Tissue Inflammation Research Articles

The anti-inflammatory effect of a magnoliae cortex and Zea mays L. extract mixture in a canine model of ligature-induced periodontitis

BackgroundPeriodontitis is common in dogs. It is characterized by destruction of the supporting tissues of the teeth due to the host-immune response triggered by plaque. Magnoliae cortex and Zea mays L. extract showed anti-inflammatory and anti-microbial effects, respectively. This study aimed to evaluate improvement in periodontitis following the administration of Magnoliae cortex and Zea mays L. extract in dogs. Periodontitis was experimentally induced in 10 beagle dogs. Five dogs were administered 40 mg of Magnoliae cortex extract and 20 mg of Zea mays L. extract orally once per day for 2 months (MZ group), whereas the other group received empty gelatin capsules (control group). Periodontal clinical parameters, complete blood count, serum chemistry parameters, and tissue inflammatory cytokines and chemokine expression were assessed before and after combined oral extracts administration.ResultsThe complete blood count and serum chemistry results of all dogs were within normal ranges. Gingival inflammation in MZ group was significantly better than that in the control group at 4 and 8 weeks post-medication (PM; p < 0.05). The periodontal pocket depth and clinical attachment loss at 8 weeks PM in the MZ group were significantly lower than the baseline values (p < 0.05). The incidence of bleeding on probing in the MZ group was significantly lower than that in the control group at 4 weeks PM (p < 0.05). Throughout the medication period, the percentages of CD4 + and CD8 + T cells were higher and lower, respectively, in the MZ group. However, these differences were only significant at 8 weeks PM. The expression of the inflammatory cytokines IL-1β, IL-6, IL-17, and TNF-α and the chemokine IL-8 in the inflamed tissues was lower in the MZ group, and the two groups showed a significant difference in TNF-α expression.ConclusionsCombined administration of Magnoliae cortex and Zea mays L. extract improved the clinical symptoms of periodontal disease in dogs. This beneficial effect may be partly due to the inhibitory effects of these extracts on the inflammatory response.

TRPC3/6 Channels Mediate Mechanical Pain Hypersensitivity via Enhancement of Nociceptor Excitability and of Spinal Synaptic Transmission.

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects.

Investigation of the Effects of Boric Acid against Post Operative Testicular Adhesion Caused by Experimental Laporotomy in Rats.

Post-operative intra-abdominal adhesions, significantly affecting testicular tissue, are a prevalent and serious complication following laparoscopic surgery. This study investigated the efficacy of boric acid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, in preventing post-operative testicular adhesions. Forty rats, were divided into four groups: control, laparoscopy (LA), boric acid (BA), and LA + BA. Following laparoscopic surgery, BA treatment was administered for seven days. While the adhesion score was around 3 in the LA group, it was 1 or below in the LA + BA group. Testicular tissues were examined by histopathological and biochemical methods. In testis tissues, in the LA group, malondialdehyde (MDA) levels increased while superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) levels decreased; these parameters normalized with BA treatment. Additionally, the LA group exhibited reduced levels of IL-10, Bcl-2, Kisspeptin-1, and GnRH, alongside elevated levels of inflammatory markers IL-1β, IL-6, TNF-α, JNK, BAX, and Caspase 3. BA treatment significantly restored these levels to normal. In conclusion, oxidative stress, inflammation, and apoptosis in testicular tissues were associated with post-operative testicular adhesions. BA demonstrated potential as an anti-adhesive agent, reducing testicular adhesions and normalizing biochemical and histological parameters following laparoscopic surgery.

Two distinct phenotypes of calcium oxalate stone formers could imply different long-term risks for renal function.

Endoscopic and biopsy findings have identified two distinct phenotypes among individuals with calcium oxalate (CaOx) kidney stones. The first type has normal renal papillae but shows interstitial mineral deposition, known as Randall's plaque. The other phenotype presents with collecting duct plugging and a higher incidence of loss of papilla tissue mass. With Randall's plaque, renal papilla injury involves the loss of small patches of calcified tissue (Randall's plaque detaching with the stone), which likely results in damage to only a few nephrons. In contrast, collecting duct mineral plugs are very large, causing obstruction to tubular flow. Since each terminal collecting duct drains thousands of nephrons, ductal plugs could lead to the degeneration of many nephrons and a significant loss of renal glomeruli. New visualization techniques for immune cells in papillary biopsies have revealed that the Randall's plaque phenotype is marked by the accumulation of macrophages around the plaque regions. In contrast, preliminary data on the plugging phenotype shows collecting duct damage with mineral plugsand increased T-lymphocytes throughout the papilla. These regions also show tubulitis, i.e., T-cell infiltration into nearby collecting duct epithelium. This suggests that while some CaOx stone formers may have some papillary inflammation but with minimal damage to nephrons, others suffer from obstruction to flow for many nephrons that may also include destructive inflammation in the renal tissue. We propose that CaOx stone formers with the plugging phenotype will have a higher long-term risk for loss of renal function.

Association of adipose tissue inflammation and physical fitness in older adults

An active lifestyle is of key importance for reduction of obesity and inflammation, as well as circulating levels of adipokines. Therefore, the aim of our study was to assess the relationship of physical fitness with chronic inflammatory status, and to evaluate biomarkers useful in the analysis of adipose tissue dysfunction. Sixty-three older adults (69.6 ± 5.1 years) were allocated to a high n = 31 (women n = 23 and men n = 8 male) or low physical fitness n = 32 (women n = 29 and men n = 3) group based on gait speed values (1.4–1.8 m/s or ≤ 1.3 m/s). The gait speed correlated with hand grip strength (rs = 0.493, p = 0.0001) and with leptin level (R = -0.372, p = 0.003), which shows the benefits of physical activity on muscle strength and circulating adipokines. In low physical fitness group, 58.1% individuals had adiponectin to leptin ratio (Adpn/Lep) < 0.5 revealing dysfunction of adipose tissue and high cardiometabolic risk; 20% of the group were obese with BMI ≥ 30 kg/m2. In high physical fitness group, 25.8% of individuals had Adpn/Lep ≥ 1.0 i.e., within the reference range. Markers of systemic inflammation were significantly related to physical fitness: CRP/gait speed (rs = -0.377) and HMGB-1/gait speed (rs = -0.264). The results of the ROC analysis for Adpn (AUC = 0.526), Lep (AUC = 0.745) and HMGB-1 (AUC = 0.689) indicated their diagnostic potential for clinical prognosis in older patients. The optimal threshold values corresponded to 1.2 μg/mL for Adpn (sensitivity 74.2%, specificity 41.9%, OR = 1.4, 95%Cl 0.488–3.902), 6.7 ng/mL for Lep (sensitivity 56.2%, specificity 93.5%, OR = 14.8, 95%Cl 3.574–112.229), 2.63 mg/L for CRP (sensitivity 51.6%, specificity 84.3%, OR = 4.4, 95% Cl 1.401- 16.063) and 34.2 ng/mL for HMGB-1 (sensitivity 62.0%, specificity 86.6%, OR = 12.0, 95%Cl 3.254—61.614). The highest sensitivity and specificity were observed for Leptin and HMGB-1. The study revealed changes in inflammatory status in older adults at various levels of physical fitness and demonstrated diagnostic usefulness of adipokines in the assessment of adipose tissue inflammation.

Dynamics of perifocal reactions to the application of antimicrobial gel in one-stage hip replacement under conditions of staphylococcal infection in the experiment

Background. Local antibacterial therapy in the treatment of osteomyelitis significantly increases the effectiveness of surgical debridement.The aim of the work. To assess in an in vivo experiment the dynamics of perifocal tissue reactions to the application of an original polyvinylpyrrolidone-based antimicrobial gel in a one-stage treatment of implant-associated infection in the hip joint in rabbits.Methods. Implant-associated infection was modeled by inserting Staphylococcus aureus-infected wires into the medullary canal of the femur of rabbits (n = 12). On the day 14, we removed the wire and performed radical surgical treatment of the suppurative focus and hip replacement. The animals were divided into two groups: experimental group – with application of the original antimicrobial gel at the stage of hip replacement (n = 6); comparison group – without gel application (n = 6). For morphological studies, animals were sacrificed on the days 10, 45 and 90 after hip replacement, changes in soft tissues and the bone marrow canal were assessed, and cell populations were counted with statistical data processing.Results. The application of the original antimicrobial gel causes statistically significant decrease in the number of neutrophils in the soft tissues surrounding the implant in the comparison group at all stages. Moreover, in the experimental group, at early stages the number of lymphocytes, plasmacytes and macrophages was statistically significantly higher; on the day 45, a statistically significantly larger number of lymphocytes was registered, and on the day 90 – a statistically significantly larger number of multinucleated and epithelioid cells.Conclusion. The experiment histologically confirmed the effectiveness of application of the original antimicrobial gel to stop infectious inflammation in soft tissues and the bone marrow canal during surgical debridement of an osteomyelitic lesion followed by hip replacement. A pronounced giant cell reaction aimed at removing the polyvinylpyrrolidone-based gel requires further research in terms of its outcomes.

The association of systemic condition and medications on alveolar bone loss and tooth attrition.

Periodontal disease is caused by subgingival bacteria that adversely affect the host immune system and create and maintain unmitigated inflammation in gingival and periodontal tissues. The condition is also linked to systemic conditions including cardiovascular disease, diabetes, and arthritis. Periodontitis elevates the bacterial load and spreads systemic inflammation through infection and inflammation. The main radiographic sign of periodontitis is marginal bone loss. Risk factors, including medications, smoking, age, and sex, are known to influence periodontal health. However, there is little information about the impact of systemic conditions and medications on tooth wear. The aim of the present study was to assess the association between systemic conditions and medications and radiographic signs of tooth wear and marginal bone loss. This retrospective analysis was conducted on a group of 2,223 consecutive patients who came for dental treatment in the clinics of a large Health Maintenance Organization in Israel. Data available for the study included details of concomitant systemic diseases and medication and full-mouth radiographic surveys. Odds ratio and logistic regression analysis were used to detect associations between systemic conditions and medication, and marginal bone loss and tooth wear. The results indicated an elevated odds ratio for tooth wear associated with age, sex, and smoking across all age groups. Among young patients, those using proton pump inhibitors and psychiatric medications had an elevated risk of tooth wear. Age, smoking, and diabetes conditions were associated with an increased odds ratio for marginal bone loss in all age groups. Psychiatric medications and sex elevated the odds ratio for marginal bone loss only among older patients. The results highlight the significant impact of age, sex, and smoking on tooth wear, and extend these risks to alveolar bone loss when combined with diabetes and psychiatric conditions.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Hepatic Steatosis and Insulin Resistance in Diet-Induced Obese Mice by Activating the FGF21-Adiponectin Axis.

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton's jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21-adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders.

Brain Stiffness Correlates With Pathological Tissue in Patients With Drug-Resistant Epilepsy Due to Rasmussen Encephalitis and Focal Cortical Dysplasia.

Complete resection of epileptogenic zone is the single most important determinant of favorable seizure outcomes in resective surgery. However, identifying and resecting this zone is challenging in patients harboring diffuse; MRI-occult malformations of cortical development, such as focal cortical dysplasia; or acquired pathology, such as Rasmussen encephalitis. Intraoperative adjuncts that can aid in identifying the lesion and/or epileptogenic zone can optimize the extent of resection and seizure outcome. We sought to study a novel intraoperative tool, brain tonometer, to measure brain stiffness and correlate with histopathological and radiological findings. Brain stiffness was measured at various presumed normal and abnormal areas of the cortex during surgery in 2 patients with drug-resistant epilepsy. These results were correlated with preoperative and intraoperative neuroimaging and histopathology. We found brain stiffness correlated well with the degree of inflammation and cortical disorganization. Brain tonometry may help to intraoperatively identify inflammatory brain tissue along with structural and histopathological abnormalities. In select cases, this could potentially allow more tailored resections of the underlying lesion, to ensure complete removal of the epileptogenic lesion and improve the probability of achieving seizure freedom, while sparing normal brain leading to better functional outcomes.

Oral Chronic Graft-Versus-Host Disease: Pathogenesis, Diagnosis, Current Treatment, and Emerging Therapies.

Chronic graft-versus-host disease (cGvHD) is a multisystem disorder that occurs in recipients of allogeneic hematopoietic (alloHCT) stem cell transplants and is characterized by both inflammatory and fibrotic manifestations. It begins with the recognition of host tissues by the non-self (allogeneic) graft and progresses to tissue inflammation, organ dysfunction and fibrosis throughout the body. Oral cavity manifestations of cGVHD include mucosal features, salivary gland dysfunction and fibrosis. This review synthesizes current knowledge on the pathogenesis, diagnosis and management of oral cGVHD, with a focus on emerging trends and novel therapeutics. Data from various clinical studies and expert consensus are integrated to provide a comprehensive overview.

Expression of Intelectin-1, also known as Omentin-1, is related to clinical phenotypes such as overweight, obesity, insulin resistance, and changes after bariatric surgery.

Intelectin-1 (ITLN1; also Omentin-1, OMNT1) is secreted by adipose tissue (AT) and plays an important role in glucose metabolism regulation, with links to obesity-associated diseases. ITLN1 activity so far has rarely been investigated using RNA-sequencing and in larger cohorts. We evaluated ITLN1 expression among three clinical cohorts of the Leipzig Obesity BioBank-a cross-sectional cohort comprising of 1480 people, a cohort of people with metabolically healthy or unhealthy obesity (31 insulin-sensitive, 42 insulin-resistant individuals with obesity), and a longitudinal two-step bariatric surgery cohort (n = 65). We hypothesized that AT ITLN1 expression is associated with serum omentin-1, clinical parameters associated with obesity, and with weight loss after bariatric surgery. We also investigated the correlation of AT ITLN1 expression with genes related to inflammatory response, lipid metabolism, obesity, and regulation of energy balance. Likewise, we inspected gene group expression and metabolic pathways associated with ITLN1 expression using gene set enrichment and gene correlation analysis. We show that ITLN1 expression differs in VAT and SAT, and should therefore be analyzed separately. Furthermore, ITLN1 expression increases with VAT tissue mass, but is negatively affected by AT tissue dysfunction among individuals with unhealthy obesity, corroborated by interplay with genes related to tissue inflammation. Gene set enrichment and gene correlation analysis of ITLN1 expression suggest that AT ITLN1 expression is related to local inflammatory processes in AT, but also in processes such as regulation of appetite, energy balance, and maintenance of body weight.

C23 ameliorates carbon tetrachloride-induced liver fibrosis in mice.

C23, an oligo-peptide derived from cold-inducible RNA-binding protein (CIRP), has been reported to inhibit tissue inflammation, apoptosis and fibrosis by binding to the CIRP receptor; however, there are few reports on its role in liver fibrosis and the underlying mechanism is unknown. To explore whether C23 plays a significant role in carbon tetrachloride (CCl4)-induced liver fibrosis. CCl4 was injected for 6 weeks to induce liver fibrosis and C23 was used beginning in the second week. Masson and Sirius red staining were used to examine changes in fiber levels. Inflammatory factors in the liver were detected and changes in α-smooth muscle actin (α-SMA) and collagen I expression were detected via immunohistochemical staining to evaluate the activation of hematopoietic stellate cells (HSCs). Western blotting was used to detect the activation status of the transforming growth factor-beta (TGF-β)/Smad3 axis after C23 treatment. CCl4 successfully induced liver fibrosis in mice, while tumor necrosis factor-alpha (TNF-α), IL (interleukin)-1β, and IL-6 levels increased significantly and the IL-10 level decreased significantly. Interestingly, C23 inhibited this process. On the other hand, C23 significantly inhibited the activation of HSCs induced by CCl4, which inhibited the expression of α-SMA and the synthesis of collagen I. In terms of mechanism, C23 can block Smad3 phosphorylation significantly and inhibits TGF-β/Smad3 pathway activation, thereby improving liver injury caused by CCl4. C23 may block TGF-β/Smad3 axis activation, inhibit the expression of inflammatory factors, and inhibit the activation of HSCs induced by CCl4, alleviating liver fibrosis.

How type-2 dendritic cells induce Th2 differentiation: Instruction, repression, or fostering T cell-T cell communication?

Allergic disease is caused by the activation of allergen-specific CD4+ type-2 T follicular helper cells (Tfh2) and T helper 2 (Th2) effector cells that secrete the cytokines IL-4, IL-5, IL-9, and IL-13 upon allergen encounter, thereby inducing IgE production by B cells and tissue inflammation. While it is accepted that the priming and differentiation of naïve CD4+ T cells into Th2 requires allergen presentation by type 2 dendritic cells (DC2s), the underlying signals remain unidentified. In this review we focus on the interaction between allergen-presenting DC2s and naïve CD4+ T cells in lymph node (LN), and the potential mechanisms by which DC2s might instruct Th2 differentiation. We outline recent advances in characterizing DC2 development and heterogeneity. We review mechanisms of allergen sensing and current proposed mechanisms of Th2 differentiation, with specific consideration of the role of DC2s and how they might contribute to each mechanism. Finally, we assess recent publications reporting a detailed analysis of DC-T cell interactions in LNs and how they support Th2 differentiation. Together, these studies are starting to shape our understanding of this key initial step of the allergic immune response.

GBT1118, a Voxelotor Analog, Ameliorates Hepatopathy in Sickle Cell Disease.

Background and Objectives: In sickle cell disease (SCD), hepatopathy is a cumulative consequence of ischemia/reperfusion (I/R) injury from a vaso-occlusive crisis, tissue inflammation, and iron overload due to blood transfusion. Hepatopathy is a major contributing factor of shortened life span in SCD patients. We hypothesized that the voxelotor, a hemoglobin allosteric modifier, ameliorates sickle hepatopathy. Materials and Methods: Townes SCD mice and their controls were treated with either chow containing GBT1118, a voxelotor analog, or normal chow. We evaluated inflammation, fibrosis, apoptosis and ferroptosis in their livers using qPCR, ELISA, histology, and immunohistochemistry. Results: GBT1118 treatment resulted in reduced hemolysis, iron overload and inflammation in the liver of SCD mice. There were significant reductions in the liver enzyme levels and bile acids. Furthermore, GBT1118-treated mice exhibited reduced apoptosis, necrosis, and fibrosis. Increased ferroptosis as evident from elevated 4-hydroxynonenal (4-HNE) staining, malondialdehyde (MDA) levels, and expression of Ptgs2 and Slc7a11 mRNAs, were also significantly reduced after GBT1118 treatment. To explain the increased ferroptosis, we evaluated iron homeostasis markers in livers. SCD mice showed decreased expression of heme oxygenase-1, ferritin, hepcidin, and ferroportin mRNA levels. GBT1118 treatment significantly increased expressions of these genes. Conclusions: Our results suggest GBT1118 treatment in SCD confers the amelioration of sickle hepatopathy by reducing inflammation, fibrosis, apoptosis, iron overload and ferroptosis.

Acute kidney injury results in long-term alterations of kidney lymphatics in mice.

The long-term effects of a single episode of acute kidney injury (AKI) induced by bilateral ischemia-reperfusion injury (BIRI) on kidney lymphatic dynamics are not known. The purpose of this study was to determine if alterations in kidney lymphatics are sustained in the long term and how they relate to inflammation and injury. Mice underwent BIRI as a model of AKI and were followed up to 9 mo. Although kidney function markers normalized following initial injury, histological analysis revealed sustained tissue damage and inflammation for up to 9 mo. Transcriptional analysis showed both acute and late-stage lymphangiogenesis, supported by increased expression of lymphatic markers, with unique signatures at each phase. Expression of Ccl21a was distinctly upregulated during late-stage lymphangiogenesis. Three-dimensional tissue cytometry confirmed increased lymphatic vessel abundance, particularly in the renal cortex, at early and late timepoints postinjury. In addition, the study identified the formation of tertiary lymphoid structures composed of CCR7+ lymphocytes and observed changes in immune cell composition over time, suggesting a complex and dynamic response to AKI involving tissue remodeling and immune cell involvement. This study provides new insights into the role of lymphatics in the progression of AKI to chronic kidney disease.NEW & NOTEWORTHY Here, we perform the first, comprehensive study of long-term lymphatic dynamics following a single acute kidney injury (AKI) event. Using improved three-dimensional image analysis and an expanded panel of transcriptional markers, we identify multiple stages of lymphatic responses with distinct transcriptional signatures, associations with the immune microenvironment, and collagen deposition. This research advances kidney lymphatic biology, emphasizing the significance of longitudinal studies in understanding AKI and the transition to chronic kidney disease.

Nociplastic Pain: A Critical Paradigm for Multidisciplinary Recognition and Management.

Our understanding of chronic pain has evolved significantly, shifting from a focus on peripheral damage to recognizing the central mechanisms underlying pain perception. This perspective article explores the concept of nociplastic pain, a term introduced by the International Association for the Study of Pain (IASP) in 2017, which describes pain arising from altered pain modulation within the central nervous system, without clear evidence of tissue damage or inflammation. The historical progression from fibrositis to fibromyalgia, and now to nociplastic pain, underscores the complexity of chronic pain syndromes and the need for a multidisciplinary approach to management. Nociplastic pain is characterized by central sensitization, leading to heightened pain sensitivity and often accompanied by comorbidities such as fatigue, sleep disturbances, and cognitive difficulties. Advances in neuroimaging have revealed altered connectivity within key brain networks, such as the default mode and salience networks, in patients with nociplastic pain, providing insights into the neural underpinnings of this condition. The article also addresses controversies surrounding the role of small fiber neuropathy and autonomic dysfunction in nociplastic pain, highlighting the ongoing debates in the field. The practical importance of recognizing nociplastic pain across various medical disciplines-including primary care, orthopedics, neurology, psychiatry, and rheumatology-is emphasized, with recommendations for integrating this knowledge into clinical practice. Emerging therapies, such as neurofeedback, hyperbaric oxygen therapy, and neuromodulation, offer new avenues for treatment, particularly for patients who do not respond to conventional approaches. The article calls for continued research into the mechanisms of nociplastic pain, the development of reliable diagnostic tools, and the exploration of novel therapeutic strategies to improve patient outcomes. The recognition and management of nociplastic pain are crucial for advancing the care of patients with chronic pain, necessitating interdisciplinary collaboration and a patient-centered approach.

Dynamic Roles and Expanding Diversity of Adipose Tissue Macrophages in Obesity.

Adipose tissue macrophages (ATMs) are key regulators of adipose tissue (AT) inflammation and insulin resistance in obesity, and the traditional M1/M2 characterization of ATMs is inadequate for capturing their diversity in obese conditions. Single-cell transcriptomic profiling has revealed heterogeneity among ATMs that goes beyond the old paradigm and identified new subsets with unique functions. Furthermore, explorations of their developmental origins suggest that multiple differentiation pathways contribute to ATM variety. These advances raise concerns about how to define ATM functions, how they are regulated, and how they orchestrate changes in AT. This review provides an overview of the current understanding of ATMs and their updated categorization in both mice and humans during obesity. Additionally, diverse ATM functions and contributions in the context of obesity are discussed. Finally, potential strategies for targeting ATM functions as therapeutic interventions for obesity-induced metabolic diseases are addressed.

Universal and tissue-specific fibroblasts in chronic inflammation and cancer

In this issue of Cancer Cell, Gao etal. map fibroblast diversity across tumors and chronic inflammatory tissues. The authors uncover universal fibroblast subtypes such as LRRC15+ and MMP1+ myofibroblasts along with specialized tissue-specific subtypes. They reveal cellular roles of fibroblasts in immunosuppression through stromal niches and cell-cell interactions.

Study on the mechanism of activating SIRT1/Nrf2/p62 pathway to mediate autophagy-dependent ferroptosis to promote healing of diabetic foot ulcers.

Diabetic foot (DF), a prevalent and grave diabetes sequela, is considered as a notable clinical concern, with SIRT1 downregulation observed in DF patients' blood specimens. Nonetheless, the regulatory mechanisms of SIRT1 in diabetic foot ulcer (DFU) remain unclear. Thus, in the current study, we investigated the role and mechanisms of SIRT1 in alleviating DFU. Western blotting was used to detect the expression of autophagy and ferroptosis-related proteins, CCK8 assay was used to measure cell proliferation. Plate colony method was used to measure bacterial growth, and the inhibitory effect on intracellular and extracellular Staphylococcus aureus was observed after drug intervention. ELISA was used to detect inflammatory cytokines and oxidative stress markers levels. ROS, total iron, and Fe2+ levels were detected using corresponding assays. Additionally, HE staining detected the thickness of the epidermis and dermis of the rat wound tissue while the collagen deposition in the wound tissue was detected using Masson staining. In addition, Prussian blue staining was used to detect iron deposition, and C11 BODIPY 581/591 lipid peroxidation probe was used to detect lipid ROS. Our results suggested that the activation of SIRT1/Nrf2/p62 signaling affects cell proliferation, colony formation, ferroptosis, and the production of lipid ROS in DFU-infected cell model through autophagy. In vivo experiments indicated that activating SIRT1/Nrf2/p62 signaling affects oxidative stress, inflammation, and autophagy in wound tissue and promotes wound healing in DFU rats through mediating autophagy-dependent ferroptosis. Taken together, the activation of SIRT1/Nrf2/p62 pathway can promote DFU healing, which might be mediated by autophagy-dependent ferroptosis.

The Role of Growth Differentiation Factor-15 in the Diagnosis of Patients with Chronic Angina Undergoing Coronary Angiography

Coronary artery disease (CAD) is considered the most prevalent leading cause of myocardial ischemia and mortality worldwide and can lead to angina pectoris and myocardial infarction (MI). Growth Differentiation Factor-15 (GDF-15) is usually measured together with other biomarkers to predict all-cause mortality. During stressful conditions associated with tissue injury and inflammation like myocardial ischemia, it is released into circulation and detected at high concentration in foam cells of the atherosclerotic plaque. Its circulating levels are associated with chronic diseases rather than acute diseases mainly cardiovascular diseases (CVDs) like CAD and chronic heart failure (CHF). The aim of the current study was to detect the role of GDF-15 as a new biomarker for the diagnosis of stable angina patients with normal left ventricular ejection fraction who were presented as having stable chest pain, so that to avoid endangering them to the invasive coronary angiography. Fasting venous blood samples were taken from 90 participants who were presented as having chest pain. They were all subjected to echocardiography, electrocardiography and coronary angiography. The left ventricular ejection fraction was calculated using the biplane M mode method. GDF-15 serum level was measured by using Human GDF-15 Sandwich ELISA Kit following the manufacturer’s instructions.The current study detected a high significant difference in the serum levels of GDF-15 and serum creatinine between the patients and the control group (P≤0.01). On the other hand, there were significant differences in the serum levels of triglycerides and VLDL-C between both study groups (P≤0.05). ROC curve analysis showed that GDF-15 had AUC= 1.00, the best cut off= 254.16 with sensitivity and specificity of 100%. So, it can be concluded that GDF-15 could be used as a biomarker for the diagnosis of stable angina patients with obstructive atherosclerotic plaque and normal LV ejection fraction.