Influence of Panax ginseng formulation on skin microbiota: A randomized, split face comparative clinical study.

Background: Skin microbiota is important for maintenance of skin homeostasis; however, its disturbance may cause an increase in pathogenic microorganisms. Therefore, we aimed to develop a red ginseng formulation that can selectively promote beneficial bacteria. Methods: The effects of red ginseng formulation on microorganism growth were analyzed by comparing the growth rates of Staphylococcus aureus, S. epidermidis, and Cutibacterium acnes. Various preservatives mixed with red ginseng formulation were evaluated to determine the ideal composition for selective growth promotion of S. epidermidis. Red ginseng formulation with selected preservative was loaded into a biocompatible polymer mixture and applied to the faces of 20 female subjects in the clinical trial to observe changes in the skin microbiome. Results: Red ginseng formulation promoted the growth of S. aureus and S. epidermidis compared to fructooligosaccharide. When 1,2-hexanediol was applied with red ginseng formulation, only S. epidermidis showed selective growth. The analysis of the release rates of ginsenoside-Rg1 and -Re revealed that the exact content of Pluronic F-127 was around 11%. The application of hydrogel resulted in a decrease in C. acnes in all subjects. In subjects with low levels of S. epidermidis, the distribution of S. epidermidis was significantly increased with the application of hydrogel formulation and total microbial species of subjects decreased by 50% during the clinical trial. Conclusion: We confirmed that red ginseng formulation with 1,2-hexanediol can help maintain skin homeostasis through improvement of skin microbiome.

Mitochondrial E3 Ubiquitin Protein Ligase 1 Mediates Cigarette Smoke-Induced Endothelial Cell Death and Dysfunction.

By virtue of the critical roles of Akt in vascular endothelial cell (EC) survival and function, cigarette smoke-induced Akt reduction may contribute to EC death and dysfunction in smokers' lungs. One of the negative Akt regulatory mechanisms is K48-linked Akt ubiquitination and subsequent proteasomal degradation. Here, we assessed the involvement of mitochondrial E3 ubiquitin protein ligase 1 (MUL1), recently revealed as a novel Akt ubiquitin E3 ligase, in cigarette smoke-induced Akt ubiquitination and its contribution to pulmonary EC death and dysfunction. In human lung microvascular ECs (HLMVECs), cigarette smoke extract (CSE) noticeably elevated MUL1 expression and K48-linked Akt ubiquitination, whereas Akt, p-Akt, eNOS, and p-eNOS levels were decreased. MUL1 knockdown suppressed CSE-induced Akt ubiquitination/degradation and cytoplasmic reductions of Akt and p-Akt. Furthermore, MUL1 knockdown attenuated reductions of eNOS and p-eNOS and alleviated EC survival, migration, and tube formation in the presence of CSE exposure. In addition, overexpression of K284R Akt, a mutant for a MUL1-ubiquitination site, produced similar effects. In HLMVECs exposed to CSE, Akt-MUL1 interaction was increased in coimmunoprecipitation and in situ proximity ligation assays. Similarly, the proximity ligation assay signals were elevated in rat lungs exposed to cigarette smoke for 3 months, during which Mul1 levels were noticeably increased. Finally, we found that CSE-mediated MUL1 induction in HLMVECs is mediated by retinoic acid receptor-related orphan receptor α. Taken together, these data suggest that cigarette smoke-induced MUL1 elevation mediates Akt ubiquitination/degradation, potentially leading to pulmonary EC death and functional impairment.

Bortezomib alleviates experimental pulmonary arterial hypertension.

Vascular remodeling and endothelial dysfunction are important pathogenic features of pulmonary arterial hypertension (PAH). There is a growing body of evidence that proteasome inhibitors may be beneficial in vascular diseases by inhibiting proliferation of vascular smooth muscle cells (VSMCs) and ameliorating endothelial dysfunction. Here, we evaluated whether bortezomib (BTZ) could alleviate hypoxia- and monocrotaline (MCT)-induced PAH. BTZ (at doses from 1 to 100 µg/kg, or a dose of 100 µg/kg) was administered to mice every other day for the last 2 weeks of a 5-week hypoxia (10% O(2)) period, or to rats once daily from Day 22 to Day 34 after MCT challenge, respectively. BTZ treatment substantially suppressed elevation of right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling in hypoxia-exposed mice. Similarly, BTZ treatment inhibited RV hypertrophy and vascular remodeling in MCT-injected rats. Strikingly, BTZ rescued 70% of MCT-injected rats up to Day 60, along with a considerable reduction in RV systolic pressure and suppression of vascular remodeling, whereas, among MCT-injected rats not administered BTZ, there were no survivors by Day 41. BTZ significantly suppressed proliferation of pulmonary VSMCs in vivo and in vitro. Furthermore, BTZ increased not only endothelial nitric oxide (NO) synthase (eNOS), phosphorylated eNOS, and NO production in vitro, but also eNOS and p-eNOS in hypoxia-exposed mice and MCT-injected rats, respectively. In contrast to the beneficial effects, BTZ increased active caspase-3 in cardiac ventricles of MCT-injected rats. Taken together, with caution for cardiotoxicity, BTZ could be a potential therapeutic strategy in PAH, possibly acting by inhibition of VSMC proliferation and amelioration of endothelial dysfunction.

Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage.

Cigarette smoking causes apoptotic death, senescence, and impairment of repair functions in lung fibroblasts, which maintain the integrity of alveolar structure by producing extracellular matrix (ECM) proteins. Therefore, recovery of lung fibroblasts from cigarette smoke-induced damage may be crucial in regeneration of emphysematous lung resulting from degradation of ECM proteins and subsequent loss of alveolar cells. Recently, we reported that bone marrow-derived mesenchymal stem cell-conditioned media (MSC-CM) led to angiogenesis and regeneration of lung damaged by cigarette smoke. In this study, to further investigate reparative mechanisms for MSC-CM-mediated lung repair, we attempted to determine whether MSC-CM can recover lung fibroblasts from cigarette smoke-induced damage. In lung fibroblasts exposed to cigarette smoke extract (CSE), MSC-CM, not only inhibited apoptotic death, but also induced cell proliferation and reversed CSE-induced changes in the levels of caspase-3, p53, p21, p27, Akt, and p-Akt. MSC-CM also restored expression of ECM proteins and collagen gel contraction while suppressing CSE-induced expression of cyclooxygenase-2 and microsomal PGE(2) synthase-2. The CSE-opposing effects of MSC-CM on cell fate, expression of ECM proteins, and collagen gel contraction were partially inhibited by LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor. In rats, MSC-CM administration also resulted in elevation of p-Akt and restored proliferation of lung fibroblasts, which was suppressed by exposure to cigarette smoke. Taken together, these data suggest that MSC-CM may recover lung fibroblasts from cigarette smoke-induced damage, possibly through inhibition of apoptosis, induction of proliferation, and restoration of lung fibroblast repair function, which are mediated in part by the PI3K/Akt pathway.