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Background. Noncystic fibrosis bronchiectasis (NCFB) is characterized by airway expansion and recurrent acute exacerbations. Macrolide has been shown to exhibit anti-inflammatory effects in some chronic airway diseases. Objective. To assess the efficacy of roxithromycin on airway inflammation and remodeling in patients with NCFB under steady state. Methods. The study involved an open-label design in 52 eligible Chinese patients with NCFB, who were assigned to control (receiving no treatment) and roxithromycin (receiving 150 mg/day for 6 months) groups. At baseline and 6 months, the inflammatory markers such as interleukin- (IL-)8, neutrophil elastase (NE), matrix metalloproteinase- (MMP)9, hyaluronidase (HA), and type IV collagen in sputum were measured, along with the detection of dilated bronchus by throat computed tomography scan, and assessed the exacerbation. Results. Forty-three patients completed the study. The neutrophil in the sputum was decreased in roxithromycin group compared with control ( P < 0.0 5 ) . IL-8, NE, MMP-9, HA, and type IV collagen in sputum were also decreased in roxithromycin group compared with the control group (all P < 0.01 ) . Airway thickness of dilated bronchus and exacerbation were reduced in roxithromycin group compared with the control (all P < 0.0 5 ) . Conclusions. Roxithromycin can reduce airway inflammation and airway thickness of dilated bronchus in patients with NCFB.

It is well documented that the juvenile hormone (JH) can function as a gonadotropic hormone that stimulates vitellogenesis by activating the production and uptake of vitellogenin in insects. Here, we describe a phenotype associated with mutations in the Drosophila JH receptor genes, Met and Gce: the accumulation of mature eggs with reduced egg length in the ovary. JH signaling is mainly activated in ovarian muscle cells and induces laminin gene expression in these cells. Meanwhile, JH signaling induces collagen IV gene expression in the adult fat body, from which collagen IV is secreted and deposited onto the ovarian muscles. Laminin locally and collagen IV remotely contribute to the assembly of ovarian muscle extracellular matrix (ECM); moreover, the ECM components are indispensable for ovarian muscle contraction. Furthermore, ovarian muscle contraction externally generates a mechanical force to promote ovulation and maintain egg shape. This work reveals an important mechanism for JH-regulated insect reproduction.

Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury. Glial scars are thought to provide a biochemical and mechanical barrier to neuronal regeneration post-injury, but the mechanical properties of the scars have not been studied in detail. Here the authors perform atomic force microscopy measurements of glial scars from the injured rat cortex and spinal cord, and find that brain tissue softens in response to the injury.

In this study, we investigated whether COL4A3 mRNA expression levels were associated with clinical outcomes after treatment with a combination of gemcitabine (Gem)/ cis -diamminedichloroplatinum(II) (CDDP) regimen for patients with advanced stage non-small cell lung cancer (NSCLC). Response and survival were correlated with the level of COL4A3 expression in 58 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1,250 mg/m 2 on days 1 and 8 plus CDDP 100 mg/m 2 on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of COL4A3/β-actin were measured using a quantitative reverse transcription-PCR (Taqman) system. COL4A3 expression was detectable in all tumors. There were no significant differences in COL4A3 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 45.8 %. There were no significant associations between COL4A3 expression and response. Median overall survival was significantly longer in patients with low COL4A3 expression tumors compared to patients with high expression tumors. COL4A3 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis. These data suggest that COL4A3 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high COL4A3 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for COL4A3 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of COL4A3 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted.

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related small vessel pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, small deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% of ischemic strokes and the vast majority of spontaneous intracerebral hemorrhage and is also the most important vascular contributor to dementia. Despite its high prevalence and potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview of the recent advances in this field. We summarize recent data highlighting the remarkable continuum between monogenic and multifactorial cSVDs involving NOTCH3, HTRA1, and COL4A1/A2 genes. Taking a vessel-centric view, we discuss possible cause-and-effect relationships between risk factors, structural and functional vessel changes, and disease manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction is rightly considered a central feature of cSVD, the contributions of smooth muscle cells, pericytes, and other perivascular cells warrant continued investigation.

The blood–brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non-cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.

Sodium/glucose cotransporter 2 (SGLT2) inhibitors are oral hypoglycemic agents used to treat patients with diabetes mellitus. SGLT2 inhibitors block reabsorption of filtered glucose by inhibiting SGLT2, the primary glucose transporter in the proximal tubular cell (PTC), leading to glycosuria and lowering of serum glucose. We examined the renoprotective effects of the SGLT2 inhibitor empagliflozin to determine whether blocking glucose entry into the kidney PTCs reduced the inflammatory and fibrotic responses of the cell to high glucose. We used an in vitro model of human PTCs. HK2 cells (human kidney PTC line) were exposed to control 5 mM, high glucose (HG) 30 mM or the profibrotic cytokine transforming growth factor beta (TGFβ1; 0.5 ng/ml) in the presence and absence of empagliflozin for up to 72 h. SGLT1 and 2 expression and various inflammatory/fibrotic markers were assessed. A chromatin immunoprecipitation assay was used to determine the binding of phosphorylated smad3 to the promoter region of the SGLT2 gene. Our data showed that TGFβ1 but not HG increased SGLT2 expression and this occurred via phosphorylated smad3. HG induced expression of Toll-like receptor-4, increased nuclear deoxyribonucleic acid binding for nuclear factor kappa B (NF-κB) and activator protein 1, induced collagen IV expression as well as interleukin-6 secretion all of which were attenuated with empagliflozin. Empagliflozin did not reduce high mobility group box protein 1 induced NF-κB suggesting that its effect is specifically related to a reduction in glycotoxicity. SGLT1 and GLUT2 expression was not significantly altered with HG or empagliflozin. In conclusion, empagliflozin reduces HG induced inflammatory and fibrotic markers by blocking glucose transport and did not induce a compensatory increase in SGLT1/GLUT2 expression. Although HG itself does not regulate SGLT2 expression in our model, TGFβ increases SGLT2 expression through phosphorylated smad3.

Epithelial-mesenchymal transition (EMT) contributes significantly to interstitial matrix deposition in diabetic kidney disease (DKD). However, detection of EMT in kidney tissue is impracticable, and anti-EMT therapies have long been hindered. We reported that phosphatase and tensin homolog (PTEN) promoted transforming growth factor beta 1 (TGF-β), sonic hedgehog (SHH), connective tissue growth factor (CTGF), interleukin 6 (IL-6), and hyperglycemia-induced EMT when PTEN was modified by a MEX3C-catalyzed K27-linked polyubiquitination at lysine 80 (referred to as PTENK27-polyUb). Genetic inhibition of PTENK27-polyUb alleviated Col4a3 knockout-, folic acid-, and streptozotocin-induced (STZ-induced) kidney injury. Serum and urine PTENK27-polyUb concentrations were negatively correlated with glomerular filtration rate (GFR) for diabetic patients. Mechanistically, PTENK27-polyUb facilitated dephosphorylation and protein stabilization of TWIST, SNAI1, and YAP in renal epithelial cells, leading to enhanced EMT. We identified that a small molecule, triptolide, inhibited MEX3C-catalyzed PTENK27-polyUb and EMT of renal epithelial cells. Treatment with triptolide reduced TWIST, SNAI1, and YAP concurrently and improved kidney health in Col4a3 knockout-, folic acid-injured disease models and STZ-induced, BTBR ob/ob diabetic nephropathy models. Hence, we demonstrated the important role of PTENK27-polyUb in DKD and a promising therapeutic strategy that inhibited the progression of DKD.

Bromine and peroxidasin (an extracellular peroxidase) are essential for generating sulfilimine cross-links between a methionine and a hydroxylysine within collagen IV, a basement membrane protein. The sulfilimine cross-links increase the structural integrity of basement membranes. The formation of sulfilimine cross-links depends on the ability of peroxidasin to use bromide and hydrogen peroxide substrates to produce hypobromous acid (HOBr). Once a sulfilimine cross-link is created, bromide is released into the extracellular space and becomes available for reutilization. Whether the HOBr generated by peroxidasin is used very selectively for creating sulfilimine cross-links or whether it also causes oxidative damage to bystander molecules (e.g., generating bromotyrosine residues in basement membrane proteins) is unclear. To examine this issue, we used nanoscale secondary ion mass spectrometry (NanoSIMS) imaging to define the distribution of bromine in mammalian tissues. We observed striking enrichment of bromine (79Br, 81Br) in basement membranes of normal human and mouse kidneys. In peroxidasin knockout mice, bromine enrichment of basement membranes of kidneys was reduced by ∼85%. Proteomic studies revealed bromination of tyrosine-1485 in the NC1 domain of α2 collagen IV from kidneys of wild-type mice; the same tyrosine was brominated in collagen IV from human kidney. Bromination of tyrosine-1485 was reduced by >90% in kidneys of peroxidasin knockout mice. Thus, in addition to promoting sulfilimine cross-links in collagen IV, peroxidasin can also brominate a bystander tyrosine. Also, the fact that bromine enrichment is largely confined to basement membranes implies that peroxidasin activity is largely restricted to basement membranes in mammalian tissues.

Alport syndrome is caused by variants in COL4A3 , COL4A4 , or COL4A5 , which encode the α3α4α5 chains of type IV collagen. These variants result in defects in the glomerular basement membrane (GBM) and impaired kidney function. Nonsense variants result in truncated proteins lacking the NC1 domain, thereby preventing proper GBM assembly and function and causing the most severe forms of the disease. Restoring full-length protein expression represents a potential therapeutic strategy for Alport syndrome and related disorders. Anticodon-edited transfer RNAs (ACE-tRNAs), which promote premature termination codon (PTC) readthrough, have shown promise in diseases such as cystic fibrosis, but their application in Alport syndrome remains unexplored. To assess the potential of ACE-tRNAs for PTC readthrough of COL4A5 nonsense variants, we employed a C-terminal NanoLuc-fused COL4A5 reporter system in which luminescence is produced only upon full-length protein translation. We introduced ACE-tRNAs into HeLa and 293T cells expressing one of four COL4A5 nonsense variants ( S36X, R1563X, S1632X, and R1683X ) identified in patients with X-linked Alport syndrome. Readthrough efficiency was evaluated via NanoLuc luminescence and western blotting. Furthermore, we assessed the efficiency of ACE-tRNA-restored α3α4α5 heterotrimer formation using a split NanoLuc-based assay. Our results show that application of ACE-tRNAs led to restored C-terminal luminescence across all four COL4A5 nonsense variants, indicating successful readthrough and full-length translation. Moreover, the restored COL4A5 proteins formed α3α4α5 heterotrimers. These findings support ACE-tRNA-mediated nonsense suppression as a promising therapeutic strategy for Alport syndrome, with the potential to restore GBM integrity in patients harboring nonsense variants.