OBJECTIVE: To explore the effect and mechanism of acupuncture at "Weizhong" (BL40) on microcirculation of paravertebral skeletal muscle in rats with chronic blunt injury of lumbar muscle based on the insulin-like growth factor-1 (IGF-1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. METHODS: Forty-eight SPF-grade SD rats were randomized into a blank group (8 rats) and a modeling group (40 rats). Chronic blunt injury model was established by weight impact method in the modeling group. Forty rats were successfully modeled, and were randomly divided into a model group, an acupuncture at Weizhong group (Weizhong group), an acupuncture at non-acupoint group (non-acupoint group), an inhibitor group, and an inhibitor+acupuncture at Weizhong group (inhibitor+Weizhong group), 8 rats in each group. In the Weizhong group and the inhibitor+Weizhong group, acupuncture was applied at bilateral "Weizhong" (BL40). In the non-acupoint group, acupuncture was applied at non-acupoints, i.e. points 0.5 cm inward from bilateral "Weizhong" (BL40). The acupuncture intervention was delivered 20 min each time, once a day for continuous 2 weeks. In the inhibitor group and the inhibitor+Weizhong group, intraperitoneal injection of IGF-1 receptor (IGF-1R) inhibitor was given once a day, at a dosage of 2 mg/100 g, for continuous 2 weeks. Before modeling and on the 1st, 7th and 14th days of intervention, the body mass was measured. Before and after modeling, and after intervention, the limb grip strength and paw withdrawal threshold (PWT) were measured. After intervention, the morphology of psoas muscle was observed by HE staining; the ultrastructure of psoas muscle capillaries was observed by electron microscopy; the levels of serum vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were detected by ELISA; and the protein and mRNA expression of IGF-1, IGF-1R, PI3K, AKT of psoas muscle was detected by Western blot and real-time PCR. RESULTS: Compared with the blank group, in the model group, the body mass on the 7th and 14th days of intervention, the limb grip strength, and the PWT of left and right hind feet were decreased (P<0.001, P<0.01); the skeletal muscle cells showed enlarged intercellular space, loosely arranged and irregularly shaped, the capillaries in the psoas muscle tissues were edematous, and the lumen of the blood vessels was obviously atrophied; the levels of serum VEGF and eNOS were decreased (P<0.001); in psoas muscle, the protein expression of IGF-1 and IGF-1R, as well as the p-PI3K/PI3K, p-AKT/AKT values were decreased (P<0.001), the mRNA expression of IGF-1, IGF-1R, PI3K and AKT was decreased (P<0.001, P<0.05). Compared with the model group, in the Weizhong group, the body weight was increased on the 7th and 14th days of intervention (P<0.001), the limb grip strength and the PWT of the left and right hind feet were increased (P<0.001, P<0.01); the arrangement of the skeletal muscle cells was relatively tight and the intercellular space was reduced, the blood vessels tended to be regular and the structure of the basement membrane was continuous, while the lumens of blood vessels were collapsed locally; the levels of serum VEGF and eNOS were increased (P<0.001); in psoas muscle, the protein expression of IGF-1 and IGF-1R, as well as the p-PI3K/PI3K, p-AKT/AKT values were increased (P<0.001), the mRNA expression of IGF-1, IGF-1R, PI3K and AKT was increased (P<0.001, P<0.01). Compared with the model group, in the inhibitor group, the body mass was decreased on the 7th and 14th days of intervention (P<0.05, P<0.01); the limb grip strength and the PWT of the left hind foot were decreased (P<0.01, P<0.001); the intercellular space of skeletal muscle cells was larger, the nuclei of the cells and erythrocytes were scattered in the intercellular space, the damage of the capillaries in the muscular tissues was serious, the collagen fibers were sparsely distributed and disorganized; the levels of serum VEGF and eNOS were decreased (P<0.001, P<0.01); in psoas muscle, the protein expression of IGF-1 and IGF-1R, as well as the p-PI3K/PI3K and p-AKT/AKT values were decreased (P<0.01, P<0.05, P<0.001), the mRNA expression of IGF-1, IGF-1R, PI3K, and AKT was decreased (P<0.01, P<0.001, P<0.05). Compared with the Weizhong group, in the non-acupoint group and the inhibitor+Weizhong group, the body mass was decreased on the 7th and 14th days of intervention (P<0.001, P<0.01), the limb grip strength was decreased (P<0.001); the morphology of muscle cell was relatively poor, with generally irregular, there was mild collapse and atrophy in the vascular lumen, and mild edema in the endothelial cells; the levels of serum VEGF and eNOS were decreased (P<0.001); in psoas muscle, the protein expression of IGF-1 and IGF-1R, as well as the p-PI3K/PI3K and p-AKT/AKT values were decreased (P<0.01, P<0.001), the mRNA expression of IGF-1, IGF-1R, PI3K, and AKT was decreased (P<0.001, P<0.01, P<0.05). Compared with the Weizhong group, the PWT of the left hind foot was decreased in the non-acupoint group (P<0.001), and PWT of the left and right hind feet was decreased in the inhibitor+Weizhong group (P<0.001). CONCLUSION Acupuncture at "Weizhong" (BL40) promotes lumbar muscle repair in chronic low back pain, its mechanism may be related to the activation of the IGF-1/PI3K/AKT pathway, thereby improving the microcirculation.
Animals ; Insulin-Like Growth Factor I/genetics* ; Acupuncture Therapy ; Rats, Sprague-Dawley ; Rats ; Proto-Oncogene Proteins c-akt/genetics* ; Male ; Humans ; Muscle, Skeletal/metabolism* ; Signal Transduction ; Phosphatidylinositol 3-Kinases/genetics* ; Wounds, Nonpenetrating/metabolism* ; Acupuncture Points

Chimeric antigen receptor T (CAR-T) cells have reshaped the treatment landscape of hematological malignancies, offering a potentially curative option for patients. Despite these major milestones in the field of immuno-oncology, growing experience with CAR-T cells has also highlighted several limitations of this strategy. The production process of CAR-T cells is complex, time-consuming, and costly, thus leading to poor drug accessibility. The potential carcinogenic risk of viral transfection systems remains a matter of controversy. Treatment-related side effects, such as cytokine release syndrome, can be life-threatening. And the biggest challenge is the inadequate efficacy related to poor infiltration and retention of CAR-T cells in tumor tissues and impaired T cell activation caused by the immunosuppressive tumor microenvironment (TME). Innovative strategies are urgently needed to address these problems, and nanomedicine offers good solutions to these challenges. In this review, we provide a comprehensive summary of recent advancements in the application of nanomaterials to enhance CAR-T cell therapy. We examine the role of innovative nanoparticle-based delivery systems in the production of CAR-T cells, with a particular focus on polymeric delivery systems and lipid nanoparticles (LNPs). Furthermore, we explore various strategies for delivering immune stimulators, which significantly enhance the efficacy of CAR-T cells by modulating T cell viability and functionality or by reprogramming the immunosuppressive TME. In addition, we discuss several novel therapeutic approaches aimed at mitigating the adverse effects associated with CAR-T therapies. Finally, we offer an integrated perspective on the future challenges and opportunities facing CAR-T therapies.
Humans ; Nanomedicine/methods* ; Receptors, Chimeric Antigen/metabolism* ; Immunotherapy, Adoptive/methods* ; T-Lymphocytes/immunology* ; Nanoparticles/chemistry* ; Animals

Curcumae Rhizoma, derived from the rhizome of Curcuma phaeocaulis, Curcuma kwangsiensis and Curcuma wenyujin, was called Ezhu in China. In the past, Curcumae Rhizoma extracts were obtained through water decoction or alternative methods, which showed significant anti-cancer effects. However, the mixed extracts contain various compound components of Curcumae Rhizoma, leading to an ambiguous mechanism of action for Curcumae Rhizoma extracts anti-cancer. Contemporary researchers have extracted the chemical components of Curcumae Rhizoma separately for experimental verification of its active ingredients in the anti-cancer field. Numerous studies demonstrated that curcumol, germacrone, β-elemene, and curcumin in Curcumae Rhizoma extracts have significant governing effects in anti-cancer activities. Pharmacological studies have shown that Curcumae Rhizoma suppresses cancer cell proliferation, invasion, and migration, triggering apoptosis and regulating cellular autophagy to achieve anticancer effects. Here, we summarized the research progress of Curcumae Rhizoma on anti-cancer effects from 2013 to 2022, aiming to explore the deeper molecular mechanisms of Curcumae Rhizoma's active components in cancer treatment.

Objective To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism.Methods SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes,and histological changes of the thoracic aorta were evaluated using HE staining.In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings,the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine(NE)-and KCl-induced constriction.The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester,indomethacin,zinc protoporphyrin Ⅸ,tetraethyl ammonium chloride,glibenclamide,barium chloride,Iberiotoxin,4-aminopyridine,or TASK-1-IN-1.The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release.Results Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology.While not obviously affecting resting aortic rings with intact endothelium,asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE,but its effects differed between endothelium-intact and endothelium-denuded rings.In endothelium-intact aortic rings pretreated with indomethacin,ZnPP Ⅸ,barium chloride,glyburide,TASK-1-IN-1 and 4-aminopyridine,asiaticoside did not produce significant effect on NE-induced vasoconstriction,and tetraethylammonium,Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside.In KCl-and NE-treated rings,asiaticoside obviously inhibited CaCl2-induced vascular contraction.Conclusion Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening,promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow,thereby reducing systolic blood pressure in rats.

Objectives:To finely divide the aortic sinus into sections and accurately localize the coronary ostium through CARTO three-dimensional mapping,and to assess the clinical effects of treating aortic sinus cusps premature ventricular contraction(ASC-PVC)and the ablation risk in the corresponding area with zero X-ray radiofrequency ablation. Methods:A total of 66 patients who underwent radiofrequency ablation for ASC-PVC from January 2020 to January 2023 were included in this analysis,patients were divided into experimental group(n=34)and conventional group(n=32).In the conventional group,the CARTO 3 system was used to create an aortic sinus model through the conventional method.The earliest stimulating target was identified by using electrical stimulation mapping(ESM).Radiofrequency ablation treatment was performed after the distance between the target and the coronary ostium was precisely measured by coronary angiography through the hollow tube of the ablation catheter or coronary angiography tube.In the experimental group,the CARTO 3 system was used to build a model of the aortic sinus and the coronary ostium and aortic sinus were divided into sections.The earliest stimulating target was identified by ESM.After localizing coronary ostium through the impedance changing pattern on the ablation catheter tips,catheter ablation was performed with zero X-ray.The data regarding the impedance of the ablation catheter in the aortic sinus were collected.The total operative time,the operative time in the aortic sinus,contrast dosage,X-ray exposure time,immediate and short-term success rates of the operation and complication rates were compared between the two groups.Besides,the distribution of successfully ablated targets and their relationship with the risk of ablation were analyzed in both groups. Results:There was no significant statistical difference in the immediate and short-term success rates between the two groups(93.8%vs.94.1%;90.6%vs.88.2%,both P>0.05).The experimental group did not receive contrast agents during the operation,and the total operation time and intra-aortic sinus operation time in the experimental group were significantly shorter than those in the conventional group([58.76±4.94]min vs.[66.91±5.94]min,P<0.001;[43.12±4.49]min vs.[50.31±5.18]min,P<0.001).During the process of moving the ablation catheter from the intra-aortic sinus to the coronary artery opening and into the coronary artery,the impedance suddenly increased,which was significantly different from the impedance in other parts of the intra-aortic sinus(all P<0.001). Conclusions:Radiofrequency ablation of ASC-PVC with zero X-ray can simplify the procedures and shorten the operative time.The steep increase in impedance at the tip of the ablation catheter can be used as a basis for localizing the coronary ostium.Dividing the aortic sinus into sections allows a detailed assessment of the risk for ablation treatment at the targets.

Objective:To explore the recovery of abdominal function and and satisfaction rate in patients who received lower abdominal skin flap repair of extensive soft tissue defects in the limbs based on three-dimensional computed tomography angiography(3D-CTA) technology.Methods:A retrospective study was performed to analyze clinical data from patients with extensive skin and soft tissue defects in the limbs, who were admitted to Shandong Provincial Third Hospital between March 2017 and February 2022. Patients were categorized into two groups: the superficial inferior epigastric artery (SIEA) group and the deep inferior epigastric perforator (DIEP) group, with SIEA flaps and DIEP flaps utilized respectively for tissue defect repair. Based on 3D-CTA imaging, the distribution range and vessel diameters of bilateral SIEA, superficial inferior epigastric veins (SIEV), and DIEP were delineated, facilitating the design and harvest of SIEA and DIEP flaps. Comparisons were drawn between preoperative 3D-CTA findings on the course and distribution of SIEA and SIEV, and intraoperative anatomical observations. In addition, the concordance between vessel diameters and pedicle lengths determined via preoperative 3D-CTA and intraoperative measurements was assessed. The flap survival, wound healing and surveyed patients’ satisfaction with wound repair were analyzed. A customized evaluation scale was utilized to assess abdominal contour one year post-surgery, scoring from 5 to 25, with higher scores indicating better outcomes. The abdominal health module of the BREAST-Q scale evaluated patients’ satisfaction with abdominal function preoperatively, three months postoperatively, and one year postoperatively, scoring from 20 to 100, with increasing scores indicating greater satisfaction. The measurement data that conform to the normal distribution were expressed as Mean±SD, and the comparison between the two groups was performed using independent samples t-test. The comparison were conducted at multiple time points, repeated measures analysis of variance was performed, and for the comparison of scores within the group, paired t-test was applied. Results:A total of 21 patients were included, 3 males and 18 females, with an age range of 21 to 60 years and a mean age of 41 years. The range of skin and soft tissue defects was from 10.0 cm × 5.0 cm to 22.0 cm × 14.0 cm, and the range of skin flap harvesting was from 11.0 cm × 6.0 cm to 23.0 cm × 15.0 cm. There were 11 cases in the SIEA group and 10 cases in the DIEP group. Preoperative 3D-CTA examination showed that the course and distribution of SIEA and SIEV were consistent with intraoperative anatomical observations. There was no statistically significant difference in the comparison of vessel diameters, pedicle lengths, and actual measurements between preoperative 3D-CTA examination and intraoperative measurements (all P > 0.05). No flap necrosis occurred postoperatively, wound healing was uneventful in all cases. At 1 year postoperatively, there was no statistically significant difference in abdominal contour scores between the SIEA and DIEP groups [(21.96±3.51) points vs. (21.62±3.17) points, P > 0.05]. Comparison of preoperative abdominal function satisfaction scores between the SIEA and DIEP groups showed no statistically significant difference [(87.56 ± 5.70) points vs. (85.79 ± 6.33) points, P > 0.05]. However, at 3 months and 1 year postoperatively, the SIEA group had higher scores than the DIEP group [at 3 months postoperatively, (77.62 ± 7.68) points vs. (65.21 ± 8.27) points; at 1 year postoperatively, (86.93 ± 5.65) points vs. (77.59 ± 5.92) points; both P < 0.01], indicating higher abdominal function satisfaction of the SIEA group postoperatively. The scores of both the SIEA and DIEP groups decreased at 3 months postoperatively compared to preoperative scores (both P < 0.01). At 1 year postoperatively, the score of the SIEA group was similar to preoperative levels, with no statistically significant difference ( P > 0.05), while the score of the DIEP group remained lower than preoperative levels ( P < 0.01). Conclusion:Reconstruction of extensive skin and soft tissue defects in the limbs using SIEA flaps, without injury to the deep tissues of the abdominal wall, allows for near-complete restoration of abdominal function and appearance to preoperative levels, with minimal impact on the donor site. Preoperative 3D-CTA reveals the anatomical variations in the vascular supply of SIEA flaps among individuals, achieving comparable wound repair outcomes to other lower abdominal flaps.

Objective This work aimed to evaluate the effect of artificial aging on the translucency and color differ-ence(ΔE)of ultra-translucent zirconia and provide a reference for clinical application.Methods The discs of ultra-translucent zirconia from six brands(Wieland,3M ESPE,Amann Girrbach,Kuraray Noritake,Upcera,and Besmile)were cut and sintered according to each manufacturer's product instructions;the experimental groups were named ZNT,LVP,AG,KAT,UPC,and BSM,respectively.IPS e.max Press was used as the control group(PLT).The specimens(n=6)were prepared with a diameter of 14 mm and a thickness of 1 mm.The specimens were subjected to artificial aging treat-ment according to the following conditions:in an auto-clave at 134℃ at 0.2 MPa for 4,8,and 12 h.According to the CIE1976Lab system,the CIE L*,a*,and b* values of the specimens before and after aging were measured by a co-lorimeter.The translucency parameter(TP)and ΔE were calculated.Results The mean TP values of each group before aging inorder were PLT>KAT>AG>ZNT>BSM>UPC>LVP.We found no significant difference in translu-cency in all experimental groups after aging for 4 and 8 h compared with those before aging.After 12 h of aging,the TP values of the KAT and ZNT groups were not significantly different from those before aging,but the TP values of the AG,BSM,LVP,and UPC groups were significantly lower than those before aging(P<0.05).The TP value of the control group was significantly higher than that of the other experimental groups at different stages(P<0.05).ΔE=3.3 was con-sidered the visible color difference,and ΔE was less than 3.3 in all groups after 4 h of aging.After aging for 8 h,ΔE of the UPC group was slightly higher than 3.3.ΔE of the BSM and UPC groups was greater than 3.3 after 12 h of aging.Conclusion The TP and ΔE of different brands of ultra-translucent zirconia may change after various aging times.The translucency of some zirconia showed a decreasing trend and the color difference showed an increasing trend with the aging time.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.

Objective To investigate the effect of asiaticoside on blood pressure and relaxation of thoracic aorta in rats and explore the underlying mechanism.Methods SD rats treated with 50 and 100 mg/kg asiaticoside by daily gavage for 2 weeks were monitored for systolic blood pressure changes,and histological changes of the thoracic aorta were evaluated using HE staining.In isolated rat endothelium-intact and endothelium-denuded thoracic aorta rings,the effects of asiaticoside on relaxation of the aortic rings were tested at baseline and following norepinephrine(NE)-and KCl-induced constriction.The vascular relaxation effect of asiaticoside was further observed in NE-stimulated endothelium-intact rat aortic rings pretreated with L-nitroarginine methyl ester,indomethacin,zinc protoporphyrin Ⅸ,tetraethyl ammonium chloride,glibenclamide,barium chloride,Iberiotoxin,4-aminopyridine,or TASK-1-IN-1.The aortic rings were treated with KCl and NE followed by increasing concentrations of CaCl2 to investigate the effect of asiaticoside on vasoconstriction induced by external calcium influx and internal calcium release.Results Asiaticoside at 50 and 100 mg/kg significantly lowered systolic blood pressure in rats without affecting the thoracic aorta histomorphology.While not obviously affecting resting aortic rings with intact endothelium,asiaticoside at 100 mg/kg induced significant relaxation of the rings constricted by KCl and NE,but its effects differed between endothelium-intact and endothelium-denuded rings.In endothelium-intact aortic rings pretreated with indomethacin,ZnPP Ⅸ,barium chloride,glyburide,TASK-1-IN-1 and 4-aminopyridine,asiaticoside did not produce significant effect on NE-induced vasoconstriction,and tetraethylammonium,Iberiotoxin and L-nitroarginine methyl ester all inhibited the relaxation effect of asiaticoside.In KCl-and NE-treated rings,asiaticoside obviously inhibited CaCl2-induced vascular contraction.Conclusion Asiaticoside induces thoracic aorta relaxation by mediating high-conductance calcium-activated potassium channel opening,promoting nitric oxide release from endothelial cells and regulating Ca2+ influx and outflow,thereby reducing systolic blood pressure in rats.

Objective To investigate whether activation of mitochondrial acetal dehydrogenase 2(ALDH2)alleviates hypoxic pulmonary hypertension by regulating the SIRT1/PGC-1α signaling pathway.Methods Thirty 8-week-old C57 BL/6 mice were randomized into control,hypoxia,and hypoxia+Alda-1(an ALDH2 activator)group(n=10),and the mice in the latter two groups,along with 10 ALDH2 knockout(ALDH2-/-)mice,were exposed to hypoxia(10%O2,90%N2)with or without daily intraperitoneal injection of Alda-1 for 4 weeks.The changes in right ventricular function and pressure(RVSP)of the mice were evaluated by echocardiography and right ventricular catheter test,and pulmonary artery pressure was estimated based on RVSP.Pulmonary vascular remodeling,right ventricular injury,myocardial α-SMA expression,distal pulmonary arteriole muscle normalization,right ventricular cross-sectional area,myocardial cell hypertrophy,and right cardiac hypertrophy index were assessed with HE staining,immunofluorescence staining and WGA staining,and the expressions of ALDH2,SIRT1,PGC-1α,P16INK4A and P21CIP1 were detected.In pulmonary artery smooth muscle cells with hypoxic exposure,the effect of Alda-1 and EX527 on cell senescence and protein expressions was evaluated using β-galactose staining and Western blotting.Results The wild-type mice with hypoxic exposure showed significantly increased RVSP,right ventricular free wall thickness and myocardial expressions of P16INK4A and P21CIP1,which were effectively lowered by treatment with Alda-1 but further increased in ALDH2-/-mice.In cultured pulmonary artery smooth muscle cells,hypoxic exposure significantly increased senescent cell percentage and cellular expressions of P16INK4A and P21CIP1,which were all lowered by treatment with Alda-1,but its effect was obviously attenuated by EX527 treatment.Conclusion ALDH2 alleviates hypoxia-induced senescence of pulmonary artery smooth muscle cells by upregulating the SIRT1/PGC-1α signaling pathway to alleviate pulmonary hypertension in mice.