Exploring the Mechanism of Zhishi-Xiebai-Guizhi Decoction for the Treatment of Hypoxic Pulmonary Hypertension Based on Network Pharmacology and Experimental Analyses.

BACKGROUND: Hypoxic Pulmonary Hypertension (HPH), a prevalent disease in highland areas, is a crucial factor in various complex highland diseases with high mortality rates. Zhishi-Xiebai-Guizhi Decoction (ZXGD), traditional Chinese medicine with a long history of use in treating heart and lung diseases, lacks a clear understanding of its pharmacological mechanism. OBJECTIVE: This study aimed to investigate the pharmacological effects and mechanisms of ZXGD on HPH. METHODS: We conducted a network pharmacological prediction analysis and molecular docking to predict the effects, which were verified through in vivo experiments. RESULTS: Network pharmacological analysis revealed 51 active compounds of ZXGD and 701 corresponding target genes. Additionally, there are 2,116 target genes for HPH, 311 drug-disease co-target genes, and 17 core target genes. GO functional annotation analysis revealed that the core target genes primarily participate in biological processes such as apoptosis and cellular response to hypoxia. Furthermore, KEGG pathway enrichment analysis demonstrated that the core targets are involved in several pathways, including the phosphatidylinositol- 3 kinase/protein kinase B (PI3K/Akt) signaling pathway and Hypoxia Inducible Factor 1 (HIF1) signaling pathway. In vivo experiments, the continuous administration of ZXGD demonstrated a significant improvement in pulmonary artery pressure, right heart function, pulmonary vascular remodeling, and pulmonary vascular fibrosis in HPH rats. Furthermore, ZXGD was found to inhibit the expression of PI3K, Akt, and HIF1α proteins in rat lung tissue. CONCLUSION: In summary, this study confirmed the beneficial effects and mechanism of ZXGD on HPH through a combination of network pharmacology and in vivo experiments. These findings provided a new insight for further research on HPH in the field of traditional Chinese medicine.

Tibetan Mesenchymal Stem Cell-derived Exosomes Alleviate Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Rats.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-ß1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, Western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFß pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFß1 and p-Smad2/3. Furthermore, TGFß1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFß1/Smad2/3 pathway via Nbl1.

Macrophage-derived inflammation promotes pulmonary vascular remodeling in hypoxia-induced pulmonary arterial hypertension mice.

The role of inflammation in pulmonary hypertension is gradually gaining increasing research attention. However, no previous study has evaluated the characteristics of inflammation during chronic hypoxia-induced pulmonary hypertension. Therefore, the aim of this study was to investigate the characteristics of the inflammatory process involved in hypoxia-induced pulmonary hypertension in mice. The current study evaluated from day 4 to day 28 of hypoxia, the PAAT and PAAT/PET decreased, accompanied by pulmonary vascular remodeling and right ventricular hypertrophy, as well as increased numbers of CD68 macrophages. The expression of the pro-inflammatory factors IL-1ß and IL-33 increased, but decreased on day 28. The expression of IL-12 increased from day 4 to day 28, whereas that of the anti-inflammatory factor IL-10 in lung tissue decreased. Furthermore, the expression of the IL-33/ST2 signaling pathway also increased over time under hypoxic conditions. In conclusion, pulmonary artery remodeling in HPH mice worsens progressively in a time-dependent manner, with inflammatory cell infiltration predominating in the early stage and pulmonary vascular remodeling occurring in the later stage.

Meta-Analysis Evaluating the Efficacy and Safety of Low-Intensity Warfarin for Patients >65 Years of Age With Non-Valvular Atrial Fibrillation.

Nonvalvular atrial fibrillation (NVAF) is the most common arrhythmia. It is of a high disability and death rate, and seriously affects quality of life. Although New oral anticoagulants (NOACs) are recommended for anticoagulation therapy of atrial fibrillation, they are not widely used for the high cost and limited availability. Warfarin is effective and economical. The risk of thromboembolism and anticoagulant hemorrhage is higher in patients >65 years with NVAF. So, it is of great clinical significance to explore the optimal anticoagulation intensity of warfarin in patients >65 years of China, and other ethnicities. Some studies suggested that low-intensity international normalized ratio (INR) has similar antithrombotic efficacy comparing to standard-intensity INR, whereas bleeding risk was significantly reduced. But others showed conflicting results. We pooled the efficacy and safety data of low- and standard-intensity warfarin therapy for patients over 65 years with NVAF by meta-analysis, as to evaluate optimal INR intensity of warfarin therapy in patients over 65 years. We identified 18 studies providing data of 2105 patients receiving anticoagulation therapy with warfarin. On meta-analysis (odds ratio [OR] [95% confidence interval {CI}]), low-intensity INR conferred similar efficacy to standard intensity INR on all thrombosis (1.28 [0.90 to 1.81]), stroke (1.09 [0.67 to 1.77]), other thromboembolism ([peripheral and pulmonary embolism] 2.26 [0.89 to 5.79]), and all cause death (1.38 [0.94 to 2.02]). Low-intensity INR conferred better safety profile than standard intensity INR in major bleeding (intracranial and gastrointestinal hemorrhage) (0.32 [0.19 to 0.52]), minor bleeding (gum, nasal cavity and conjunctival hemorrhage, skin ecchymosis, hematuria, hemoptysis) (0.30 [0.20 to 0.45]), and all bleeding (0.30 [0.22 to 0.40]). In conclusion, low-intensity INR (1.5 to 2.0) of warfarin therapy is as effective as standard intensity INR (2.0 to 3.0) therapy in reducing thromboembolic risk in patients>65 years with NVAF, and has a safer profile of bleeding.

Lysophosphatidic acid enhances human hepatocellular carcinoma cell migration, invasion and adhesion through P38 MAPK pathway.

BACKGROUND/AIMS: Lysophosphatidic acid (LPA) has diverse biological activities implicated in tumor progression, including increasing cell migration, invasion and metastasis. However, the underlying mechanisms for LPA-induced human hepatocellular carcinoma (HCC) migration and invasion are poorly understood. METHODOLOGY: We sought to determine the promoting effect of LPA on HCC migration, invasion and adhesion by transwell and matrix adhesion assays, respectively. Levels of matrix metalloproteinase, MMP-2 and MMP- 9 from cells were assayed by ELISA and p38 mitogenactivated protein kinase (MAPK) signaling was determined by western blot analysis. RESULTS: In the present study, LPA was found to increase HCC cell migration, invasion and adhesion. In addition, LPA increased MMP-9 expression level and induced activation of the p38 mitogen- activated protein kinase (MAPK) signaling. Furthermore, pharmacological inhibition of p38 MAPK signal pathway with SB203580 significantly attenuated LPA-induced HCC cell migration, invasion, and adhesion and abrogated LPA-induced MMP-9 expression and p38 MAPK phosphorylation. CONCLUSIONS: We demonstrated a mechanism that LPA can activate p38 MAPK signaling, which is required for LPA-induced HCC cell migration, invasion, adhesion and MMP-9 expression, providing a novel biomarker and potential therapeutic target for HCC.

Combined invagination and duct-to-mucosa techniques with modifications: a new method of pancreaticojejunal anastomosis.

BACKGROUND: Soft pancreatic texture and a small main pancreatic duct are thought to be the most significant risk factors for the occurrence of pancreatic fistula (PF), a common and serious complication after pancreaticoduodenectomy (PD). This is in part due to the technical difficulties of pancreaticojejunostomy (PJ) posed by a soft gland with a normal-sized duct. To deal with this problem, we developed a new anastomotic technique which combines the two most widely used techniques, namely, the invagination technique and the duct-to-mucosa technique, with a modification of the suture route and insertion of a temporary stent tube. METHODS: Between January 2003 and December 2009, ninety-two consecutive patients underwent PD in which the new PJ technique was used. Charts and follow-up data of these patients were reviewed for operative details, early postoperative events, and outcomes at 6 months after the operation. PF was defined by the International Study Group on Pancreatic Fistula (ISGPF) guidelines and graded (A, B or C) according to the clinical procedures and outcome. RESULTS: In this group of 92 patients, there was only 1 early death from acute renal failure. PF was observed in 11 patients (12.0%), 8 in grade A, 1 in grade B, and 2 in grade C. For the 2 patients in grade C, PF was surgically managed. There were no early or late deaths attributable to PF. Six months after the operation, all of the patients were free of PJ-related symptoms except for 2, who were found to have steatorrhea. CONCLUSIONS: Our modified technique is simple and safe in PD. Present data suggest that this technique produces excellent early and medium-term results.

Modified Sugiura procedure for the management of 160 cirrhotic patients with portal hypertension.

BACKGROUND: Portal hypertension is a common disease with a high mortality and serious effect on the life quality of patients. Presently, shunt and disconnection are commonly used for surgical treatment of portal hypertension. The aim of this study was conducted to analyze the results of a modified Sugiura procedure for the management of 160 cirrhotic patients with portal hypertension. METHODS: The results of a modified Sugiura procedure for the treatment of 160 cirrhotic patients with portal hypertension from January 1991 to July 2002 were retrospectively analyzed. RESULTS: The operative mortality for the procedure was zero. Postoperative intra-abdominal bleeding was noted in 2 patients, drowned lung in 1, pneumonia in 1, and splenic venous thrombosis in 4. Of the 160 patients, 157 (98%) were followed up from 6 months to 11.5 years. Of the 157 patients, only one died of hepatic coma 6 years after operation, and 3 of rebleeding. The absolute and relative survival rates were 97.5%(156/160) and 99%(159/160), respectively. The absolute and relative occurrence rates of hepatic coma were 2.5%(4/160) and 0.6%(1/157), respectively. The absolute and relative occurrence rates of rebleeding were 3.8%(6/160) and 1.9%(3/157), respectively. In 96 of 116 Child B patients (82.8%), liver function improved from preoperative class B to A 3 months after operation. Sixty-five patients were subjected to gastroscopy and 22 patients, esophageal barium photography 6 months after operation. Gastro-esophageal varices disappeared in 56 patients (64.4%, 56/87), obviously improved in 30 (34.5%, 30/87), and unchanged in 1 (1.2%, 1/87). The occurrence rate of portal hypertensive gastropathy (PHG) was 13.9%(9/65). CONCLUSION: Our results showed that the modified Sugiura procedure is effective in the treatment of portal hypertension, with a low rate of operative complication, bleeding recurrence, and hepatic coma.

Pancreaticoduodenectomy with Roux-Y anastomosis in reconstructing the digestive tract: report of 26 patients.

OBJECTIVE: To explore the way to lower the morbidity and mortality of patients after pancreaticoduodenectomy. METHODS: Between March 1998 and March 2001, 26 patients with periampullary tumors received pancreaticoduodenectomy (PD) with Roux-Y anastomosis to reconstruct the digestive tract. Of these patients, 6 had ductal cell carcinoma at the head of the pancreas, 8 distal common bile duct carcinoma, 5 ampullar adenocarcinoma of the Vater, 6 duodenal adenocarcinoma, and 1 duodenal malignant lynphoma. A 30-40 cm free vascularized segment of the proximal jejunum was taken and pulled up to the bed of the duodenum for end-to-end pancreaticojejunostomy, end-to-side choledocojejunostomy or side-to-side jejunojejunostomy by a single loop. RESULTS: The operative mortality was zero. Postoperative intraabdominal hemorrhage occurred in 2 patients, but no leakage during pancreaticojejunostomy or choledocojejunostomy as well as abdominal infection. The patients were discharged from the hospital on the tenth to fourteenth day after operation. Follow-up for 5 to 36 months (mean 21 months) revealed chronic steatorrhea and malnutrition in one patient (3.85%), and good digestive function and normal nutritional status in 25 (96.15%). No bile reflux gastritis, retrograde infection, anastomotic ulcer, and dumping syndrome were observed. CONCLUSION: Our results show that this procedure can effectively reduce the morbidity and mortality of patients after PD.