1.Tanshinone II A Facilitates Chemosensitivity of Osteosarcoma Cells to Cisplatin via Activation of p38 MAPK Pathway.
Da-Ming XIE ; Zhi-Yun LI ; Bing-Kai REN ; Rui GONG ; Dong YANG ; Sheng HUANG
Chinese journal of integrative medicine 2025;31(4):326-335
OBJECTIVE:
To examine the mechanism of action of tanshinone II A (Tan II A) in promoting chemosensitization of osteosarcoma cells to cisplatin (DDP).
METHODS:
The effects of different concentrations of Tan II A (0-80 µ mol/L) and DDP (0-2 µ mol/L) on the proliferation of osteosarcoma cell lines (U2R, U2OS, 143B, and HOS) at different times were examined using the cell counting kit-8 and colony formation assays. Migration and invasion of U2R and U2OS cells were detected after 24 h treatment with 30 µ mol/L Tan II A, 0.5 µ mol/L DDP alone, and a combination of 10 µ mol/L Tan II A and 0.25 µ mol/L DDP using the transwell assay. After 48 h of treatment of U2R and U2OS cells with predetermined concentrations of each group of drugs, the cell cycle was analyzed using a cell cycle detection kit and flow cytometry. After 48 h treatment, apoptosis of U2R and U2OS cells was detected using annexin V-FITC apoptosis detection kit and flow cytometry. U2R cells were inoculated into the unilateral axilla of nude mice and then the mice were randomly divided into 4 groups of 6 nude mice each. The 4 groups were treated with equal volume of Tan II A (15 mg/kg), DDP (3 mg/kg), Tan II A (7.5 mg/kg) + DDP (1.5 mg/kg), and normal saline, respectively. The body weight of the nude mice was weighed, and the tumor volume and weight were measured. Cell-related gene and signaling pathway expression were detected by RNA sequencing and Kyoto Encyclopedia of Genes and Genomes pathway analysis. p38 MAPK signaling pathway proteins and apoptotic protein expressions were detected by Western blot.
RESULTS:
In vitro studies have shown that Tan II A, DDP and the combination of Tan II A and DDP inhibit the proliferation, migration and invasion of osteosarcoma cells. The inhibitory effect was more pronounced in the Tan II A and DDP combined treatment group (P<0.05 or P<0.01). Osteosarcoma cells underwent significantly cell-cycle arrest and cell apoptosis by Tan II A-DDP combination treatment (P<0.05 or P<0.01). In vivo studies demonstrated that the Tan II A-DD combination treatment group significantly inhibited tumor growth compared to the Tan II A and DDP single drug group (P<0.01). Additionally, we found that the combination of Tan II A and DDP treatment enhanced the p38 MAPK signaling pathway. Western blot assays showed higher p-p38, cleaved caspase-3, and Bax and lower caspase-3, and Bcl-2 expressions with the combination of Tan II A and DDP treatment compared to the single drug treatment (P<0.01).
CONCLUSION
Tan II A synergizes with DDP by activating the p38/MAPK pathway to upregulate cleaved caspase-3 and Bax pro-apoptotic gene expressions, and downregulate caspase-3 and Bcl-2 inhibitory apoptotic gene expressions, thereby enhancing the chemosensitivity of osteosarcoma cells to DDP.
Abietanes/therapeutic use*
;
Osteosarcoma/enzymology*
;
Cisplatin/therapeutic use*
;
Humans
;
Cell Line, Tumor
;
Animals
;
Apoptosis/drug effects*
;
Mice, Nude
;
Cell Proliferation/drug effects*
;
Cell Movement/drug effects*
;
p38 Mitogen-Activated Protein Kinases/metabolism*
;
MAP Kinase Signaling System/drug effects*
;
Bone Neoplasms/enzymology*
;
Cell Cycle/drug effects*
;
Xenograft Model Antitumor Assays
;
Mice
;
Drug Resistance, Neoplasm/drug effects*
;
Neoplasm Invasiveness
;
Mice, Inbred BALB C
2.Successful thrombolysis and mechanical thrombectomy in an early pregnant woman with protein S deficiency and arterial ischemic stroke: A case report
Ma. Ericka S. Del Mundo ; Diana-lynn Que ; Remy Margarette Berroya-Moreno
Philippine Journal of Neurology 2024;27(2):16-21
Protein S deficiency causing arterial ischemic stroke during pregnancy is uncommon. Delay or omission of treatment with perfusion therapies may worsen outcomes for both the mother and the fetus. In this paper, we report a case of an early pregnant woman with protein S deficiency and multiple history of chronic cerebrovascular disease who underwent successful thrombolysis and mechanical thrombectomy. The patient is a 35-year-old woman, eight weeks pregnant, with a history of protein S deficiency and chronic cerebrovascular disease, presenting with rightsided weakness and aphasia. Initial National Institutes of Health Stroke Scale was 10 with cranial magnetic resonance imaging findings of acute infarcts on the left caudate, lentiform nucleus, insula, and frontal lobe with a large vessel occlusion on the proximal M1 segment of the left middle cerebral artery. Intravenous thrombolysis and mechanical thrombectomy were performed with complete recanalization. The patient improved and delivered without any complications after 8 months. Protein S deficiency can contribute to arterial thrombosis including ischemic stroke. Arterial ischemic stroke and large vessel occlusion can cause significant disability if not treated appropriately. Reperfusion therapies in pregnant women show favorable outcomes and should be performed if the benefits outweigh the risks.
Human ; Female ; Adult: 25-44 Yrs Old ; Arteries ; Ischemic Stroke ; Thrombectomy ; Protein S ; Protein S Deficiency ; Pregnant Women
3.Hereditary protein S deficiency in a patient with prominent mesenteric venous thrombosis: A case report.
Journal of Peking University(Health Sciences) 2024;56(6):1106-1109
Hereditary protein S deficiency (PSD) is an autosomal dominant disorder caused by mutations in the PROS1 gene which can cause venous thrombosis. Individuals with PSD usually present with recurrent deep vein thrombosis and/or pulmonary embolism, but thrombosis may occur at unusual sites, such as the mesenteric and portal veins. Here we report a case of hereditary protein S deficiency patient with predominant mesenteric venous thrombosis. A 57-year-old man was admitted for abdominal pain and bilateral lower limber swelling. His sister had a history of thrombotic disease. On admission, His temperature was 37.4 ℃, the pulse was regular, and the blood pressure was 130/79 mmHg. Abdominal examination showed right lower abdomen tenderness, rebound tenderness and suspected muscle rigidity. Abdominal computed tomography (CT) angiography found that the patient had superior mesenteric venous thrombosis (MVT) and perforation of intestine. Vascular ultrasound of lower limb indicated bilateral deep venous thrombosis. Although treatment of fasting, water restriction, parenteral nutrition solution, acid suppression, anti-biotic treatment and low molecular weight heparin for anticoagulation were given, abdominal pain were not relieved. Small intestine resection and anastomosis was done after. Pathology of intestine did not show changes indicative of vasculitis. To investigate the cause of multiple thrombosis, a work-up for hypercoagulability (protein C and S activities, antithrombin, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein Ⅰ antibody) was done and the result showed increased dRVVT ratio and the significantly decreased protein S levels. Anti-phospholipid syndrome (APS) was suspected because of the thrombosis and positive lupus anticoagulant, but at the time of the test the patient was on oral anticoagulants which might influence the result of lupus anticoagulant. The lupus anticoagulant was normal after discontinuing oral anticoagulants and APS was excluded. Because of his personal and family history of thrombotic disease, a hereditary thrombophilia was suspected and a laboratory analysis showed a reduced protein S activity. Further examination of the whole exome sequencing indicated a heterozygous mutation in the PROS1 gene. He was diagnosed with hereditary protein S deficiency and was started on anticoagulant therapy with rivaroxaban. He had been followed up for 1 year, and his condition kept stable without newly developed thrombosis or bleeding.
Humans
;
Male
;
Protein S Deficiency/genetics*
;
Middle Aged
;
Venous Thrombosis/etiology*
;
Mesenteric Veins
;
Protein S/genetics*
;
Mutation
;
Abdominal Pain/etiology*
4.Comparison of coagulation function between adrenocorticotropic hormone independent Cushing syndrome and nonfunctional adrenal adenoma and its influence factors.
Wei WANG ; Jia Ning WANG ; Wei YU ; Sai Nan ZHU ; Ying GAO ; Jun Qing ZHANG
Journal of Peking University(Health Sciences) 2023;55(6):1062-1067
OBJECTIVE:
To investigate the coagulation function indicators and identify influence factors of hypercoagulability in patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS).
METHODS:
In our retrospective study, the electronic medical records system of Peking University First Hospital was searched for the patients diagnosed with ACTH independent CS on discharge from January 2014 to June 2019. Nonfunctional adrenal adenoma patients were chosen as control group and matched 1 ∶1 by body mass index (BMI), gender, and discharge date. Clinical features and coagulation function indicators were compared between the two groups.
RESULTS:
In the study, 171 patients were included in each group. Compared with control group, activated partial thromboplastin time (APTT), and prothrombin time (PT) in ACTH independent CS group were significantly lower [(29.22±3.39) s vs. (31.86±3.63) s, P < 0.001; (29.22±3.39) s vs. (31.86±3.63) s, P < 0.001], and both D-dimer and fibrin degradation products (FDP) levels were significantly higher (P < 0.05). Percentage of APTT levels under the lower limit of reference range in the CS patients was significantly higher than that in nonfunctional group (21.6% vs. 3.5%, P < 0.001). Percentage of D-dimer levels over the upper limit of reference range in the CS patients was significantly higher than that in nonfunctional group (13.5% vs. 6.6%, P=0.041). There were three patients with deep venous thrombosis and one patient with pulmonary embolism in CS group, however none was in control group. The area under curve (AUC) of serum cortisol rhythm (8:00, 16:00 and 24:00) levels was negatively associated with the levels of PT (r=-0.315, P < 0.001) and APTT (r=-0.410, P < 0.001), and positively associated with FDP (r=0.303, P < 0.001) and D-dimer levels (r=0.258, P < 0.001). There were no differences in coagulation function indicators among different histopathologic subgroups (adrenocortical adenoma, adrenocortical hyperplasia, oncocytic adenoma, adrenocortical carcinoma). With Logistic regression analysis, the AUC of cortisol and glycosylated hemoglobin A1c (HbA1c) levels were independent risk factors for hypercoagulability in the ACTH independent CS patients (P < 0.05).
CONCLUSION
ACTH independent CS patients were more likely in hypercoagulable state compared with nonfunctional adrenal adenoma, especially in ACTH independent CS patients with higher levels of cortisol AUC and HbA1c. These patients should be paid attention to for the hypercoagulability and thrombosis risk.
Humans
;
Cushing Syndrome/complications*
;
Adrenocortical Adenoma/complications*
;
Adrenocorticotropic Hormone
;
Hydrocortisone
;
Retrospective Studies
;
Glycated Hemoglobin
;
Adrenal Cortex Neoplasms/diagnosis*
;
Adenoma/diagnosis*
;
Thrombophilia/complications*
7.A combined regimen based on bortezomib and glucocorticoids for 6 patients with recurrent/refractory immune thrombotic thrombocytopenic purpura.
Jie YIN ; Hong TIAN ; Dan Qing KONG ; Yun LI ; Cheng Yuan GU ; De Pei WU ; Zi Qiang YU
Chinese Journal of Hematology 2023;44(5):413-417
Objective: To observe the efficacy and adverse reactions of a combination therapy regimen based on bortezomib and glucocorticoids in recurrent/refractory immune thrombocytopenic purpura (iTTP) . Methods: Six patients with recurrent/refractory TTP were included and treated with a glucocorticoid and two courses of bortezomib-based regimen. The clinical remission status of patients, changes in ADAMTS13 activity/ADAMTS13 inhibitor, and the occurrence of treatment-related adverse reactions were observed. Results: Of the 6 patients, 2 were males and 4 were females, with a median age of 21.5 (18-68) years. Refractory TTP was found in 1 case and recurrent TTP in 5 cases. Glucocorticoids were administered with reference to prednisone at 1 mg·kg(-1)·d(-1), and gradually reduced in dosage after achieving clinical remission. Bortezomib is subcutaneously administered at 1.3 mg/m(2) on days 1, 4, 8, and 11 with a 28-day treatment course consisting of 2 courses. Six patients achieved clinical remission after receiving bortezomib as the main treatment. ADMATS13 activity returned to normal in all patients with TTP after treatment, and the ADAMTS13 inhibitor turned negative. Thrombocytopenia is the most common adverse reaction after treatment, with other adverse reactions, including peripheral neuritis and abdominal pain, but ultimately all patients returned to normal. In a median follow-up of 26 (9-41) months, 5 patients maintained sustained remission, and 1 patient relapsed after 16 months of bortezomib treatment. Conclusion: Combination therapy of bortezomib and glucocorticoids has a satisfactory therapeutic effect and controllable adverse reactions for recurrent/refractory iTTP.
Male
;
Female
;
Humans
;
Young Adult
;
Adult
;
Middle Aged
;
Aged
;
Bortezomib/therapeutic use*
;
Glucocorticoids/therapeutic use*
;
Rituximab/therapeutic use*
;
Purpura, Thrombotic Thrombocytopenic/drug therapy*
;
Purpura, Thrombocytopenic, Idiopathic/drug therapy*
;
ADAMTS13 Protein/therapeutic use*
9.PROSI Mutation With Clinical Heterogeneity in Protein S Deficiency:Report of One Case.
Xin-Yu WEI ; Juan WANG ; Bang-Yun TAN ; Zi-Jian LI
Acta Academiae Medicinae Sinicae 2023;45(5):863-866
Reduced protein S activity is one of the high-risk factors for venous thromboembolism.Hereditary protein S deficiency is an autosomal dominant disorder caused by mutations in the PROS1 gene.We reported a female patient with a mutation of c.292 G>T in exon 3 of the PROS1 gene,which was identified by sequencing.The genealogical analysis revealed that the mutation probably originated from the patient's mother.After searching against the PROS1 gene mutation database and the relevant literature,we confirmed that this mutation was reported for the first time internationally.
Humans
;
Female
;
Protein S/genetics*
;
Protein S Deficiency/genetics*
;
Pedigree
;
Mutation
10.Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene.
Lulu YAN ; Yifan HUO ; Yingwen LIU ; Yuxin ZHANG ; Chunxiao HAN ; Juan CAO ; Haibo LI
Chinese Journal of Medical Genetics 2023;40(11):1330-1333
OBJECTIVE:
To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage.
METHODS:
Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents.
RESULTS:
The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4).
CONCLUSION
The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.
Female
;
Pregnancy
;
Humans
;
Protein C Deficiency
;
Fetus
;
Genetic Counseling
;
Genomics
;
Hydrocephalus/genetics*
;
Mutation

Result Analysis
Print
Save
E-mail