosa Ledeb. This compound is highly lipophilic and readily crosses the blood-brain barrier. In recent years, interest has grown in the use of AM as a multitarget natural treatment for various diseases, such as cancer, inflammation, hepatic injury, myocardial damage, and diabetes mellitus. The potential mechanisms of these pharmacological effects have been clarified at cellular and molecular levels. AM shows no cytotoxicity over a range of concentrations in different types of cells, providing evidence for its good safety profile in vitro. These findings indicate that AM is a promising medicinal agent. However, most studies on AM's pharmacological activities, mechanisms of action, and safety lack substantial animal or human data. Additionally, the pharmacokinetics, metabolism, and disposition of this compound have received little attention. This review highlights the status of current information regarding the sources, properties, pharmacological effects, and safety of AM. Furthermore, potential strategies to resolve problematic issues identified in previous studies are fully discussed. This summary and analysis of the research progress of AM may inspire deeper investigations and more extensive applications of AM in the future.

Marital status is an independent prognostic factor for cervical adenocarcinoma: A population-based study.

Marriage has been reported as a beneficial factor associated with improved survival among cancer patients, but conflicting results have been observed in cervical adenocarcinoma (AC). Thus, this study is aimed to examine the relationship between the prognosis of cervical AC and marital status. Eligible patients were selected from 2004 to 2015 using the surveillance, epidemiology and end results (SEER) database. Cancer-specific survival (CSS) and overall survival (OS) were compared between married and unmarried groups. A total of 3096 patients had been identified, with married ones accounting for 51.29% (n = 1588). Compared to unmarried groups, more patients in the married group were relatively younger (aged ≤ 45) and belonged to white race, with grade I/II, Federation of International of Gynecologists and Obstetricians (FIGO) stage I/II and tumor size ≤4 cm. Apart from that, more patients received surgery, whereas fewer patients received chemotherapy and radiotherapy (all P < 0.05). The 5-year CSS and OS rates were 80.16% and 78.26% in married patients, 68.58% and 64.62% in the unmarried group (P < .0001). Multivariate analysis showed that marital status was an independent prognostic factor, and the married group performed better CSS (hazard ratio [HR]: 0.770; 95% confidence interval [CI]: 0.663-0.895; P = .001) as well as OS (HR: 0.751; 95%CI: 0.653-0.863; P < .001). As demonstrated by the results of subgroup analysis, married patients had better CSS and OS survival than unmarried ones in nearly all the subgroups. Marital status was identified as an independent prognostic factor for improved survival in patients with cervical AC.

[Research Progress on the Role of Laminin Subunit Alpha 4 in Diseases].

Laminin subunit alpha 4 (LAMA4),a member of the laminin family,is present in the intercellular matrix of adult tissues as a major component of basement membrane.LAMA4 is involved in the adhesion of cells and can bind to corresponding integrins to activate relevant signaling pathways,playing an essential role in the growth,proliferation,and migration of cells.It has been demonstrated that LAMA4 is associated with the occurrence and development of a variety of diseases including tumors,and the expression of LAMA4 can be used as a biomarker of tumor diagnosis and prognosis.This paper summarizes the current research progress in LAMA4 with the focus on the relationship between LAMA4 and diseases,especially tumor,with a view to provide new directions for the future research.

Efficacy of intramuscular injection of Xiyanping injection for the treatment of acute bronchitis in children: a multicenter, randomized, parallel-controlled clinical study / 中国当代儿科杂志

OBJECTIVES@#To study the efficacy and safety of Xiyanping injection through intramuscular injection for the treatment of acute bronchitis in children.@*METHODS@#A prospective study was conducted from December 2021 to October 2022, including 78 children with acute bronchitis from three hospitals using a multicenter, randomized, parallel-controlled design. The participants were divided into a test group (conventional treatment plus Xiyanping injection; n=36) and a control group (conventional treatment alone; n=37) in a 1:1 ratio. Xiyanping injection was administered at a dose of 0.3 mL/(kg·d) (total daily dose ≤8 mL), twice daily via intramuscular injection, with a treatment duration of ≤4 days and a follow-up period of 7 days. The treatment efficacy and safety were compared between the two groups.@*RESULTS@#The total effective rate on the 3rd day after treatment in the test group was significantly higher than that in the control group (P<0.05), while there was no significant difference in the total effective rate on the 5th day between the two groups (P>0.05). The rates of fever relief, cough relief, and lung rale relief in the test group on the 3rd day after treatment were higher than those in the control group (P<0.05). The cough relief rate on the 5th day after treatment in the test group was higher than that in the control group (P<0.05), while there was no significant difference in the fever relief rate and lung rale relief rate between the two groups (P>0.05). The cough relief time, daily cough relief time, and nocturnal cough relief time in the test group were significantly shorter than those in the control group (P<0.05), while there were no significant differences in the fever duration and lung rale relief time between the two groups (P>0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05).@*CONCLUSIONS@#The overall efficacy of combined routine treatment with intramuscular injection of Xiyanping injection in the treatment of acute bronchitis in children is superior to that of routine treatment alone, without an increase in the incidence of adverse reactions.

Research Progress on the Role of Laminin Subunit Alpha 4 in Diseases / 中国医学科学院学报

Laminin subunit alpha 4 (LAMA4),a member of the laminin family,is present in the intercellular matrix of adult tissues as a major component of basement membrane.LAMA4 is involved in the adhesion of cells and can bind to corresponding integrins to activate relevant signaling pathways,playing an essential role in the growth,proliferation,and migration of cells.It has been demonstrated that LAMA4 is associated with the occurrence and development of a variety of diseases including tumors,and the expression of LAMA4 can be used as a biomarker of tumor diagnosis and prognosis.This paper summarizes the current research progress in LAMA4 with the focus on the relationship between LAMA4 and diseases,especially tumor,with a view to provide new directions for the future research.

Mental health problems of preschool children during the COVID-19 home quarantine: A cross-sectional study in Shanghai, China.

Objective: As the coronavirus disease 2019 (COVID-19) pandemic spread across Shanghai, China, in late February 2022 and protective measures to mitigate its impact were enacted, this study aimed to estimate how home quarantine affected the mental health of preschool children in Shanghai, China and explore the association between lifestyle factors and mental health during this special period. Methods: A cross-sectional online survey of 2,110 preschool students from Shanghai, China, was conducted during May 20-25,2022. Preschooler' mental health (Strengths and Difficulties Questionnaire, SDQ) and daily activities were reported by parents. Results: The sample involved 2,110 children with a mean age of 4.65 years [standard deviation (SD): 0.91, range: 3-6 years]. Boys and children whose mother's education level were college and high school had higher rate of mental health problems. Boys had significantly higher rates of peer problems and prosocial behaviors than girls. The 3-year-old group had significantly higher rates of prosocial behaviors than other groups. As compared to the Shanghai norm and the SDQ results of preschool children in Shanghai in 2019 (SH2019), there were a significant decrease in emotional symptoms score, as well as a significant increase in conduct problems score. Additionally, peer problems score significantly increased compared to SH2019. Decreased time spent on daily sleep was associated with the increased risk for preschoolers' mental health problems. Conclusion: There was an increase in the frequency of emotional and behavioral problems, especially regarding conduct problems and peer problems, in preschool children during the COVID-19 home quarantine in Shanghai, China. Boys, younger preschool children and children whose mother's education level were college and high school may be especially vulnerable to emotional and behavioral problems. It was also found that decreased time spent on sleep may aggravate preschool children's mental health problems. It may be beneficial to differentiate and focus on conducting psychoeducation and implementing psycho-behavioral interventions to solve these issues.

The Comparison of PCR Kits for the Detection of Erythrocytic Parasites on Filter Paper.

Dried blood spot (DBS) based PCR was considered an inexpensive and feasible method for detecting pathogens in the blood. The DBS carrier filter paper and PCR kits are crucial for accurate diagnosis. We evaluated 4 types of filter papers and 20 PCR kits for DBS samples. The PCR detecting Plasmodium results showed that the minimum detection limit of the 4 filter papers was 1 × 102 parasites/µL, and the positive rates of 20 PCR kits ranged from 0% to 100%. PCR results were satisfactory for detecting Plasmodium falciparum (P. falciparum) and Plasmodium. vivax (P. vivax) in archived DBS samples and Babesia gibsoni (B. gibsoni) in fresh pet DBS samples. Our results provided a useful reference for the detection of blood pathogens with DBS samples and direct PCR, especially for screening the cost-efficacy combination of filter paper and PCR kit in resource-limited areas.

Advances of synthetic biology of flavonoids / 药学学报

Flavonoids is one of the biggest families of the plant-derived secondary metabolites with structural diversity. Until now, over 10 000 kinds of flavonoids with distinct structures have been purified and identified from plants, and some of them possess a range of important pharmacological effects, such as anticancer, anti-inflammatory and so on. So far, a number of genes and enzymes responsible for the biosynthesis of flavonoids have been reported, especially, a great of progress has been achieved in the synthetic biology of flavonoids in the recent years. Herein, based upon a brief introduction on the biosynthesis of flavonoids, this review summarizes the research advances in synthetic biology of flavonoids in the past two decades (2001-2021), highlighting the cell factories construction of the representative flavonoids. And, a brief discussion and prospects of the relevant metabolic bottlenecks and optimizing strategies are proposed.

Application of immune checkpoint inhibitors in the treatment of small cell lung cancer / 国际肿瘤学杂志

The emergence of immune checkpoint inhibitors (ICIs) have changed the pattern of anti-tumor therapy and brought new hope to the treatment of small cell lung cancer (SCLC). Currently, ICIs are most widely studied mainly include programmed death-1/ligand-1 and cytotoxic T-lymphocyte antigen-4. Altezumab is recommended for the first-line treatment of extensive SCLC, while pebrizizumab is recommended for the third-line treatment of extensive SCLC. There has been no breakthrough in the second-line and maintenance treatment of SCLC with ICIs.

Pharmacokinetic incompatibility of the Huanglian-Gancao herb pair.

BACKGROUND: Pharmacokinetic interaction is one of the most important indices for the evaluation of the compatibility of herbal medicines. Both Gancao (Glycyrrhizae Radix et Rhizoma) and Huanglian (Coptidis Rhizoma) are commonly used traditional Chinese medicines (TCMs). In this study, the influence of Gancao on the pharmacokinetics of Huanglian was systematically studied by using berberine as a pharmacokinetic marker. METHODS: Extracts of the herbal pieces of Huanglian and the herb pair (Huanglian plus Gancao) were prepared with boiling water. The concentration of berberine in the samples was analyzed using liquid chromatography-mass spectrometry. The total amounts of berberine in all extract samples were compared. Comparative pharmacokinetic studies of Huanglian and the herb pair were conducted in ICR mice. In vitro berberine absorption and efflux were studied using mice gut sacs. The equilibrium solubility of berberine in the extracts was determined. The in vitro dissolution of berberine was comparatively studied using a rotating basket method. RESULTS: Gancao significantly reduced berberine exposure in the portal circulation (425.8 ng·h/mL vs. 270.4 ng·h/mL) and the liver (29,500.8 ng·h/mL vs. 15,422.4 ng·h/mL) of the mice. In addition, Gancao decreased the peak concentration (Cmax) of berberine in the portal circulation (104.3 ng·h/mL vs. 76.5 ng·h/mL) and liver (4926.1 ng·h/mL vs. 2642.8 ng·h/mL) of mice. Significant influences of Gancao on the amount of berberine extracted (32% reduction), the solubility of berberine (34.7% compared with the control group), and dissolution (88.7% vs. 66.1% at 15 min in acid buffer and 68% vs. 51.8% at 15 min in phosphate buffer) were also revealed. Comparative pharmacokinetic studies in ICR mice indicated that the formation of sediment was unfavorable in terms of berberine absorption (345.3 ng·h/mL vs. 119.8 ng·h/mL). CONCLUSIONS: Gancao was able to reduce intestinal absorption and in vivo exposure of berberine in Huanglian via the formation of sediment, which caused reductions in the extracted amount, solubility, and dissolution of berberine.

Pharmacokinetics, bioavailability and tissue distribution studies of rhodojaponin III in mice using QTRAP LC-MS/MS.

Rhodojaponin III is a bioactive diterpenoid isolated from the medicinal plant Rhododendron molle G. Don. Quantitative analysis of rhodojaponin III was challenging and the pharmacokinetics of oral rhodojaponin III remained to be investigated. Here, a rapid and sensitive liquid chromatography tandem mass spectrometric (LC-MS/MS) method was developed and validated. The calibration curve was linear over the concentration range of 1-200 ng/mL (r = 0.992). The method was further validated following internationally approved guidelines and all the issues including intra- and inter-day precision, accuracy, carryover, extraction recovery, matrix effects and stability met the recommended limits. The method was then applied to study the pharmacokinetics of rhodojaponin III in mice after intravenous (0.06 mg/kg) or oral (0.24 mg/kg) administration. The results showed that rhodojaponin III had fast oral absorption (time to peak concentration, 0.08 h) and good oral bioavailability (73.6%). In addition, rhodojaponin III was quickly eliminated after it was intravenously or orally administered, with half-life values of 0.19 and 0.76 h, respectively. After oral administration, it was widely distributed in tissues including kidney, lung, heart, spleen and thymus, but had extremely low concentrations in liver and brain. The data presented in this study is beneficial for the further study of rhodojaponin III.

Zhujie Hewei Granules Ameliorated Reflux Esophagitis in Rats.

BACKGROUND: Gastroesophageal reflux disease (GERDs) is a common chronic digestive system disease, in which the symptoms of reflux esophagitis (RE) seriously affect the quality of life. AIMS: We aimed to study the therapeutic effect of Zhujie Hewei granules (ZHG) on reflux esophagitis in model rats. MATERIALS AND METHODS: A rat model of RE was established with the steps of half pylorus ligation, cardiotomy, and hydrochloric acid perfusion. The rats in treatment groups were orally administered with 1.30, 2.60, or 5.20 g/kg ZHG once daily for 28 days. Histopathological changes of the esophagus were observed with hematoxylin-eosin staining. The content of total bilirubin and pH in gastric juice was determined. Esophageal mucosal injury was assessed by macroscopic observation scores, mucosal injury index scores, and esophageal inflammation scores. The levels of gastrin (GAS), motilin (MTL), and vasoactive intestinal peptide (VIP) in serum were evaluated by using ELISA kits. RESULTS: After treatment with ZHG, the body weight of RE rats tended to increase drastically, the macroscopic observation scores of the esophagus mucous membrane decreased (P < 0.05), the mucosal injury index scores decreased (P < 0.05), the gastric pH values increased (P < 0.05), and the levels of serum MTL and VIP decreased (P < 0.05). In addition, the high dose of the ZHG-treated group showed lower serum GAS (P < 0.05), while the high and middle doses of the ZHG-treated groups showed lower esophageal inflammation scores (P < 0.05). CONCLUSIONS: ZHG was effective in treating RE in rats due using mechanisms including improving the pH value of gastric contents, decreasing the gastrointestinal hormones (including GAS, MTL, and VIP), and improving the inflammatory damage.

Postoperative Interleukin-6 Predicts Intra-abdominal Septic Complications at an Early Stage After Elective Intestinal Operation for Crohn's Disease Patients.

BACKGROUND: The role of interleukin-6 (IL-6) in the prediction of intra-abdominal septic complications (IASCs) in patients with Crohn's disease (CD) remains unclear. We assessed the serum IL-6 time course and its association with postoperative IASCs in patients undergoing elective intestinal operations for CD. METHODS: In total, 118 patients who underwent intestinal operations for CD were prospectively evaluated. They were divided into an IASC group and non-IASC group. Multivariate analyses were used to identify risk factors, and receiver operating characteristic curve analysis was performed. RESULTS: Multivariate analysis showed that a high IL-6 concentration of >137.25 pg/mL on postoperative day (POD) 1 was independently associated with IASCs (odds ratio, 5.74; 95% confidence interval [CI], 1.46-22.67; P = 0.012) and a longer postoperative length of hospitalization (6 vs 9 days, P < 0.001). The median interval between surgery and IASCs (interquartile range) was 6 (4-22) days, and the IL-6 concentration was significantly different between patients with and without IASCs on PODs 1, 3, and 5. The ideal IL-6 cutoff value on POD 1 for the prediction of postoperative IASCs was 137.25 pg/mL, yielding a sensitivity of 81%, specificity of 58%, and area under the curve of 0.71 (95% CI, 0.59-0.83), with a negative predictive value of 0.93. CONCLUSIONS: A high IL-6 concentration on POD 1 is independently associated with the occurrence of postoperative IASCs in patients undergoing elective surgery for CD and could allow for earlier diagnosis and earlier intervention for IASCs compared with C-reactive protein.

Influence of γ-H2AX expression on prognosis in patients with newly diagnosed multiple myeloma / 重庆医学

Objective To investigate the expression of bone marrow γ-H2AX in the patients with multiple myeloma(MM) and its correlation with the prognosis.Methods The patients with newly diagnosed MM in this hospital were selected as the case group,and the patients with non-hemopoietic system tumor without obvious morphological abnormalities by bone marrow smear and biopsy served as the control group.The immunohistochemistry was adopted to detect the expression level of bone marrow γ-H2AX in the cases group and control group,the image-Pro Plus(IPP) semiquantitative analysis was performed.The expression differences were compared between the two groups,moreover the case group was re-divided into the strong expression group and weak expression group according to γ-H2AX expression level.Then the relation ship between γ-H2AX expression level and the prognosis in the patients with MM.Results The bone marrow γ-H2AX expression level in the case group was significantly higher than that in the control group (P＜0.05);the level of γ-H2AX expression in the strong expression group was significantly stronger than that in the weak expression group (P＜0.05).Conclusion The level of γ-H2AX expression was higher among MM patients,and the over expression of γ-H2AX predicts the shorter survival time.

Studies on OAZI-1 protein complex in inducing specific antitumor effects in mice / 中国免疫学杂志

Objective:To analyze whether the OAZI-1 (ornithine decarboxylase antizyme inhibitor-1) protein complex isolated from tumor cells could induce specific antitumor effects in the experiment mice .Methods:OAZI-1 protein complexes were isolated from B16-F1 melanoma cells by immune magnetic beads coated with OAZI-1 antibody and used as the vaccine to immune the C 57BL/6 mice.After immunization,the mice were inoculated subcutaneously with live B 16-F1 cells and then tumor formation and growth were ob-served.ELISA was used to determine the level of cytokine IFN-γin the serum of immunized mice.Lactate dehydrogenase assay (LDH) was performed to evaluate killing effect of spleen lymphocytes on B 16-F1 cells.The mice immunized by purified OAZI-1 from prokaryotic expression and PBS were used as controls in the animal experiment .Results: Compared with the control mice ,the spleen lymphocytes ( effector cells ) from the mice inoculated with OAZI-1 protein complexes had stronger killing ability on B 16-F1 cells (target cells).At three different effector:target ratio (10:1,50:1,100:1),the killing ability of these spleen lymphocytes were 46.2%, 59.5%and 92.5% respectively,which was significantly higher than the spleen lymphocytes from the mice inoculated with purified AZIN-1 protein (36.1%,26.8% and 45.9%) or inoculated with PBS (24.6%,24.0% and 27.2%).In addition,the content of serum anti-tumor cytokine IFN-γwas also significantly higher in the mice inoculated with OAZI-1 protein complexes (538.3 pg/ml) than the mice inoculated with purified AZIN-1 ( 256.2 pg/ml ) or with PBS ( 131.0 pg/ml ) .When B16-F1 live cells were subcutaneously inoculated into the immunized mice described above ,the tumor formation rate was only 40%in the mice immunized with OAZI-1 protein complex ,but 100%in the mice immunized with PBS or purified OAZI-1.The growth of inoculated tumors in the mice immunized with OAZI-1 protein complex was also much slower than the control mice .Conclusion:The results in this study suggest that the OAZI-1 protein complex isolated from B 16-F1 tumor cells could contain some tumor antigens .When used as tumor vaccine to inoculate mice ,this complex can induce anti-tumor immune killing activity in experimental animals .

Relationship between factor-1α and epithelial mesenchymal transformation / 国际肿瘤学杂志

Hypoxia inducible factor (HIF-1α) is a hypoxia response regulator,which is highly expressed in malignant tumors.Researches have shown that HIF-1α plays an important role in epithelial mesenchymal transformation.It can regulate epithelial mesenchymal transition through a series of signal pathways and mechanisms at many levels,to participate in the invasion and metastasis of tumors.To explore the mechanism of HIF-lα controlling epithelial mesenchymal transformation has important significance for the development of new,effective tumor treatment methods.