Impaired mitochondrial fusion, due in part to decreased mitofusin 2 (Mfn2) expression, contributes to unrestricted cell proliferation and apoptosis‐resistance in hyperproliferative diseases like ...pulmonary arterial hypertension (PAH) and non‐small cell lung cancer (NSCLC). We hypothesized that Mfn2 levels are reduced due to increased proteasomal degradation of Mfn2 triggered by its phosphorylation at serine 442 (S442) and investigated the potential kinase mediators. Mfn2 expression was decreased and Mfn2 S442 phosphorylation was increased in pulmonary artery smooth muscle cells from PAH patients and in NSCLC cells. Mfn2 phosphorylation was mediated by PINK1 and protein kinase A (PKA), although only PINK1 expression was increased in these diseases. We designed a S442 phosphorylation deficient Mfn2 construct (PD‐Mfn2) and a S442 constitutively phosphorylated Mfn2 construct (CP‐Mfn2). The effects of these modified Mfn2 constructs on Mfn2 expression and biological function were compared with those of the wildtype Mfn2 construct (WT‐Mfn2). WT‐Mfn2 increased Mfn2 expression and mitochondrial fusion in both PAH and NSCLC cells resulting in increased apoptosis and decreased cell proliferation. Compared to WT‐Mfn2, PD‐Mfn2 caused greater Mfn2 expression, suppression of proliferation, apoptosis induction, and cell cycle arrest. Conversely, CP‐Mfn2 caused only a small increase in Mfn2 expression and did not restore mitochondrial fusion, inhibit cell proliferation, or induce apoptosis. Silencing PINK1 or PKA, or proteasome blockade using MG132, increased Mfn2 expression, enhanced mitochondrial fusion and induced apoptosis. In a xenotransplantation NSCLC model, PD‐Mfn2 gene therapy caused greater tumor regression than did therapy with WT‐Mfn2. Mfn2 deficiency in PAH and NSCLC reflects proteasomal degradation triggered by Mfn2‐S442 phosphorylation by PINK1 and/or PKA. Inhibiting Mfn2 phosphorylation has potential therapeutic benefit in PAH and lung cancer.
Classification of benign and malignant pulmonary nodules can provide useful indicators for estimating the risk of lung cancer. In this study, an improved random forest (RF) algorithm is proposed for ...classification of benign and malignant pulmonary nodules in thoracic computed tomography images. First, an improved random walk algorithm is proposed to automatically segment pulmonary nodules. Then, intensity, geometric and texture features based on the grey-level co-occurrence matrix, rotation invariant uniform local binary pattern and Gabor filter methods are combined to generate an effective and discriminative feature vector. Mutual information is employed to reduce the dimensionality. Finally, an improved RF classifier is trained to classify benign and malignant nodules. An appropriate feature subset is selected by the bootstrap method and an effective combination method is introduced to predict a class label. The proposed classification method on the lung images dataset consortium dataset achieves a sensitivity of 0.92 and the area under the receiver-operating-characteristic curve of 0.95. An additional evaluation is performed on another dataset coming from General Hospital of Guangzhou Military Command. A mean sensitivity and a mean specificity of the proposed method are 0.85 and 0.82, respectively. Experimental results demonstrate that the proposed method achieves the satisfactory classification performance.
Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue (BAT). Using high-throughput library screening of secreted peptides, we identify two fibroblast growth ...factors (FGF), FGF6 and FGF9, as potent inducers of UCP1 expression in adipocytes and preadipocytes. Surprisingly, this occurs through a mechanism independent of adipogenesis and involves FGF receptor-3 (FGFR3), prostaglandin-E2 and interaction between estrogen receptor-related alpha, flightless-1 (FLII) and leucine-rich-repeat-(in FLII)-interacting-protein-1 as a regulatory complex for UCP1 transcription. Physiologically, FGF6/9 expression in adipose is upregulated by exercise and cold in mice, and FGF9/FGFR3 expression in human neck fat is significantly associated with UCP1 expression. Loss of FGF9 impairs BAT thermogenesis. In vivo administration of FGF9 increases UCP1 expression and thermogenic capacity. Thus, FGF6 and FGF9 are adipokines that can regulate UCP1 through a transcriptional network that is dissociated from brown adipogenesis, and act to modulate systemic energy metabolism.
The
(
) eradication rate is decreasing in the general population of China.
To evaluate the
eradication status in real-world clinical practice and to explore factors related to eradication failure.
...Patients with
infection who were treated with standard 14-d quadruple therapy and received a test of cure at a provincial medical institution between June 2018 and May 2019 were enrolled. Demographic and clinical data were recorded. Eradication rates were calculated and compared between regimens and subgroups. Multivariate analysis was performed to identify predictors of eradication failure.
Of 2610 patients enrolled, eradication was successful in 1999 (76.6%) patients. Amoxicillin-containing quadruple regimens showed a higher eradication rate than other quadruple therapy regimens (83.0%
69.0%,
< 0.001). The quadruple therapy containing amoxicillin plus clarithromycin achieved the highest eradication rate (83.5%). Primary therapy had a higher eradication rate than rescue therapy (78.3%
66.5%,
< 0.001). In rescue therapy, the amoxicillin- and furazolidone-containing regimens achieved the highest eradication rate (80.8%). Esomeprazole-containing regimens showed a higher eradication rate than those containing other proton pump inhibitors (81.8%
74.9%,
= 0.001). Multivariate regression analysis found that older age, prior therapy, and use of omeprazole or pantoprazole were associated with an increased risk of eradication failure.
The total eradication rate is 76.6%. Amoxicillin-containing regimens are superior to other regimens. Age, prior therapy, and use of omeprazole or pantoprazole are independent risk factors for eradication failure.
The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of ...indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear.
Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined.
In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in
,
,
, and
. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (
<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 95% CI, 1.257-3.816;
=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1β and interleukin-6 and lower interleukin-4 and IgG galactosylation levels.
This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.
Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the pulmonary vasculature and elevated pulmonary arterial pressure, ultimately leading to right ...heart failure and death. Despite its clinical significance, the precise molecular mechanisms driving PAH pathogenesis warrant confirmation. Compelling evidence indicates that during the development of PAH, pulmonary vascular cells exhibit a preference for energy generation through aerobic glycolysis, known as the “Warburg effect”, even in well-oxygenated conditions. This metabolic shift results in imbalanced metabolism, increased proliferation, and severe pulmonary vascular remodeling. Exploring the Warburg effect and its interplay with glycolytic enzymes in the context of PAH has yielded current insights into emerging drug candidates targeting enzymes and intermediates involved in glucose metabolism. This sheds light on both opportunities and challenges in the realm of antiglycolytic therapy for PAH.
The formation and evolution of the crust-mantle transition zone (CMTZ) under oceanic slow-ultraslow spreading centers, compared with the well-documented examples that developed under fast spreading ...centers, remain largely unknown due to the lack of suitable targets. In this study, we systematically examine the CMTZ of the Xigaze ophiolite in the Yarlung Zangbo suture zone (south Tibet). This ophiolite represents a rare lithospheric fragment produced in oceanic slow-ultraslow spreading settings. We conduct detailed field mapping and petrological as well as geochemical studies on the CMTZ in the Dazhuka massif, the easternmost segment of the Xigaze ophiolite. Our aim is to characterize the lithological architecture and associated melt-fluid-peridotite interaction history of the CMTZ. The CMTZ (~1800 m thick) in the Dazhuka ophiolite consists of 4 subzones with complex lithological associations. They range successively from clinopyroxene-rich harzburgite with weak metasomatism and without amphibole in Zone 1 (the bottom) to clinopyroxene-poor harzburgite with strong melt impregnation and more amphibole in Zone 3 (the upper part, with Zone 2 transitional harzburgite in between), all cut by a wealth of dyke rocks (gabbro, dolerite and dunite). The Al2O3 contents decrease consistently in whole-rock (2.97–0.57 wt%), orthopyroxene (4.99–0.85 wt%) and clinopyroxene (5.25–1.22 wt%) for the harzburgites from Zones 1–3, contrary to the trends for the spinel Cr# (0.17–0.65) and clinopyroxene Li/Y, and bulk rare earth element (REE), Pb and Sr contents. The plagioclase-bearing peridotite (commonly enclosed in layered gabbro) in Zone 4 (the top) has remarkably elevated TiO2 contents (0.12–0.34 wt%) and Cr# values (0.45–0.53) in spinel, suggesting equilibration and strongest interaction with MORB-like melts among the CMTZ. The troctolite in Zone 4 has olivine Mg# (80.6–84.2) and NiO (0.37–0.45 wt%) and spinel Cr# (0.68–0.73). The fluid-mobile elements (U, Pb, Sr and Li) in both whole rock and clinopyroxene as well as amphibole abundances increase consistently from Zones 1–4, implying that the interaction of the mantle rocks with hydrothermal fluids became increasingly intensive from bottom to top of the CMTZ.
These vertical variations collectively suggest the complex melt-fluid-peridotite interaction during the upward movement of deeply sourced melts and the downward penetration of seawater. We propose that such interactions are ultimately controlled by the relative slow spreading rates, where the less melt supply and very thin or even missing oceanic crust facilitate the downward seawater injection and enhance pervasive fluid metasomatism. This may represent a suitable explanation for the CMTZ with intriguing lithological and chemical heterogeneity under many other active or fossil oceanic slow-ultraslow spreading environments.
•Dazhuka crust-mantle transition zone (CMTZ) shows large lithological diversities.•Complex melt-fluid-peridotite interaction is recorded in the Dazhuka CMTZ.•Intensity of the interaction increases from bottom to top of the CMTZ.•The intensity of interaction is controlled by the oceanic spreading rates.
Opsin3 (Opn3) is a transmembrane heptahelical G protein-coupled receptor (GPCR) with the potential to produce a nonvisual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals ...that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin resistance. At the cellular level, Opn3-KO brown adipocytes cultured in darkness had decreased glucose uptake and lower nutrient-induced mitochondrial respiration than wild-type (WT) cells. Light exposure promoted mitochondrial activity and glucose uptake in WT adipocytes but not in Opn3-KO cells. Brown adipocytes carrying a defective mutation in Opn3's putative G protein-binding domain also exhibited a reduction in glucose uptake and mitochondrial respiration in darkness. Using RNA-sequencing, we identified several novel light-sensitive and Opn3-dependent molecular signatures in brown adipocytes. Importantly, direct exposure of brown adipose tissue (BAT) to light in living mice significantly enhanced thermogenic capacity of BAT, and this effect was diminished in Opn3-KO animals. These results uncover a previously unrecognized cell-autonomous, light-sensing mechanism in brown adipocytes via Opn3-GPCR signaling that can regulate fuel metabolism and mitochondrial respiration. Our work also provides a molecular basis for developing light-based treatments for obesity and its related metabolic disorders.
PDF
