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Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to its desmoplastic reaction, which impedes therapeutic effectiveness, highlighting the need for advanced vitro models to better mimic the complex tumor environment. The current three-dimensional co-culture models of fibroblasts and endothelial cells are lacking, [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges due to its desmoplastic reaction, which impedes therapeutic effectiveness, highlighting the need for advanced vitro models to better mimic the complex tumor environment. The current three-dimensional co-culture models of fibroblasts and endothelial cells are lacking, which presents a challenge for performing more comprehensive in vitro research. Our study developed triple co-culture spheroid models using MiaPaCa-2 and BxPC-3 cancer cell lines, with RLT-PSC and hPSC21 pancreatic stellate cell lines and the endothelial cell line HMEC-1. These models were assessed through growth assays, multicolor flow cytometry to optimize cell ratios, cell viability assays to evaluate drug responses, and a tube formation assay with a spheroid-conditioned medium to examine angiogenesis. Our triple co-culture spheroids effectively replicate the PDAC microenvironment, showing significant variations in drug responses influenced by cellular composition, density, and spatial arrangement. The tube formation assay showcased the potential of our models to quantitatively assess a treatment-induced angiogenic response. These cost-effective triple-co-culture in vitro spheroid models provide vital insights into the PDAC microenvironment, significantly improving the quality of the in vitro evaluation of treatment responses.Full article

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Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay [...] Read more.

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.Full article

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Abnormalities in epidermal keratinocyte proliferation are a characteristic feature of a range of dermatological conditions. These include hyperproliferative states in psoriasis and dermatitis as well as hypoproliferative states in chronic wounds. This emphasises the importance of investigating the proliferation kinetics under conditions of [...] Read more.

Abnormalities in epidermal keratinocyte proliferation are a characteristic feature of a range of dermatological conditions. These include hyperproliferative states in psoriasis and dermatitis as well as hypoproliferative states in chronic wounds. This emphasises the importance of investigating the proliferation kinetics under conditions of healthy skin and identifying the key regulators of epidermal homeostasis, maintenance, and recovery following wound healing. Animal models contribute to our understanding of human epidermal self-renewal. Human skin xenografting overcomes the ethical limitations of studying human skin during regeneration. The application of this approach has allowed for the identification of a single population of stem cells and both slowly and rapidly cycling progenitors within the epidermal basal layer and the mapping of their location in relation to rete ridges and hair follicles. Furthermore, we have traced the dynamics of the proliferation pattern reorganization that occurs during epidermal regeneration, underlining the role of YAP activity in epidermal relief formation.Full article

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies forEGFR-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in theEGFR or other genes that lead to resistance have been identified, but resistance mechanisms have not [...] Read more.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are standard therapies forEGFR-mutated non-small-cell lung cancer (NSCLC); however, their efficacy is inconsistent. Secondary mutations in theEGFR or other genes that lead to resistance have been identified, but resistance mechanisms have not been fully identified. Chromosomal instability (CIN) is a hallmark of cancer and results in genetic diversity. In this study, we demonstrated by transcriptomic analysis that CIN activates the cGAS–STING signaling pathway, which leads to EGFR-TKI refractoriness in a subset ofEGFR-mutated NSCLC patients. Furthermore,EGFR-mutated H1975dnMCAK cells, which frequently underwent chromosomal mis-segregation, demonstrated refractoriness to the EGFR-TKI osimertinib compared to control cells. Second, H1975dnMCAK cells exhibited activation of cGAS–STING signaling and its downstream signaling, including tumor-promoting cytokine IL-6. Finally, chromosomally unstableEGFR-mutated NSCLC exhibited enhanced epithelial–mesenchymal transition (EMT). Blockade of cGAS–STING-TBK1 signaling reversed EMT, resulting in restored susceptibility to EGFR-TKIs in vitro and in vivo. These results suggest that CIN may lead to the activation of cGAS–STING signaling in someEGFR-mutated NSCLC, resulting in EMT-associated EGFR-TKI resistance.Full article

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Limb–girdle muscular dystrophy R1 (LGMDR1) is characterized by progressive proximal muscle weakness due to mutations in theCAPN3 gene. Little is known about CAPN3’s function in muscle, but its loss results in aberrant sarcomere formation. Human muscle structure was analyzed in this study, [...] Read more.

Limb–girdle muscular dystrophy R1 (LGMDR1) is characterized by progressive proximal muscle weakness due to mutations in theCAPN3 gene. Little is known about CAPN3’s function in muscle, but its loss results in aberrant sarcomere formation. Human muscle structure was analyzed in this study, with observations including integrin β1D isoform (ITGβ1D) mislocalization, a lack of Talin-1 (TLN1) in the sarcolemma and the irregular expression of focal adhesion kinase (FAK) in LGMDR1 muscles, suggesting a lack of integrin activation with an altered sarcolemma, extracellular matrix (ECM) assembly and signaling pathway deregulation, which may cause frailty in LGMDR1 muscle fibers. Additionally, altered nuclear morphology, centrosome distribution and microtubule organization have been found in muscle cells derived from LGMDR1 patients.Full article

The EFR3 (Eighty-Five Requiring 3) protein and its homologs are rather poorly understood eukaryotic plasma membrane peripheral proteins. They belong to the armadillo-like family of superhelical proteins. In higher vertebrates two paralog genes, A and B were found, each expressing at least 2–3 [...] Read more.

The EFR3 (Eighty-Five Requiring 3) protein and its homologs are rather poorly understood eukaryotic plasma membrane peripheral proteins. They belong to the armadillo-like family of superhelical proteins. In higher vertebrates two paralog genes, A and B were found, each expressing at least 2–3 protein isoforms. EFR3s are involved in several physiological functions, mostly including phosphatidyl inositide phosphates, e.g., phototransduction (insects), GPCRs, and insulin receptors regulated processes (mammals). Mutations in theEFR3A were linked to several types of human disorders, i.e., neurological, cardiovascular, and several tumors. Structural data on the atomic level indicate the extended superhelical rod-like structure of the first two-thirds of the molecule with a typical armadillo repeat motif (ARM) in the N-terminal part and a triple helical motif in its C-terminal part. EFR3s’ best-known molecular function is anchoring the giant phosphatidylinositol 4-kinase A complex to the plasma membrane crucial for cell signaling, also linked directly to theKRAS mutant oncogenic function. Another function connected to the newly uncovered interaction of EFR3A with flotillin-2 may be the participation of the former in the organization and regulation of the membrane raft domain. This review presents EFR3A as an intriguing subject of future studies.Full article

Increasing evidence has suggested that dihydrolipoamide S-acetyltransferase (DLAT), a subunit of the pyruvate dehydrogenase complex, is crucial for pyruvate metabolism and the regulation of cell death. The excessive death of granulosa cells (GCs) hinders the progression of follicular growth. However, the [...] Read more.

Increasing evidence has suggested that dihydrolipoamide S-acetyltransferase (DLAT), a subunit of the pyruvate dehydrogenase complex, is crucial for pyruvate metabolism and the regulation of cell death. The excessive death of granulosa cells (GCs) hinders the progression of follicular growth. However, the relationship betweenDLAT and follicular growth is poorly understood. Here, we found that pyruvate significantly shortened the age of pubertal initiation in mice and promoted follicular growth by promoting the proliferation of GCs. In addition, pyruvate up-regulated the expression ofDLAT and the high level ofDLAT was observed in large follicles, which were associated with follicular growth. Mechanistically,DLAT increased the mRNA and protein levels of proliferation pathways such asPCNA andMCL1 to promote GC proliferation. Additionally, DLAT bound to CASP3 and CASP9 proteins to inhibit the apoptosis of GCs. Taken together, these results reveal a mechanism that pyruvate regulatedDLAT to promote follicular growth, andDLAT represents a promising target that supports new strategies for improving the growth of follicles.Full article

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Despite improved neonatal intensive care, the risk of premature-born infants developing bronchopulmonary dysplasia (BPD) and encephalopathy of prematurity (EoP) remains high. With hyperoxia being a major underlying factor, both preterm-birth-related complications are suggested to be closely interrelated. However, experimental models are lacking for [...] Read more.

Despite improved neonatal intensive care, the risk of premature-born infants developing bronchopulmonary dysplasia (BPD) and encephalopathy of prematurity (EoP) remains high. With hyperoxia being a major underlying factor, both preterm-birth-related complications are suggested to be closely interrelated. However, experimental models are lacking for the assessment of the potentially close interplay between both organs. To establish a model, suitable for the assessment of both affected organs, Wistar rats were exposed to 80% oxygen from postnatal day 2 (P2) for seven days. Brain and lung tissues were analysed via histomorphometry, immunohistochemistry, real-time PCR, and western blot at term P11. In the brain, hyperoxia induced significant hypomyelination accompanied by a reduction in oligodendrocytes and CD68 expression on microglia cells. These changes correlate with arrested alveolarisation and an increased number of macrophages in the lung. Interestingly, in contrast to the reduced formation of pulmonary microvessels, an increased vascular density was detected in the brain. Seven days of hyperoxia induces typical characteristics of BPD and EoP in neonatal rats, thereby linking impaired alveolarisation with disturbed myelination in the brain and providing an experimental model for understanding pathophysiological mechanisms and identifying organ-spanning novel therapeutic interventions targeting both diseases.Full article

Accurate DNA replication is essential for the maintenance of genome stability and the generation of healthy offspring. When DNA replication is challenged, signals accumulate at blocked replication forks that elicit a multifaceted cellular response, orchestrating DNA replication, DNA repair and cell cycle progression. [...] Read more.

Accurate DNA replication is essential for the maintenance of genome stability and the generation of healthy offspring. When DNA replication is challenged, signals accumulate at blocked replication forks that elicit a multifaceted cellular response, orchestrating DNA replication, DNA repair and cell cycle progression. This replication stress response promotes the recovery of DNA replication, maintaining chromosome integrity and preventing mutations. Defects in this response are linked to heightened genetic instability, which contributes to tumorigenesis and genetic disorders. Iron–sulfur (Fe-S) clusters are emerging as important cofactors in supporting the response to replication stress. These clusters are assembled and delivered to target proteins that function in the cytosol and nucleus via the conserved cytosolic Fe-S cluster assembly (CIA) machinery and the CIA targeting complex. This review summarizes recent advances in understanding the structure and function of the CIA machinery in yeast and mammals, emphasizing the critical role of Fe-S clusters in the replication stress response.Full article

Background: Pediatric sepsis remains the main cause of morbidity and mortality among children. Interleukin (IL)-6 is usually produced after infection, and elevated IL-6 levels may cause multisystemic damage. This study aimed to evaluate the effect of tocilizumab, an IL-6 receptor antibody, on children [...] Read more.

Background: Pediatric sepsis remains the main cause of morbidity and mortality among children. Interleukin (IL)-6 is usually produced after infection, and elevated IL-6 levels may cause multisystemic damage. This study aimed to evaluate the effect of tocilizumab, an IL-6 receptor antibody, on children with septic shock. Methods: We conducted a retrospective cohort study of children diagnosed with septic shock and admitted to the pediatric intensive care unit (PICU) between 2018 and 2024. Tocilizumab was administered within 24 h to patients with high IL-6 levels who developed refractory septic shock. Outcomes, including 28-day mortality, morbidity, length of PICU stay, and shock duration, were analyzed between septic children with different etiologies and differed treatments. Results: Fifty-four children with refractory septic shock were included. Patients treated with tocilizumab (n = 21) showed improved outcomes compared to those without tocilizumab (n = 33), including shorter PICU stays and lower mortality rates (14.2% vs. 54.5%,p = 0.03). Subgroup analysis revealed that in the non-hematologic group, tocilizumab-treated patients had a 0% mortality rate compared to 50% in untreated patients (p = 0.006). In the hematologic group, tocilizumab-treated patients exhibited a 27.2% mortality rate compared to 61.5% in untreated patients (p = 0.09). Trends in IL-6 levels (D1 to D7) were significantly higher in non-survivors compared to survivors and in patients with hematological malignancies compared to those without. No adverse events, including secondary infections or long-term liver impairment, were observed. Conclusions: Tocilizumab appears to mitigate systemic inflammation and improve outcomes in children with refractory septic shock and elevated IL-6 levels. Further prospective studies are warranted to confirm these findings and establish treatment guidelines.Full article

Wound-induced hair-follicle neogenesis (WIHN) is the phenomenon of regenerating new hair follicles from wounds in mammals. The WIHN involves both developmental and adult wound-healing processes. Moreover, the WIHN is regulated by a variety of factors, particularly multiple molecular signaling pathways produced in several [...] Read more.

Wound-induced hair-follicle neogenesis (WIHN) is the phenomenon of regenerating new hair follicles from wounds in mammals. The WIHN involves both developmental and adult wound-healing processes. Moreover, the WIHN is regulated by a variety of factors, particularly multiple molecular signaling pathways produced in several types of cells. Here, the role of multiple signaling in different types of cells in WIHN is comprehensively described. Furthermore, the lack of dermal γδ T cells in the human scalp has hindered the clinical application of WIHN, but the development of drugs such as Wnt signaling activators is increasing the effectiveness of WIHN in humans. Overall, understanding the underlying mechanisms that regulate WIHN may help treat skin diseases, including alopecia.Full article

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Originally identified in proteomic-based studies of the Golgi, Golgi phosphoprotein 3 (GOLPH3) is a highly conserved protein from yeast to humans. GOLPH3 localizes to the Golgi through the interaction with phosphatidylinositol-4-phosphate and is required for Golgi architecture and vesicular trafficking. Many studies revealed [...] Read more.

Originally identified in proteomic-based studies of the Golgi, Golgi phosphoprotein 3 (GOLPH3) is a highly conserved protein from yeast to humans. GOLPH3 localizes to the Golgi through the interaction with phosphatidylinositol-4-phosphate and is required for Golgi architecture and vesicular trafficking. Many studies revealed that the overexpression of GOLPH3 is associated with tumor metastasis and a poor prognosis in several cancer types, including breast cancer, glioblastoma multiforme, and colon cancer. The purpose of this review article is to provide the current progress of our understanding of GOLPH3 molecular and cellular functions, which may potentially reveal therapeutic avenues to inhibit its activity. Specifically, recent papers have demonstrated that GOLPH3 protein functions as a cargo adaptor for COP I-coated intra Golgi vesicles and impinges on Golgi glycosylation pathways. In turn, GOLPH3-dependent defects have been associated with malignant phenotypes in cancer cells. Additionally, the oncogenic activity of GOLPH3 has been linked with enhanced signaling downstream of mechanistic target of rapamycin (mTOR) in several cancer types. Consistent with these data, GOLPH3 controls organ growth in Drosophila by associating with mTOR signaling proteins. Finally, compelling evidence demonstrates that GOLPH3 is essential for cytokinesis, a process required for the maintenance of genomic stability.Full article

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Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examinesCgmGluR5 [...] Read more.

Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examinesCgmGluR5 expression and downstream signaling activation in Pacific oyster (Crassostrea gigas) hemocytes following glutamate (Glu) andVibrio splendidus treatment. Glu treatment significantly induced the expression ofCgmGluR5 and key signaling molecules, including PLC, DAG, IP3, Ca²⁺, and PKC, while enhancing mRNA levels ofCgIL17-1,CgIL17-5, andCgCaspase3. Elevated Ca²⁺ content andCgIL17 expression in hemocytes were observed at 12 h post-Glu exposure, indicatingCgmGluR5-mediated immune regulation through the phosphoinositide pathway. A 1.14-fold increase in the apoptosis rate was found in the Glu treatment group compared to the control group. Knockdown ofCgmGluR5 suppressedCgIL17-1 andCgIL17-5 expression and reduced granulocyte proportions, reflecting its role in immune regulation. This study shows thatCgmGluR5 mediates long-term immune regulation in oysters through the phosphoinositide pathway, providing new theoretical insights for aquaculture immune management.Full article

Hypoxia-Inducible Factor-1α (HIF-1α) is crucial in the progression of ovarian cancer, especially in influencing its tumor microenvironment and promoting pathogenic pathways that worsen female infertility. In hypoxic settings, HIF-1α is stabilized and activates the transcription of genes associated with angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal [...] Read more.

Hypoxia-Inducible Factor-1α (HIF-1α) is crucial in the progression of ovarian cancer, especially in influencing its tumor microenvironment and promoting pathogenic pathways that worsen female infertility. In hypoxic settings, HIF-1α is stabilized and activates the transcription of genes associated with angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition, and therapeutic resistance. Angiogenesis and glycolytic reprogramming mediated by HIF-1 tumor proliferation, survival, and metastasis. Its dysfunction concurrently impairs ovarian homeostasis, undermining follicular growth, hormone synthesis, and the ovarian vascular network, consequently contributing to infertility. Moreover, HIF-1α induces persistent inflammation and oxidative stress, promoting an environment damaging to reproductive health. Due to its dual function in ovarian cancer growth and infertility, HIF-1α is a potential therapeutic target. Strategies including small molecule inhibitors and nanoparticle-mediated delivery of drugs possess the potential to reduce HIF-1α activity, hence reducing cancer progression while protecting fertility. This review seeks to clarify the molecular basis of HIF-1α in ovarian cancer and its effects on female infertility, providing insights into novel treatment approaches that target both controlling the disease and preserving fertility.Full article

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Cell therapy utilizing mesenchymal stromal cells (MSCs) through paracrine mechanisms holds promise for regenerative purposes. Peritoneal fibrosis (PF) is a significant complication of peritoneal dialysis. Various strategies have been proposed to protect the peritoneal membrane (PM). This study explores the effectiveness of adipose-tissue-derived [...] Read more.

Cell therapy utilizing mesenchymal stromal cells (MSCs) through paracrine mechanisms holds promise for regenerative purposes. Peritoneal fibrosis (PF) is a significant complication of peritoneal dialysis. Various strategies have been proposed to protect the peritoneal membrane (PM). This study explores the effectiveness of adipose-tissue-derived stem cells (ASCs) and extracellular vesicles (EVs) at mitigating PF using a rat model of PF induced by chlorhexidine gluconate. ASC and EV treatments effectively prevented an increase in the thickness of the PM and diminished the number of myofibroblasts, fibronectin expression, collagen III expression, and PF-related factors such as TGF-β and FSP-1. Smad3 gene expression decreased in the treatment groups, whereas Smad7 gene expression increased in treated animals. In addition, ASC and EV injections showed potent anti-inflammatory effects. Glucose transport through the PM remained unaffected in relation to the PF group; both treatments promoted an increase in ultrafiltration (UF) capacity. The PF+EVs treated group showed the highest increase in UF capacity. Another critical aspect of ASC and EV treatments was their impact on neoangiogenesis in the PM which is vital for UF capacity. Although the treated groups displayed a significant decrease in VEGF expression in the PM, peritoneal function remained effective. In conclusion, within the experimental PF model, both ASC and EV treatments demonstrated anti-inflammatory effects and comparably hindered the progression of PF. The EV treatment exhibited superior preservation of peritoneal function, along with enhanced UF capacity. These findings suggest the potential of ASCs and EVs as novel therapeutic approaches to prevent the development of PF associated with peritoneal dialysis.Full article

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To better understand adult neurogenesis, the biomolecular specificity of the subgranular zone should be investigated in comparison to other layers of the hippocampus. Adult neurogenesis occurs at a reduced rate in adulthood compared to the period of development, but it can be increased [...] Read more.

To better understand adult neurogenesis, the biomolecular specificity of the subgranular zone should be investigated in comparison to other layers of the hippocampus. Adult neurogenesis occurs at a reduced rate in adulthood compared to the period of development, but it can be increased with exposure to an enriched environment (EE). This can be used to investigate the regulatory role of molecules present in the extracellular matrix, such as tenascin C (TnC). This study, using Synchrotron radiation Fourier Transform Infrared spectroscopy (SR-FTIR), shows that the differences between the hippocampal layers in adolescence are maintained as subtle and significant in adulthood. The main difference in FTIR spectra was observed for nucleic acid and carbohydrate and for the comparison of the subgranular zone (SGZ) with hippocampal CA3. Moreover, we have detected changes in the protein and nucleic acid content of the SGZ that accompany the process of neurogenesis under the influence of an enriched environment. The latter effects are, however, lacking in mice with a gene ablation for tenascin C. Overall, these results show that observed discrete biomolecular differences in hippocampal layers follow the rate of neurogenesis that is enhanced by EE and dependent on TnC.Full article

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Chronic kidney disease (CKD) is considered an important health issue worldwide. The renin–angiotensin–aldosterone system (RAAS) blockade through the administration of angiotensin II receptor blockers, such as Losartan (LOS), has been considered the best strategy for CKD treatment for decades. However, this approach promotes [...] Read more.

Chronic kidney disease (CKD) is considered an important health issue worldwide. The renin–angiotensin–aldosterone system (RAAS) blockade through the administration of angiotensin II receptor blockers, such as Losartan (LOS), has been considered the best strategy for CKD treatment for decades. However, this approach promotes only partial detention of CKD progression and cannot reverse renal damage. The aim of the present study was to investigate whether the therapeutic administration of extracellular vesicles (EVs) derived from adipose stem cells (ASCs), associated to LOS treatment, would promote additional renoprotection in rats underwent the 5/6 renal ablation CKD model. ASC-derived EV were administered locally, in the renal subcapsular area, 15 days after CKD induction, when LOS therapy also began. Animals were followed for additional 15 days and our results demonstrated that subcapsular injection of ASC-derived EV associated with LOS significantly reduced glomerulosclerosis, renal interstitial infiltration by myofibroblasts, and macrophages in the 5/6 CKD model. Additionally, LOS + EV abrogated systemic hypertension, proteinuria, and albuminuria, and stimulated local gene overexpression of the endogenous anti-inflammatoryIl-4. Although more studies are still required to establish the best EV dose and administration route, these findings point to therapy with ASC-derived EV as a potential adjuvant in CKD treatmentFull article

Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterised by vasculopathy with progressive fibrosis of the skin and internal organs. Tissue fibrosis is driven by activated fibroblasts (myofibroblasts) with exacerbated contractile and secretory properties. We previously reported that the long non-coding [...] Read more.

Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterised by vasculopathy with progressive fibrosis of the skin and internal organs. Tissue fibrosis is driven by activated fibroblasts (myofibroblasts) with exacerbated contractile and secretory properties. We previously reported that the long non-coding RNA HOTAIR is a key driver of SSc fibroblast activation. HOTAIR interacts with the chromatin modifiers, the polycomb repressor complex (PRC2) and coREST complex, promoting expression of pro-fibrotic genes. In this study, we show that acute activation of dermal fibroblasts from healthy subjects or SSc patients with transforming growth factor-β and other fibrotic stimuli requires the activity of the lysine-specific demethylase 1 (LSD1) subunit of the co-REST complex. Unexpectedly, LSD1 catalytic activity plays a minor role in fibrotic gene expression in HOTAIR-overexpressing fibroblasts and in maintenance of the stable myofibroblast phenotype of SSc fibroblasts. However, silencing of LSD1 in SSc fibroblasts has a profound effect on pro-fibrotic gene expression, supporting a non-canonical scaffolding function. Our study shows for the first time an essential non-canonical role for LSD1 in pro-fibrotic gene expression in SSc; however, given that this function is insensitive to LSD1 inhibitors, the therapeutic opportunities will depend on future identification of a targetable mediator.Full article

Toll-like receptors (TLRs) play a crucial role in the innate immune response, mediating cellular interactions with the microenvironment and influencing periodontal disease progression. This in vitro study aimed to comprehensively characterize the TLR expression profile of periodontal ligament mesenchymal stem/progenitor cells (PDLSCs) and [...] Read more.

Toll-like receptors (TLRs) play a crucial role in the innate immune response, mediating cellular interactions with the microenvironment and influencing periodontal disease progression. This in vitro study aimed to comprehensively characterize the TLR expression profile of periodontal ligament mesenchymal stem/progenitor cells (PDLSCs) and investigate its modulation by inflammatory stimuli associated with periodontal disease. PDLSCs (n = 6) were isolated, selected using anti-STRO-1 antibodies, and cultured to evaluate their colony-forming abilities and stem/progenitor characteristics. Baseline and inflammation-induced TLR expressions were evaluated using RT-PCR and protein analyses following cytokine-mediated stimulation. PDLSCs exhibited the expected stem cell characteristics and expressed multiple TLRs under both conditions. Notably, inflammatory stimulation significantly upregulated TLR1 and TLR2 while downregulating TLR10 (p < 0.05). These findings provide a comprehensive characterization of TLR expression in PDLSCs and demonstrate how inflammation modulates their innate immune profile. The observed shifts in TLR expression may influence PDLSC responses to microbial pathogens and impact their immunomodulatory and regenerative properties in periodontal tissues. Understanding these interactions could contribute to developing targeted strategies for improving PDLSC-based therapies in periodontal disease.Full article