Stem Cell Growth Factor Research Articles

Exploring therapeutical targets and innovative treatments for ischemic stroke: a comprehensive review

This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors.

Utility of multi-biomarker panel on discriminating disease activity in patients with psoriatic arthritis

ObjectiveTo investigate the correlation of serum protein biomarkers and disease activity in patients with PsA. Methods176 patients fulfilled the CASPAR (ClASsification criteria for Psoriatic ARthritis) were recruited in this cross-sectional study. The level of 48 protein biomarkers, cartilage and bone turn-over markers were assessed. The patients were randomly divided into a derivation-cohort and a validation-cohort at a ratio of 7:3. Patients were further categorized based on their disease activity states using cDAPSA (remission/low disease activity and moderate/high disease activity). Least absolute shrinkage and selection operator (LASSO) was used to select biomarkers which were associated with moderate/high disease activity in the derivation cohort. Receiver operating characteristic (ROC) curve, GiViTI calibration belt were used to assess the performance of the model in both cohorts. ResultsThe cohort [age: 55.5 (44.0–62.75) years, male: 80 (45.5 %)] had moderate disease activity [DAPSA: 15.9 (8.3–26.9); PASI: 3.2 (0.5–6.8)]. 101 PsA patients (57.4 %) had clinical DAPSA moderate/high disease activity. Biomarker levels associated with moderate/high disease activity included SAA (Serum amyloid A), IL-8 (Interleukin 8), IP10 (Interferon gamma-induced protein 10)/CXCL10, M-CSF (Macrophage colony-stimulating factor), SCGF-β (Stem cell growth factor), SDF-1α (Stromal cell-derived factor 1α)/CXCL12. The model’s equation including the 6 biomarker levels was applied to the validation-cohort. The area under the ROC curve (AUC) for discriminating moderate/high disease activity was 0.802 and 0.835 for the derivation-and-validation-cohorts, respectively. The multi-biomarkers panel model had higher-AUC when compared with that of C-reactive protein (CRP) (AUC = 0.727, p = 0.022). The P-values of calibration charts in the two sets were 0.902 and 0.123. ConclusionsThe multi-biomarkers panel demonstrated the ability to discriminate patients with moderate/high disease activity from those with low disease activity/remission.

An "R-spondin code" for multimodal signaling ON-OFF states.

R-spondins (RSPOs) are a family of secreted proteins and stem cell growth factors that are potent co-activators of Wnt signaling. Recently, RSPO2 and RSPO3 were shown to be multifunctional, not only amplifying Wnt- but also binding BMP- and FGF receptors to downregulate signaling. The common mechanism underlying these diverse functions is that RSPO2 and RSPO3 act as "endocytosers" that link transmembrane proteins to ZNRF3/RNF43 E3 ligases and trigger target internalization. Thus, RSPOs are natural protein targeting chimeras for cell surface proteins. Conducting data mining and cell surface binding assays we report additional candidate RSPO targets, including SMO, PTC1,2, LGI1, ROBO4, and PTPR(F/S). We propose that there is an "R-spondin code" that imparts combinatorial signaling ON-OFF states of multiple growth factors. This code involves the modular RSPO domains, notably distinct motifs in the divergent RSPO-TSP1 domains to mediate target interaction and internalization. The RSPO code offers a novel framework for the understanding how diverse signaling pathways may be coordinately regulated in development and disease.

Exploring the impact of inflammatory cytokines on alcoholic liver disease: a Mendelian randomization study with bioinformatics insights into potential biological mechanisms

ABSTRACT Background: Alcoholic liver disease (ALD) significantly contributes to global morbidity and mortality. The role of inflammatory cytokines in alcohol-induced liver injury is pivotal yet not fully elucidated. Objectives: To establish a causal link between inflammatory cytokines and ALD using a Mendelian Randomization (MR) framework. Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between inflammatory cytokines and ALD risk, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, protein-protein interactions (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and analysis of immune cell infiltration. Results: Our findings reveal that increased levels of stem cell growth factor beta (SCGF-β, beta = 0.141, p = .032) and interleukin-7 (IL-7, beta = 0.311, p = .002) are associated with heightened ALD risk, whereas higher levels of macrophage inflammatory protein-1α (MIP-1α, beta = -0.396, p = .004) and basic fibroblast growth factor (bFGF, beta = -0.628, p = .008) are linked to reduced risk. The sensitivity analyses support these robust causal relationships. Bioinformatics analyses around inflammatory cytokine-associated SNP loci suggest multiple pathways through which cytokines influence ALD. Conclusion: The genetic evidence from this study convincingly demonstrates that certain inflammatory cytokines play directional roles in ALD pathogenesis. These findings provide insights into the complex biological pathways involved and underscore the potential for developing targeted therapies that modulate these inflammatory responses, ultimately improving clinical outcomes for ALD patients.

Inflammatory factors and the risk of urolithiasis: a bidirectional Mendelian randomization study.

Urolithiasis is a prevalent condition encountered in urology. Over the past decade, its global incidence has been on an upward trajectory; paired with a high recurrence rate, this presents considerable health and economic burdens. Although inflammatory factors are pivotal in the onset and progression of urolithiasis, their causal linkages remain elusive. Mendelian randomization (MR) is predicated upon genome-wide association studies (GWASs). It integrates bioinformatics analyses to reveal causal relationships between exposures and outcomes, rendering it an effective method with minimized bias. Drawing from a publicly accessible GWAS meta-analysis comprising 8,293 samples, we identified 41 genetic variations associated with inflammatory cytokines as instrumental variables. Outcome data on upper urinary tract stones, which included renal and ureteral stones (9,713 cases and 366,693 controls), and lower urinary tract stones, including bladder and urethral stones (1,398 cases and 366,693 controls), were derived from the FinnGen Consortium R9 dataset. By leveraging the bidirectional MR methodology, we aimed to decipher the causal interplay between inflammatory markers and urolithiasis. Our study comprehensively elucidated the association between genetic inflammatory markers and urolithiasis via bidirectional Mendelian randomization. Post-MR analysis of the 41 genetic inflammation markers revealed that elevated levels of circulating interleukin-2 (IL-2) (OR = 0.921, 95% CI = 0.848-0.999) suggest a reduced risk for renal stone disease, while heightened stem cell growth factor beta (SCGF-β) (OR = 1.150, 95% CI = 1.009-1.310) and diminished macrophage inflammatory protein 1 beta (MIP-1β) (OR = 0.863, 95% CI = 0.779-0.956) levels suggest an augmented risk for lower urinary tract stones. Furthermore, renal stone disease appeared to elevate IL-2 (β = 0.145, 95% CI = 0.013-0.276) and cutaneous T cell-attracting chemokine (CTACK) (β = 0.145, 95% CI = 0.013-0.276) levels in the bloodstream, whereas lower urinary tract stones were linked to a surge in interleukin-5 (IL-5) (β = 0.142, 95% CI = 0.057-0.226), interleukin-7 (IL-7) (β = 0.108, 95% CI = 0.024-0.192), interleukin-8 (IL-8) (β = 0.127, 95% CI = 0.044-0.210), growth regulated oncogene alpha (GRO-α) (β = 0.086, 95% CI = 0.004-0.169), monokine induced by interferon-gamma (MIG) (β = 0.099, 95% CI = 0.008-0.191) and macrophage inflammatory protein 1 alpha (MIP-1α) (β = 0.126, 95% CI = 0.044-0.208) levels. These discoveries intimate the instrumental role of IL-2 in the onset and progression of upper urinary tract stones. SCGF-β and MIP-1β influence the development of lower urinary tract stones. Urolithiasis also impacts the expression of cytokines such as IL-2, CTACK, IL-5, IL-7, IL-8, GRO-α, MIG, and MIP-1α. There is a pressing need for further investigation to ascertain whether these biomarkers can be harnessed to prevent or treat urolithiasis.

A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts.

The Complementary Roles of Neurological and Musculoskeletal Physical Therapy and Regenerative Medicine: A Comprehensive Review.

Regenerative medicine, encompassing various therapeutic approaches aimed at tissue repair and regeneration, has emerged as a promising field in the realm of physical therapy. Aim: This comprehensive review seeks to explore the evolving role of regenerative medicine within the domain of physical therapy, highlighting its potential applications, challenges, and current trends. Researchers selected publications of pertinent studies from 2015 to 2024 and performed an exhaustive review of electronic databases such as PubMed, Embase, and Google Scholar using the targeted keywords "regenerative medicine", "rehabilitation", "tissue repair", and "physical therapy" to screen applicable studies according to preset parameters for eligibility, then compiled key insights from the extracted data. Several regenerative medicine methods that are applied in physical therapy, in particular, stem cell therapy, platelet-rich plasma (PRP), tissue engineering, and growth factor treatments, were analyzed in this research study. The corresponding efficacy of these methods in the recovery process were also elaborated, including a discussion on facilitating tissue repair, alleviating pain, and improving functional restoration. Additionally, this review reports the challenges concerning regenerative therapies, among them the standardization of protocols, safety concerns, and ethical issues. Regenerative medicine bears considerable potential as an adjunctive therapy in physiotherapy, providing new pathways for improving tissue repair and functional results. Although significant strides have been made in interpreting the potential of regenerative techniques, further research is warranted to enhance protocols, establish safety profiles, and increase access and availability. Merging regenerative medicine into the structure of physical therapy indicates a transformative alteration in clinical practice, with the benefit of increasing patient care and improving long-term results.

Investigating the effects of cytokine biomarkers on HIV incidence: a case study for individuals randomized to pre-exposure prophylaxis vs. control.

Understanding and identifying the immunological markers and clinical information linked with HIV acquisition is crucial for effectively implementing Pre-Exposure Prophylaxis (PrEP) to prevent HIV acquisition. Prior analysis on HIV incidence outcomes have predominantly employed proportional hazards (PH) models, adjusting solely for baseline covariates. Therefore, models that integrate cytokine biomarkers, particularly as time-varying covariates, are sorely needed. We built a simple model using the Cox PH to investigate the impact of specific cytokine profiles in predicting the overall HIV incidence. Further, Kaplan-Meier curves were used to compare HIV incidence rates between the treatment and placebo groups while assessing the overall treatment effectiveness. Utilizing stepwise regression, we developed a series of Cox PH models to analyze 48 longitudinally measured cytokine profiles. We considered three kinds of effects in the cytokine profile measurements: average, difference, and time-dependent covariate. These effects were combined with baseline covariates to explore their influence on predictors of HIV incidence. Comparing the predictive performance of the Cox PH models developed using the AIC metric, model 4 (Cox PH model with time-dependent cytokine) outperformed the others. The results indicated that the cytokines, interleukin (IL-2, IL-3, IL-5, IL-10, IL-16, IL-12P70, and IL-17 alpha), stem cell factor (SCF), beta nerve growth factor (B-NGF), tumor necrosis factor alpha (TNF-A), interferon (IFN) alpha-2, serum stem cell growth factor (SCG)-beta, platelet-derived growth factor (PDGF)-BB, granulocyte macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and cutaneous T-cell-attracting chemokine (CTACK) were significantly associated with HIV incidence. Baseline predictors significantly associated with HIV incidence when considering cytokine effects included: age of oldest sex partner, age at enrollment, salary, years with a stable partner, sex partner having any other sex partner, husband's income, other income source, age at debut, years lived in Durban, and sex in the last 30 days. Overall, the inclusion of cytokine effects enhanced the predictive performance of the models, and the PrEP group exhibited reduced HIV incidences compared to the placebo group.

A Mendelian randomization study investigating the causal relationships between inflammation and immunoglobulin A nephropathy

BackgroundImmunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by the production of galactose‑deficient IgA1 (Gd‑IgA1) and the deposition of immune complexes in the kidney. Exploring the landscape of immune dysregulation in IgAN is valuable for pathogenesis and disease treatment. We conducted Mendelian randomization (MR) to assess the causal correlations between inflammation and IgAN. MethodsBased on available genetic datasets, we investigated potential causal links between inflammation and the risk of IgAN using two-sample MR. We used genome-wide association study (GWAS) summary statistics of 5 typical inflammation markers, 41 inflammatory cytokines, and 731 immune cell signatures, accessed from the public GWAS Catalog. The primary method employed for MR analysis was Inverse Variance Weighted (IVW). To confirm consistency across results, four supplementary MR methods were also conducted: MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. To assess pleiotropy, we used the MR-Egger regression intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Cochrane’s Q statistic was applied to evaluate heterogeneity. Additionally, the stability of the MR findings was verified through the leave-one-out sensitivity analysis. ResultsThis study revealed that interleukin-7 (IL-7) and stem cell growth factor beta (SCGF-β) were possibly associated with the risk of IgAN according to the IVW approach, with estimated odds ratios (OR) of 1.059 (95 % confidence interval [CI] 1.015 to 1.104, P = 0.008) and 1.043 (95 % CI 1.002 to 1.085, P = 0.037). Five immune traits were identified that might be linked to IgAN risk, each with P-values below 0.01, including natural killer T %T cell (OR = 1.058, 95 % CI: 1.020 to 1.097, P = 0.002), natural killer T %lymphocyte (OR = 1.055, 95 % CI: 1.016 to 1.096, P = 0.006), CD25++ CD8+ T cell %T cell (OR = 1.057, 95 % CI: 1.016 to 1.099, P = 0.006), CD3 on effector memory CD4+ T cell (OR = 1.045, 95 % CI: 1.019 to 1.071, P = 0.001), and CD3 on CD28+ CD45RA+ CD8+ T cell (OR = 1.042, 95 % CI: 1.016 to 1.068, P = 0.001). CD4 on central memory CD4+ T cell might be a protective factor for IgAN (OR = 0.922, 95 % CI: 0.875 to 0.971, P = 0.002). Moreover, IgAN may be implicated in a high risk of elevated granulocyte colony-stimulating factor (G-CSF) (OR = 1.114, 95 % CI 1.002 to 1.239, P = 0.046). ConclusionOur study revealed exposures among typical inflammation markers, inflammatory cytokines, and immune cell signatures that may potentially linked to IgAN risk by MR analysis. This insight may advance our understanding of the etiology of IgAN and support the development of targeted therapeutic strategies.

Knockdown the moyamoya disease susceptibility gene, RNF213, upregulates the expression of basic fibroblast growth factor and matrix metalloproteinase-9 in bone marrow derived mesenchymal stem cells.

Moyamoya disease (MMD) is a chronic, progressive cerebrovascular occlusive disease. Ring finger protein 213 (RNF213) is a susceptibility gene of MMD. Previous studies have shown that the expression levels of angiogenic factors increase in MMD patients, but the relationship between the susceptibility gene RNF213 and these angiogenic mediators is still unclear. The aim of the present study was to investigate the pathogenesis of MMD by examining the effect of RNF213 gene knockdown on the expression of matrix metalloproteinase-9 (MMP-9) and basic fibroblast growth factor (bFGF) in rat bone marrow-derived mesenchymal stem cells (rBMSCs). Firstly, 40 patients with MMD and 40 age-matched normal individuals (as the control group) were enrolled in the present study to detect the levels of MMP-9 and bFGF in serum by ELISA. Secondly, Sprague-Dawley male rat BMSCs were isolated and cultured using the whole bone marrow adhesion method, and subsequent phenotypic analysis was performed by flow cytometry. Alizarin red and oil red O staining methods were used to identify osteogenic and adipogenic differentiation, respectively. Finally, third generation rBMSCs were transfected with lentivirus recombinant plasmid to knockout expression of the RNF213 gene. After successful transfection was confirmed by reverse transcription-quantitative PCR and fluorescence imaging, the expression levels of bFGF and MMP-9 mRNA in rBMSCs and the levels of bFGF and MMP-9 protein in the supernatant of the culture medium were detected on the 7th and 14th days after transfection. There was no significant difference in the relative expression level of bFGF among the three groups on the 7th day. For the relative expression level of MMP-9, there were significant differences on the 7th day and 14th day. In addition, there was no statistically significant difference in the expression of bFGF in the supernatant of the RNF213 shRNA group culture medium, while there was a significant difference in the expression level of MMP-9. The knockdown of the RNF213 gene affects the expression of bFGF and MMP-9. However, further studies are needed to determine how they participate in the pathogenesis of MMD. The findings of the present study provide a theoretical basis for clarifying the pathogenesis and clinical treatment of MMD.

Non-TGFβ profibrotic signaling in ulcerative colitis after in vivo experimental intestinal injury in humans.

Although impaired regeneration is important in many gastrointestinal diseases including ulcerative colitis (UC), the dynamics of mucosal regeneration in humans are poorly investigated. We have developed a model to study these processes in vivo in humans. Epithelial restitution (ER) and extracellular matrix (ECM) regulation after an experimental injury of the sigmoid colonic mucosa was assessed by repeated high-resolution endoscopic imaging, histological assessment, RNA sequencing, deconvolution analysis, and 16S rDNA sequencing of the injury niche microbiome of 19 patients with UC in remission and 20 control subjects. Human ER had a 48-h lag before induction of regenerative epithelial cells [wound-associated epithelial (WAE) and transit amplifying (TA) cells] along with the increase of fibroblast-derived stem cell growth factor gremlin 1 mRNA (GREM1). However, UC deconvolution data showed rapid induction of inflammatory fibroblasts and upregulation of major structural ECM collagen mRNAs along with tissue inhibitor of metalloproteinase 1 (TIMP1), suggesting increased profibrotic ECM deposition. No change was seen in transforming growth factor β (TGFβ) mRNA, whereas the profibrotic cytokines interleukin 13 (IL13) and IL11 were upregulated in UC, suggesting that human postinjury responses could be TGFβ-independent. In conclusion, we found distinct regulatory layers of regeneration in the normal human colon and a potential targetable profibrotic dysregulation in UC that could lead to long-term end-organ failure, i.e., intestinal damage.NEW & NOTEWORTHY The study reveals the regulatory dynamics of epithelial regeneration and extracellular matrix remodeling after experimental injury of the human colon in vivo and shows that human intestinal regeneration is different from data obtained from animals. A lag phase in epithelial restitution is associated with induction of stromal cell-derived epithelial growth factors. Postinjury regeneration is transforming growth factor β-independent, and we find a profibrotic response in patients with ulcerative colitis despite being in remission.

Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial

Morbidity and mortality in pulmonary arterial hypertension (PAH) remain high. Activation of platelet-derived growth factor receptor, colony stimulating factor 1 receptor, and mast or stem cell growth factor receptor kinases stimulates inflammatory, proliferative, and fibrotic pathways driving pulmonary vascular remodelling in PAH. Seralutinib, an inhaled kinase inhibitor, targets these pathways. We aimed to evaluate the efficacy and safety of seralutinib in patients with PAH receiving standard background therapy. The TORREY trial was a phase 2, randomised, multicentre, multinational, double-blind, placebo-controlled study. Patients with PAH from 40 hospital and community sites were randomly assigned 1:1 via interactive response technologies to receive seralutinib (60 mg twice daily for 2 weeks, then increased to 90 mg twice daily as tolerated) or placebo by dry powder inhaler twice daily for 24 weeks. Randomisation was stratified by baseline pulmonary vascular resistance (PVR; <800 dyne·s/cm5 and ≥800 dyne·s/cm5). Patients were eligible if classified as WHO Group 1 PH (PAH), WHO Functional Class II or III, with a PVR of 400 dyne·s/cm5 or more, and a 6 min walk distance of between 150 m and 550 m. The primary endpoint was change in PVR from baseline to 24 weeks. Analyses for efficacy endpoints were conducted in randomly assigned patients (intention-to-treat population). Safety analyses included all patients who received the study drug. TORREY was registered with ClinicalTrials.gov (NCT04456998) and EudraCT (2019-002669-37) and is completed. From Nov 12, 2020, to April 20, 2022, 151 patients were screened for eligibility, and following exclusions, 86 adults receiving PAH background therapy were randomly assigned to seralutinib (n=44; four male, 40 female) or placebo (n=42; four male, 38 female), and comprised the intention-to-treat population. At baseline, treatment groups were balanced except for a higher representation of WHO Functional Class II patients in the seralutinib group. The least squares mean change from baseline to week 24 in PVR was 21·2 dyne·s/cm5 (95% CI -37·4 to 79·8) for the placebo group and -74·9 dyne·s/cm5 (-139·7 to -10·2) for the seralutinib group. The least squares mean difference between the seralutinib and placebo groups for change in PVR was -96·1 dyne·s/cm5 (95% CI -183·5 to -8·8; p=0·03). The most common treatment-emergent adverse event in both treatment groups was cough: 16 (38%) of 42 patients in the placebo group; 19 (43%) of 44 patients in the seralutinib group. Treatment with inhaled seralutinib significantly decreased PVR, meeting the primary endpoint of the study among patients receiving background therapy for PAH. Gossamer Bio.

Effect of coffee, tea and alcohol intake on circulating inflammatory cytokines: a two sample-Mendelian randomization study.

Despite the abundance of research examining the effects of coffee, tea, and alcohol on inflammatory diseases, there is a notable absence of conclusive evidence regarding their direct causal influence on circulating inflammatory cytokines. Previous studies have primarily concentrated on established cytokines, neglecting the potential impact of beverage consumption on lesser-studied but equally important cytokines. Information regarding the consumption of coffee, tea, and alcohol was collected from the UK Biobank, with sample sizes of 428,860, 447,485, and 462,346 individuals, respectively. Data on 41 inflammatory cytokines were obtained from summary statistics of 8293 healthy participants from Finnish cohorts. The consumption of coffee was found to be potentially associated with decreased levels of Macrophage colony-stimulating factor (β = -0.57, 95% CI -1.06 ~ -0.08; p = 0.022) and Stem cell growth factor beta (β = -0.64, 95% CI -1.16 ~ -0.12; p = 0.016), as well as an increase in TNF-related apoptosis-inducing ligand (β = 0.43, 95% CI 0.06 ~ 0.8; p = 0.023) levels. Conversely, tea intake was potentially correlated with a reduction in Interleukin-8 (β = -0.45, 95% CI -0.9 ~ 0; p = 0.045) levels. Moreover, our results indicated an association between alcohol consumption and decreased levels of Regulated on Activation, Normal T Cell Expressed and Secreted (β = -0.24, 95% CI -0.48 ~ 0; p = 0.047), as well as an increase in Stem cell factor (β = 0.17, 95% CI 0.02 ~ 0.31; p = 0.023) and Stromal cell-derived factor-1 alpha (β = 0.20, 95% CI 0.04 ~ 0.36; p = 0.013). Revealing the interactions between beverage consumption and various inflammatory cytokines may lead to the discovery of novel therapeutic targets, thereby facilitating dietary interventions to complement clinical disease treatments.

Pengembangan Terapi Regeneratif pada Osteoartritis Sendi Temporomandibula : Telaah Pustaka

Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative condition that affects the temporomandibular joint, causing pain, stiffness, and limited jaw movement. Conventional therapies such as medications, physical therapy, and surgery often only provide temporary solutions and cannot permanently restore joint function. Therefore, regenerative therapy has emerged as a promising approach to address TMJ OA by harnessing the body's natural healing potential. This literature review aims to provide a comprehensive overview of the development of regenerative therapies for TMJ OA, including therapeutic strategies, challenges, and future opportunities. Regenerative therapies for TMJ OA encompass various strategies, such as stem cell injections, biomaterial scaffolds, growth factors, gene therapy, and combination therapies. Although regenerative therapies have shown promising results in preclinical studies, several challenges remain, such as safety, efficacy, and translation into clinical applications. It can be concluded that regenerative therapy offers an innovative and potential approach to addressing TMJ OA by utilizing the body's natural healing capabilities, with the hope of restoring joint function and improving the quality of life for TMJ OA patients in the future.

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity

Major depressive disorder (MDD) is accompanied by activated neuro-immune pathways, increased physiosomatic and chronic fatigue-fibromyalgia (FF) symptoms. The most severe MDD phenotype, namely major dysmood disorder (MDMD), is associated with adverse childhood experiences (ACEs) and negative life events (NLEs) which induce cytokines/chemokines/growth factors. To delineate the impact of ACE + NLEs on physiosomatic and FF symptoms in first episode (FE)-MDMD, and examine whether these effects are mediated by immune profiles. ACEs, NLEs, physiosomatic and FF symptoms, and 48 cytokines/chemokines/growth factors were measured in 64 FE-MDMD patients and 32 normal controls. Physiosomatic, FF and gastro-intestinal symptoms belong to the same factor as depression, anxiety, melancholia, and insomnia. The first factor extracted from these seven domains is labeled the physio-affective phenome of depression. A part (59.0%) of the variance in physiosomatic symptoms is explained by the independent effects of interleukin (IL)-16 and IL-8 (positively), CCL3 and IL-1 receptor antagonist (inversely correlated). A part (46.5%) of the variance in physiosomatic (59.0%) symptoms is explained by the independent effects of interleukin (IL)-16, TNF-related apoptosis-inducing ligand (TRAIL) (positively) and combined activities of negative immunoregulatory cytokines (inversely associated). Partial least squares analysis shows that ACE + NLEs exert a substantial influence on the physio-affective phenome which are partly mediated by an immune network composed of interleukin-16, CCL27, TRAIL, macrophage-colony stimulating factor, and stem cell growth factor. The physiosomatic and FF symptoms of FE-MDMD are partly caused by immune-associated neurotoxicity due to T helper (Th)-1 polarization and M1 macrophage activation and relative lowered compensatory immunoregulatory protection.

Systemic inflammatory regulators and preeclampsia: a two-sample bidirectional Mendelian randomization study.

Systemic inflammatory regulators have been associated with preeclampsia (PE) during pregnancy; however, there is inconsistent evidence from animal models and observational results. Using summary data from genome-wide association studies (GWASs), we performed a bidirectional Mendelian randomization (MR) analysis of two samples of systemic inflammatory regulators (n = 8,186) and PE (n = 267,242) individuals of European ancestry. As our primary analysis, we used the random-effects inverse-variance weighted (IVW) approach. Sensitivity and pleiotropy analyses were conducted using the MR-Egger method, weighted median, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and Cochran's Q test. The results indicate that there is a correlation between a higher circulating level of tumor necrosis factor alpha (TNF-α) and interleukin-9 (IL-9) and an increased risk of PE (odds ratio [OR] = 1.32, 95% confidence interval [CI] = 1.09-1.60, p = 0.004 and OR = 1.28, 95% CI: 1.02-1.62, p = 0.033, respectively). Conversely, lower levels of stem cell growth factor beta (SCGF-β) (OR = 0.89, 95% CI: 0.80-0.99, p = 0.027) and interleukin-5 (IL-5) (OR = 0.80, 95% CI: 0.65-0.98, p = 0.030) are linked to an increased risk of PE. The macrophage migration inhibitory factor (MIF) is the downstream inflammatory regulator of PE, according to reverse magnetic resonance imaging studies. Our study suggests that SCGF-β, IL-5, IL-9, and TNF-α causally affect the PE risk, while PE is causally associated with MIF. Further studies are needed to validate these biomarkers in managing PE.

Causal relationship between inflammatory cytokines and autoimmune thyroid disease: a bidirectional two-sample Mendelian randomization analysis.

Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive. A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers. Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-β and low levels of stem cell growth factor-β were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1β, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, β-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels. Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD.

Genetic liability to elevated circulating IP-10, IFNγ and SCGFβ levels in relation to thoracic aortic aneurysm: A mendelian randomization study

Inflammation is associated with thoracic aortic aneurysm (TAA) but the effects of each circulating inflammatory factor on TAA remain unclear. In this study, we explored the relationship between circulating inflammatory factors and TAA risk using Mendelian randomization (MR) approach based on summary statistics from the latest genome-wide association study (GWAS) of 41 circulating inflammatory factors in 8293 Finns and a GWAS involving 1351 TAA cases and 18,295 controls of European ancestry. In univariable MR, higher interferon gamma-induced protein 10 (IP-10) levels, higher interferon gamma (IFNγ) levels and higher stem cell growth factor beta (SCGFβ) levels were associated with an increased risk of TAA (OR = 1.37, 95 % CI = 1.17–1.59, p = 7.42 × 10−5; OR = 1.43, 95 % CI = 1.19–1.74, p = 2.04 × 10−4; OR = 1.27, 95 % CI = 1.09–1.48, p = 2.40 × 10−3, respectively). In multivariable MR, the patterns of associations for the three cytokines remained adjusting for each other or smoking, but were attenuated differently with adjustment for other cardiovascular risk factors, especially for lipids and body mass index. Bidirectional MR approach did not identify any significant associations between cytokines and risk factors. Our results indicated that circulating cytokines may play mediation roles in the pathogenesis of TAA. Further studies are needed to determine whether these biomarkers can be used to prevent and treat TAA.

Exploring regenerative medicine strategies for osteoporosis treatment: Progress, potential, and hurdles

A major worldwide health problem is osteoporosis, particularly in older people. There are restrictions on current therapies, such as anti-resorptive medications. Promising techniques including stem cell treatment, gene therapy, and growth factors are available in regenerative medicine. Preclinical and clinical research indicate promise for mesenchymal stem cells derived from bone marrow, adipose tissue, and umbilical cord blood. Enhancing bone regeneration with gene therapy that targets osteogenic factors such as BMPs is a promising approach. In order to mend bones, growth factors, cytokines, and scaffold materials are essential. Realising the benefits of regenerative medicine in treating osteoporosis requires cooperation and ongoing research, despite obstacles such limited clinical acceptability and regulatory barriers.

Associations of the circulating levels of cytokines with risk of systemic sclerosis: a bidirectional Mendelian randomized study.

Systemic sclerosis(SSc) remains unclear, studies suggest that inflammation may be linked to its pathogenesis. Hence, we conducted a bidirectional Mendelian randomization (MR) analysis to evaluate the association between cytokine and growth factor cycling levels and the risk of SSc onset. In our study, the instrumental variables(IVs) for circulating cytokines were sourced from the genome-wide association study (GWAS) dataset of 8293 Finnish individuals. The SSc data comprised 302 cases and 213145 controls, and was included in the GWAS dataset. We employed four methods for the MR analysis: MR Egger, Inverse variance weighted (IVW), Weighted medium, and Weighted Mode, with IVW being the primary analytical method. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropy testing, and the Leave One Out (LOO) method. We also conducted a reverse MR analysis to determine any reverse causal relationship between SSc and circulating cytokines. After Bonferroni correction, MR analysis revealed that the Interleukin-5 (IL-5) cycle level was associated with a reduced risk of SSc [odds ratio (OR)=0.48,95% confidence interval (CI): 0.27-0.84, P=0.01]. It also indicated that the Stem cell growth factor beta (SCGF-β) cycling level might elevate the risk of SSc (OR = 1.36, 95% CI: 1.01-1.83, P = 0.04). However, the reverse MR analysis did not establish a causal relationship between SSc and circulating cytokine levels. Additionally, sensitivity analysis outcomes affirm the reliability of our results. Our MR study suggests potential causal relationships between IL-5, SCGF-β, and the risk of SSc. Further research is essential to determine how IL-5 and SCGF-β influence the development of SSc.