Transforming Growth Factor Research Articles

ULK1 methylation promotes TGF-β1-induced endometrial fibrosis via the FOXP1/DNMT1 axis.

Intrauterine adhesion (IUA) is the second most common cause of secondary infertility in women and can also lead to menstrual abnormalities and multiple adverse pregnancy outcomes. Therefore, elucidating the mechanism of its development is crucial for the prevention and treatment of IUA. This study will investigate the function and mechanism of forkhead box P1 (FOXP1)/DNA methyltransferase 1 (DNMT1)/unc-51-like autophagy activating kinase 1 (ULK1) in IUA. Expression levels of key genes were detected using western blot and quantitative - real time reverse transcription polymerase chain reaction. Cell proliferation was detected by CCK-8 and EdU staining. Transcriptional regulation relationships were detected by dual luciferase reporter gene and chromatin immunoprecipitation (ChIP) assay. Methylation station of ULK1 was detected by methylmion specific PCR (MSP). Fibrosis and pathological changes in the uterine cavity tissues were detected by Masson and hematoxylin and eosin staining. It was observed that the expression of FOXP1 and DNMT1 increased in transforming growth factor (TGF)-β1-induced cells, while ULK1 expression decreased. Downregulation of FOXP1 could inhibit human endometrial stromal cells proliferation and autophagy, as well as decrease the expression of fibrogenic factors (collagen type I alpha 1 chain [COL1A1], fibronectin [FN], and alpha-smooth muscle actin [α-SMA]). The results of MSP and ChIP experiments showed that DNMT1 promotes methylation of the ULK1 promoter region and inhibits its transcription. In an animal model, knockdown of FOXP1 alleviated pathological fibrosis and uterine adhesions. Knockdown of FOXP1 can inhibit endometrial fibrosis in IUA rats; FOXP1 could be a potential target for the treatment of IUA.

Effect of Prednisolone on Clinical and Cytokine mRNA Profiling in Complex Regional Pain Syndrome.

The cardinal clinical features of complex regional pain syndrome type I (CRPS-I) are pain, edema, autonomic changes, and limitation of motoric movement, which may indicate the role of inflammation and cytokines. We report the effect of prednisolone on the clinical severity and mRNA profiling of proinflammatory (tumor necrosis factor (TNF)-α and interleukin (IL)-2) and anti-inflammatory cytokines (IL-10 and transforming growth factor (TGF)-β) in the patient with CRPS-I. Thirty-nine patients with CRPS-I of shoulder joint were enrolled. Their CRPS, Visual Analog Scale (VAS) and Daily Sleep Interference Scale (DSIS) scores were recorded. TNF-α, IL-2, IL-10, and TGF-β gene expressions at mRNA of whole blood were measured by reverse transcriptase polymerase chain reaction. Patients were randomized to prednisolone 20mg or 40mg using 1: 1 randomization. The primary outcome was change in VAS score, and secondary outcomes were change in CRPS and DSIS scores at 1month. Side effects were noted. The patients had increased expressions of TNF-α (p < 0.001) and IL-2 (p < 0.001) and reduced IL-10 (p < 0.01) mRNA compared to the healthy controls. The baseline characteristics were matched between the two treatment arms. At 1month, CRPS, VAS, and DSIS scores improved significantly compared to baseline, which paralleled with improvement in IL-10 (p < 0.032) and reduction in TNF-α (p = 0.046). The improvement in clinical and biomarkers was similar in prednisolone 20mg and 40mg arms. None had to be withdrawn due to severe side effects. Future study in larger cohort may validate these findings.

Profiling Pro-Inflammatory Proteases as Biomolecular Signatures of Material-Induced Subcutaneous Host Response in Immuno-Competent Mice.

Proteases are important modulators of inflammation, but they remain understudied in material-induced immune response, which is critical to clinical success of biomedical implants. Herein, molecular expression and proteolytic activity of three distinct proteases, namely neutrophil elastase, matrix metalloproteinases, cysteine cathepsins (cathepsin-K and cathepsin-B) are comprehensively profiled, in the subcutaneous host response of immuno-competent mice against different biomaterial implants. Quantitative non-invasive monitoring with activatable fluorescent probes reveals that different microparticulate materials induce distinct levels of protease activity with degradable poly(lactic-co-glycolic) acid inducing the strongest signal compared to nondegradable materials such as polystyrene and silica oxide. Furthermore, protein expression of selected proteases, attributable to both their inactive and active forms, notably deviates from their activities associated only with their active forms. Protease activity exhibits positive correlations with protein expression of pro-inflammatory cytokines tumor necrosis factor α and interleukin 6 but negative correlation with pro-fibrotic cytokine transforming growth factor β1. This study also demonstrates the predictive utility of protease activity as a non-invasive, pro-inflammatory parameter for evaluation of the anti-inflammatory effects of model bioactive compounds on material-induced host response. Overall, the findings provide new insights into protease presence in material-induced immune responses, facilitating future biomaterial assessment to evoke appropriate host responses for implant applications.

BMP-9 mediates fibroproliferation in fibrodysplasia ossificans progressiva through TGF-β signaling.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder presenting with progressive heterotopic ossification (HO) in soft tissues. Early-stage FOP is characterized by recurrent episodes of painful tissue swelling (flare-ups), with numerous proliferation-activated mesenchymal stromal cells (MSCs) subsequently causing HO. However, the mechanisms underlying flare-up progression remain unclear. In this study, we evaluated the proliferation of MSCs obtained from FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) to elucidate the mechanisms underlying flare-ups and found that bone morphogenetic protein (BMP)-9 mediated enhanced proliferation by abnormal activation of transforming growth factor (TGF)-β signaling pathway in MSCs from FOP-iPSCs. In FOP model mice, elevated BMP-9 levels correlated with elevated phosphorylation of SMAD2/3 and increased cellular proliferation in the affected tissues, while systemic BMP-9 neutralization and knockout mitigated flare-ups and HO. Thus, BMP-9 aberrantly transduces TGF-β signaling and induces fibroproliferation, initiating flare-ups. This study provides novel insights into the development of future FOP therapies.

RNA-seq analysis of the biological process and regulatory signal of TGF-β1-mediated changes in ovarian granulosa cells in small-tail Han sheep

Transforming growth factor beta-1 (TGF-β1) regulates the proliferation of ovarian granulosa cells and participates in follicular development in small-tail Han sheep via the SMAD pathway. However, which additional biological processes and regulatory mechanisms are involved in TGF-β1-mediated regulation of granulosa cell changes remains unknown. In this study, TGF-β1-treated (10 ng/mL) ovarian granulosa cells of small-tail Han sheep were used as the model, RNA-Seq was employed to screen differentially expressed genes (DEGs), and rescue experiments were used to verify selected key pathways. In total, 1179 upregulated and 873 downregulated DEGs were screened using RNA-Seq. Gene Ontology (GO) enrichment analysis showed that the DEGs were mainly involved in the biological processes of cell adhesion, cell migration, cell cycle, cell proliferation and apoptosis, and endocrine regulation. Meanwhile, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the DEGs were primarily associated with pathways relating to ECM-receptor interaction, PI3K-AKT, focal adhesion, MAPK, TNF, and FOXO signaling, among others. The addition of doramapimod confirmed that the p38 pathway participates in the TGF-β1-induced proliferation and apoptosis of ovarian granulosa cells as well as the regulation of steroid hormone secretion. These results revealed a novel TGF-β1/p38 pathway-mediated mechanism that induces both the proliferation and apoptosis of ovarian granulosa cells. Our findings provide a basis for better understanding the genetic mechanism of TGF-β1 action in follicle development.

Cycling alpha cells in regenerative drug-treated human pancreatic islets may serve as key beta cell progenitors.

Diabetes results from an inadequate number of insulin-producing human beta cells. There is currently no clinically available effective means to restore beta cell mass in millions of people with diabetes. Although the DYRK1A inhibitors, either alone or in combination with GLP-1 receptor agonists (GLP-1) or transforming growth factor β (TGF-β) superfamily inhibitors (LY), induce beta cell replication and increase beta cell mass, the precise mechanisms of action remain elusive. Here we perform single-cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone or with GLP-1 or LY. We identify cycling alpha cells as the most responsive cells to DYRK1A inhibition. Lineage trajectory analyses suggest that cycling alpha cells may serve as precursor cells that transdifferentiate into beta cells. Collectively, in addition to enhancing expression of beta cell phenotypic genes in beta cells, our findings suggest that regenerative drugs may be targeting cycling alpha cells in human islets.

Association of ambient ozone exposure with early cardiovascular damage among general urban adults: A repeated-measures cohort study in China

Longitudinal evidence of long-term ozone exposure on heart rate variability (HRV, an early indicator of cardiovascular damage) is lacking and the potential mechanism remains largely unclear. Our objectives were to evaluate the cross-sectional and longitudinal associations of ozone exposure with HRV alteration, and the potential roles of protein carbonyl (PC, biomarker of oxidative protein damage) and transforming growth factor (TGF)-β1 in this association. This repeated-measures prospective study included 4138 participants with 6617 observations from the Wuhan-Zhuhai cohort. Ozone concentrations were estimated using a high temporospatial resolution model for each participant. HRV indices, PC, and TGF-β1 were also repeatedly measured. Cross-sectional and longitudinal relationships of ozone exposure with HRV alteration were evaluated by linear mixed model. Cross-sectionally, the strongest lag effect of each 10 ppb increment in short-term ozone exposure showed a 12.40 %, 8.47 %, 4.31 %, 8.03 %, 3.69 %, and 2.41 % decrement on very low frequency (VLF, lag 3 weeks), LF (lag 2 weeks), high frequency (HF, lag 0–7 days), total power (TP, lag 2 weeks), standard deviation of all normal-to-normal intervals (SDNN, lag 3 weeks), and square root of the mean squared difference between adjacent normal-to-normal intervals (lag 2 weeks), respectively. Longitudinally, each 10 ppb increment of annual average ozone was related with an annual change rate of −0.024 ms2/year in VLF, −0.009 ms2/year in LF, −0.013 ms2/year in HF, −0.014 ms2/year in TP, and −0.004 ms/year in SDNN. Mediation analyses indicated that PC mediated 20.77 % and 12.18 % of ozone-associated VLF and TP decline, respectively; TGF-β1 mediated 16.87 % and 27.78 % of ozone-associated VLF and SDNN reduction, respectively. Our study demonstrated that ozone exposure was cross-sectionally and longitudinally related with HRV decline in general Chinese urban adults, and oxidative protein damage and increased TGF-β1 partly mediated ozone exposure-related HRV reduction.

Fabrication of a transforming growth factor β1 functionalized silk sericin hydrogel through genetical engineering to repair alveolar bone defects in rabbit

Cleft palate is one of the most prevalent congenital craniofacial birth defects in human congenital facial anomaly. Severe cleft palate is usually accompanied by alveolar bone defects (ABDs). Growth factors (GFs) are considered as desirable opportunity to promote the craniofacial healing post the surgery. However, limited resource, susceptibility to degradation, and lack of appropriate delivery systems greatly hinder the clinic application of GFs in the ABDs repair. In this study, a transforming growth factor β1 variant (eTGF-β1) with enhanced extracellular matrix (ECM) binding efficiency was engineered to generate transgenic silkworm using the silk gland biosynthesizing system for cost effective and massive bio-synthesis of the eTGF-β1 functionalized silk fibers. The eTGF-β1 achieved a highly-efficient expression in the middle silk gland (MSG) cells of transgenic silkworm, and secretion and distribution in the sericin layer of silk fiber which accounted for approximately 5.57±0.72% of the cocoon shell weight. The eTGF-β1 functionalized silk sericin hydrogel (eTGF-β1 SH) was then fabricated with excellent mechanical and processing properties, injectability, biocompatibility, biodegradability, sustained release of eTGF-β1, and capability to promote cell proliferation, which significantly accelerated the bone defect repair particularly the osteoblast maturation and new bone formation through regulating the expressions of the bone formation-related genes in a rabbit alveolar process cleft model. This study provides a valuable strategy for future the treatments of ABDs in rabbit with cleft palate using the genetically engineered eTGF-β1 silk sericin hydrogel.

Menaquinone-7 and its therapeutic potential in type 2 diabetes mellitus based on a Zucker diabetic fatty rat model

BackgroundType 2 diabetes mellitus (T2DM) is marked by insulin resistance, low grade chronic inflammation, and endothelial dysfunction. Vitamin K2, especially menaquinone-7 (MK-7), might delay T2DM progression and alleviate its consequences. Hence, this study evaluated the effects of MK-7 on serum and urine markers of diabetes in an animal model of T2DM. MethodsHetero- (fa/+, control) and homozygous (fa/fa, diabetic) male Zucker diabetic fatty (ZDF) rats were supplemented or not with MK-7 for 12 weeks. After euthanasia, vitamin K1, menaquinone-4 and MK-7 serum concentrations were analyzed via reversed phase high pressure liquid chromatography. Glucose (serum), fructosamine (serum) and creatinine (serum and urine) levels were assessed photometrically, serum cystatin C and urinary total protein were turbidimetrically determined. Serum transforming growth factor beta1 (TGF-β1) and procollagen type III N-terminal peptide (PIIINP) were quantified with enzyme-linked immunosorbent assay. Urinary marker proteins were analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Nephropathy was assessed histologically. ResultsSupplementation led to significantly elevated MK-7 serum levels and a significant reduction of PIIINP serum levels in both hetero- and homozygous ZDF rats. Additionally, not statistically significant reductions of TGF-β1 serum levels, proteinuria as well as the nephropathy score were observed. In vivo body mass, serum fructosamine, glucose, cystatin C and creatinine levels were unaffected. ConclusionMK-7 reduced serum markers of fibrosis, histological features of nephropathy and urinary protein excretion, but failed to affect serum markers of T2DM. The therapeutic potential of MK-7 in T2DM and its mode of action should be further investigated in more detail.

Farrerol suppresses epithelial-mesenchymal transition in hepatocellular carcinoma via suppression of TGF-β1/Smad2/3 signaling

BackgroundEpithelial-mesenchymal transition (EMT) is an essential process for the metastasis of multiple malignancies, including hepatocellular carcinoma (HCC). Farrerol is a plant-derived flavonoid and has significant pharmacological effects. However, the anticancer activities of farrerol have not been fully elucidated. Here, we investigated the effects of farrerol on HCC progression. MethodsThe potential of farrerol to prevent HCC cell migration and invasiveness was evaluated by wound healing and transwll matrix assays. Immunoblotting, immunofluorescence, and qPCR were used to detect the levels of EMT-related proteins. Transforming growth factor beta (TGF-β) (10ng/ml) was used to stimulate HCC cells, followed by measurement of cell migration, invasiveness, and the EMT. TGF-β1/Smads signaling was examined by immunoblotting. A xenograft mouse model was used to assess the anticancer efficacy of farrerol in vivo. The expression levels of EMT- and angiogenesis-related proteins in xenograft tumors were evaluated by immunoblotting or immunohistochemistry. ResultsWe found that farrerol blocked HCC cell migration and invasiveness. Farrerol upregulated E-cadherin levels and reduced N-cadherin and vimentin levels. Farrerol also downreuglated the expression levels of EMT-related transcription factors including slug, snail, twist, and zeb1. Furthermore, farrerol suppressed TGF-β-stimulated migration, invasiveness, and the EMT in HCC cells. The phosphorylation of Smad 2/3 induced by TGF-β was inhibited by farrerol. Importantly, farrerol suppressed HCC growth and the EMT in vivo. Farrerol also inhibited tumor angiogenesis by inhibiting hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in vivo. ConclusionOverall, farrerol suppresss HCC by inhibiting migration, invasiveness, the EMT, and angiogenesis, implying that farrerol could be a promising antimetastasis agent for HCC.

Therapeutic potential of agents targeting cannabinoid type 2 receptors in organ fibrosis.

The endocannabinoid system has garnered attention as a potential therapeutic target in a range of pathological disorders. Cannabinoid receptors type 2 (CB2) are a class of G protein-coupled receptors responsible for transmitting intracellular signals triggered by both endogenous and exogenous cannabinoids, including those derived from plants (phytocannabinoids) or manufactured synthetically (synthetic cannabinoids). Recent recognition of the role of CB2 receptors in fibrosis has fueled interest in therapeutic targeting of CB2 receptors in fibrosis. Fibrosis is characterized by the alteration of the typical cellular composition within the tissue parenchyma, resulting from exposure to diverse etiological factors. The pivotal function of CB2 agonists has been widely recognized in the regulation of inflammation, fibrogenesis, and various other biological pathologies. The modulation of CB2 receptors, whether by enhancing their expression or activating their function, has the potential to provide benefits in numerous conditions, particularly by avoiding any associated adverse effects on the central nervous system. The sufficient activation of CB2 receptors resulted in the complete suppression of gene expression related to transforming growth factor β1 and its subsequent fibrogenic response. Multiple reports have also indicated the diverse functions that CB2 agonists possess in mitigating chronic inflammation and subsequent fibrosis development in various types of tissues. While currently in the preclinical stage, the advancement of CB2 compounds has garnered significant attention within the realm of drug discovery. This review presents a comprehensive synthesis of various independent experimental studies elucidating the pivotal role of identified natural and synthetic CB2 agonists in the pathophysiology of organ fibrosis, specifically in the cardiac, hepatic, and renal systems.

3D confinement alters smooth muscle cell responses to chemical and mechanical cues.

Smooth muscle cell (SMC) phenotypic switching is a hallmark of many vascular diseases. Although prior work has established that chemical and mechanical cues contribute to SMC phenotypic switching, the impact of three-dimensional (3D) confinement on this process remains elusive. Yet, in vivo, arterial SMCs reside within confined environments. In this study, we designed a microfluidic assay to investigate the interplay between 3D confinement and different environmental stimuli in SMC function. Our results show that tightly, but not moderately, confined SMCs acquire a contractile phenotype when exposed to collagen I. Elevated compressive forces induced by hydrostatic pressure abolish this upregulation of the contractile phenotype and compromise SMC survival, particularly in tightly confined spaces. Transforming growth factor beta 1, which promotes the contractile state in moderate confinement, fails to enhance the contractility of tightly confined cells. Fibronectin and engagement of cadherin 2 suppress the contractile phenotype of SMCs regardless of the degree of confinement. In contrast, homophilic engagement of cadherin 11 upregulates SMC-specific genes and enhances contractility in both moderately and tightly confined cells. Overall, our work introduces 3D confinement as a regulator of SMC phenotypic responses to chemical and mechanical signals.

The role of the molecular pathway of transforming growth factor β in the progression of myocardial fibrosis

To date, the consequences of progressive myocardial fibrosis are an urgent problem. Fibrosis is the basis for the progression of many cardiovascular diseases and leads to structural remodeling of the myocardium. Fibrosis isolates groups of cardiomyocytes and individual cells, disrupts the connection between them, which causes rhythm disturbances, including the development of atrial fibrillation. Fibrosis is the result of pathological remodeling in many tissues and contributes to the development of clinical diseases. At the moment, it is of great interest to identify means of slowing down and stopping the progression of tissue fibrogenesis. The progression of myocardial fibrosis is based on mechanisms that are associated with both cellular and molecular pathways. The main cellular element is an activated fibroblast, which produces a large amount of extracellular matrix. One of the main molecular mechanisms are transforming growth factor β, platelet-derived growth factor, connective tissue growth factor, vasoactive compounds (angiotensin II), cytokine-induced extracellular matrix pathways. It is these elements of the pathogenesis of the disease that can become the objects of new therapeutic interventions. This review article will present data on the prevalence and frequency of visits to medical institutions on issues related to developed gastric arrhythmias against the background of interstitial fibrosis, on the molecular processes involved in the initiation of myocardial fibrosis, as well as on non-coding RNAs regulating specific cellular signals, and on the studied therapeutic drugs inhibiting the transforming growth factor β signaling pathway. Generalized and structured information will help expand the understanding of molecular processes and, in the future, change approaches to the treatment of many heart diseases.

Paraoxonase-1 Is a Pivotal Regulator Responsible for Suppressing Allergic Airway Inflammation Through Adipose Stem Cell-Derived Extracellular Vesicles

Although adipose stem cell (ASC)-derived extracellular vesicles (EVs) are as effective as ASCs in the suppression of Th2 cell-mediated eosinophilic inflammation, the role of identified pulmonary genes has not been well documented. Thus, we assessed the immunomodulatory effects of paraoxonase-1 (PON1) on allergic airway inflammation in a mouse model of asthma. Five-week-old female C57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection and challenged intranasally with OVA. To evaluate the effect of PON1 on allergic airway inflammation, the intranasal and intraperitoneal injections of recombinant mouse serum PON1 (5 μg/50 μL) were performed before the OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, and eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), cytokine profiles of BALF and lung draining lymph nodes (LLNs), the expression of interleukin (IL)-25 and transforming growth factor (TGF)-β in mouse lung epithelial cell (MLE-12 cell), and dendritic cell (DC) differentiation. The intraperitoneal and intranasal administration of PON1 significantly decreased AHR, total inflammatory cells and eosinophils in BALF, eosinophilic airway inflammation, serum total, and OVA-specific IgE. PON1 treatment, which marked reduced IL-4, IL-5, and IL-13 in the BALF and LLN but significantly increased interferon-γ and TGF-β. Furthermore, PON1 treatment significantly decreased the expression of IL-25 and increased TGF-β in MLE-12 cells. The expressions of CD40, CD80, and CD86 in immature DCs were significantly increased by PON1 treatment. The administration of PON1 ameliorated allergic airway inflammation and improved AHR through the downregulation of IL-4, IL-5, and IL-13 and upregulation of TGF-β in asthmatic mice. Furthermore, PON1 treatment decreased Th2-mediated inflammation induced by Aspergillus protease antigen by decreasing IL-25 and increasing TGF-β.

Photoaging Protective Effects of Quercitrin Isolated from ‘Green Ball’ Apple Peel

Premature skin aging, also known as photoaging, refers to the changes in the structure and function of the skin caused by chronic sun exposure. The ultraviolet radiation in sunlight is one of the key factors that cause photoaging. Thus, matrix metalloproteinases (MMPs), transforming growth factor beta-1 (TGFB1), and nuclear factor kappa B (NF-κB) signaling can be an effective therapeutic strategy for ultraviolet B (UVB) exposure. In this study, we used human dermal fibroblast and mouse macrophage cells to identify the mediators of skin photoaging. Quercitrin isolated from ‘Green Ball’ apple peel was treated to UVB-irradiated fibroblast cells and lipopolysaccharide (LPS)-induced macrophages to identify the photoaging prevention effect of quercitrin. Genes that are associated with photoaging were determined by using enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative polymerase chain reaction (qPCR). Quercitrin increased the collagen biosynthesis in UVB-irradiated fibroblast cells via regulating MMPs, TIMP metallopeptidase inhibitor 1 (TIMP-1), TGFB1, hyaluronan synthase 2 (HAS2), and collagen type I alpha 1 chain (COL1A2). In addition, quercitrin regulated p-65, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), and its mediators (prostaglandin E2 and nitric oxide), in the NF-κB signaling process, and it inhibited the production of cytokines in LPS-induced macrophages. These results indicate that quercitrin can improve photoaging damaged skin by regulating MMPs, TGFB1, and NF-κB signaling pathway modulators.

Urinary transforming growth factor beta-1 levels correlate with the effect of renorrhaphy on functional outcomes post-laparoscopic partial nephrectomy: A pilot-study

ABSTRACT Purpose Preservation of functional renal parenchyma is one of the main targets of partial nephrectomy. We investigated the effects of suture on renal parenchyma in tumor bed and on short-term renal function. Materials and Methods Patients with unilateral cT1 renal masses candidate for laparoscopic partial nephrectomy (PN) have been recruited. After tumor excision, medullary sutures were replaced by argon beam in Group 1, while Group 2 had conventional 2-layer renorrhaphy. Groups have been matched using propensity score. Transforming growth factor beta-1 (TGFb1) levels in urine have been measured at the 1st and 30th day post-PN. Glomerular filtration rate has been estimated (eGFR) at baseline and 3 months post-PN. Results Sixteen cases were matched in each group. There was no difference between groups regarding baseline, operative and perioperative data. Number of sutures in group 1 is nearly half that in group 2 (10 vs 19, respectively, p < 0.001). Group 1 showed lower urinary TGFb1 levels at the 1st and 30th day post-PN (p < 0.01 for each), higher eGFR after 3 months (p = 0.01), and less decline of eGFR from baseline (p = 0.046). Conclusion TGFb1 levels in urine after PN are related to the number of sutures. Reduced number of sutures in tumor bed has a positive effect on short term eGFR changes possibly by reducing tumor bed fibrogenic healing response as well as preserving renal parenchymal volume.

K-line guided approach selection and outcomes assessment for Cervical Ossification of Posterior Longitudinal Ligament (OPLL): A case series with literature review from Pakistan

Objectives: To analyze the efficacy of K-line in surgical planning of approach selection for ossification of posterior longitudinal ligament (OPLL) and outcomes assessment by Nurick grading and Modified Japanese Orthopaedic Association (mJOA) scores. Methods: This is a retrospective case series study conducted at the Departments of Neurosurgery, Punjab Institute of Neurosciences, Lahore in the months of January and February 2024. Patients with complete records were considered. Google Form was used for data. Nurick grading and Modified Japanese Orthopaedic Association (mJOA) scores were calculated for each patient pre- and post-operatively. K-line assessment was done on computerized tomography (CT). Data analysis was performed using Microsoft excel in terms of frequency and percentages. Results: This study included ten patients with the mean age at presentation was 48.20 ± 9.37 years. Preoperative Nurick grading in our patients was Grade-V (five patients), Grade-IV (two patients) and Grade-III (three patients) with mean of 4.2 ± 0.91 SD whereas six months follow-up Nurick grading was Grade-V (three patients), Grade-IV (three patients) and Grade-III (four patients) with the mean of 3.90 ± 0.87 SD, which indicates neurological improvement. Types of OPLL present in our patients were segmental (4, 40%), continuous (3, 30%), mixed (2, 20%) and localized/others (1, 10%). There were 2 (20%) K-line (+) and 8 (80%) K-line (-) cases. Anterior approach was used in 2 (20%) cases whereas posterior approach was used for the rest of 8 (80%) cases. Mean preoperative mJOA was 10.30 ± 2.45 and mean postoperative mJOA was12.40 ± 2.01 at 6-month follow up, which indicates improvement in our cases. Conclusion: K-line is a useful radiological indicator in selecting anterior versus posterior approach for patients with cervical OPLL in terms of Nurick grading and mJOA scores. List of Abbreviations: OPLL: Ossified Posterior Longitudinal Ligament, DISH: Diffuse Idiopathic Skeletal Hyperostosis, CT: Computed Tomography, mJOA: Modified Japanese Orthopaedic Association, BMP: Bone Morphogenetic Protein, TGF-b: Transforming Growth Factor Beta, ACCF: Anterior Cervical Corpectomy and Fusion. doi: https://doi.org/10.12669/pjms.40.12(PINS).11094 How to cite this: Qadri HM, Khan M, Ansari N, Khizar A, Bukhari SFA, Bashir A. K-line guided approach selection and outcomes assessment for Cervical Ossification of Posterior Longitudinal Ligament (OPLL): A case series with literature review from Pakistan. Pak J Med Sci. 2024;40(12):S63-S68. doi: https://doi.org/10.12669/pjms.40.12(PINS).11094 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

Prostaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in moderate-to-severe asthma patients. However, in Phase III, DP2 antagonism failed to lower the rate of exacerbations, and DP2 as a target was shelved. Here, using a preclinical model of chronic experimental asthma, we demonstrate that rhinovirus-induced exacerbations increase PGD2 release, mucus production, transforming growth factor (TGF)-β1 and type-2 inflammation. DP2 antagonism or DP1 agonism ablates these phenotypes, increases epithelial EGF expression and decreases ASM area via increased IFN-γ. In contrast, dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuates endogenous PGD2, prevented ASM resolution. We demonstrate that DP2 antagonism resolves ASM remodelling via PGD2/DP1-mediated upregulation of IFN-γ expression, and that dual DP2 antagonism/corticosteroid therapy, as often occurred in the human trials, impairs the efficacy of DP2 antagonism by suppressing endogenous PGD2 and IFN-γ production.

BAMBI Is a Prognostic Biomarker Associated with Macrophage Polarization, Glycolysis, and Lipid Metabolism in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. Affected patients have poor prognoses due to high rates of post-surgical recurrence and metastasis. Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) reportedly contributes to the development and progression of various human cancers. Thus far, there have been no comprehensive studies regarding the expression of BAMBI in HCC; similarly, no studies have investigated the prognostic significance of BAMBI and its associated mechanisms in HCC. In this study, we analyzed the expression profiles of BAMBI, along with its contributions to pathological findings, metastasis characteristics, and prognosis, in multiple human cancers. We found that upregulation of BAMBI was associated with poor prognosis in HCC. Next, we explored the associations of BAMBI with multiple cell signaling pathways, immune cells, and immune checkpoints in HCC. The results showed that BAMBI was associated with tumor proliferation, epithelial–mesenchymal transition (EMT) markers, glycolysis, fatty acid biosynthesis and degradation pathways, and immune checkpoint regulation in HCC. In vitro and in vivo experiments showed that BAMBI promoted polarization of M1 macrophages and is linked to the expression of key genes involved in glycolipid metabolism. Furthermore, protein–protein interaction analysis suggested that BAMBI plays multiple roles in HCC by regulating genes in the transforming growth factor (TGF)-β and Wnt signaling pathways. Our findings elucidated that BAMBI is a prognostic biomarker and is associated with macrophage polarization, glycolysis, and lipid metabolism in HCC.

Targeting fibroblast phenotype switching in cardiac remodelling as a promising antifibrotic strategy.

Myocardial fibrosis, a common feature of heart disease, remains an unsolved clinical challenge. Fibrosis resolution requires activation of cardiac fibroblasts exhibiting context-dependent beneficial and detrimental dichotomy. Here, we explored the hypothesis of fibroblast reversible transition between quiescence and activated myofibroblastic states as a manifestation of cell phenotypic switching in myocardial remodelling. In support, gene regulatory networks executing conversion of cardiac fibroblasts to myofibroblasts and vice versa in fibrosis resolution are reconstructed using TRANSPATH database. In a scenario of fibroblast activation triggered by transforming growth factor β, a cardinal mediator of tissue fibrosis, signalling cascades governing entry into or exit from specific fibroblast statures in cardiac fibrotic remodelling were dissected. It is suggested that fibroblast phenotypic switching constitutes the central gait toward guiding cell state-gating strategies to counteract adverse cardiac fibrosis, a devastating disorder with no approved therapeutic option.