Reactivating mitochondrial quality control via the Nrf2 pathway to combat metabolic stress in diabetic osteoarthritis.

Aging is a multifactorial biological process characterized by progressive functional decline and increased susceptibility to chronic diseases. Targeting the molecular mechanisms underlying aging has therefore emerged as an important strategy for promoting healthy aging. Natural polyphenols, widely present in fruits, vegetables, tea, and medical and aromatic plants, have attracted considerable attention due to their geroprotective properties. This review examines current evidence on the ability of major dietary polyphenols, including resveratrol, epigallocatechin gallate (EGCG), curcumin, and quercetin, to modulate the hallmarks of aging, with particular emphasis on mitochondrial quality control as a central regulatory mechanism. Evidence indicates that polyphenols regulate key signaling pathways involved in aging biology, including AMP-activated protein kinase (AMPK), sirtuins (SIRT), mechanistic target of rapamycin (mTOR), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-κB (NF-κB). Through coordinated modulation of these pathways, polyphenols influence mitochondrial biogenesis, mitophagy, redox homeostasis, cellular senescence, and chronic inflammation. In addition, interactions between dietary polyphenols and the gut microbiome generate bioactive metabolites, such as urolithin A, which further contribute to mitochondrial regulation. Overall, polyphenols represent promising modulators of aging-associated pathways and may support strategies aimed at improving healthspan and reducing age-related disease risk.

Osteoarthritis (OA), one of the most prevalent joint diseases affecting more than 240 million people, strongly influences human health and reduces life quality. This review aims to fill the current research gap regarding the application and potential of mitochondrial quality control (MQC) based therapies in the treatment of OA, thereby providing guidance for future research and clinical practice. Chondrocytes respond to the inflammatory microenvironment via an array of signaling pathways and thus are critical in cartilage degeneration and OA progression. Mitochondria, as an important metabolic center in chondrocytes, play a vital role in responding to inflammatory stimuli. Multiple MQC mechanisms, including mitochondrial antioxidant defense, mitochondrial protein quality control, mitochondrial DNA repair, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, sustain mitochondrial homeostasis under pathological conditions. Despite extensive OA research, effective therapies remain limited. Elucidating MQC mechanisms in disease progression and post-traumatic cartilage repair is crucial. While preclinical studies demonstrate potential, clinical translation requires addressing protocol standardization, patient stratification, and long-term efficacy, as well as safety validation. Future research should focus on developing personalized MQC-based OA therapies guided by biomarker profiling and signaling pathway modulation. However, translational challenges persist, particularly regarding pervasive off-target effects, inadequate OA-specific targeting capacity, interpatient heterogeneity, and reliable evaluation of long-term therapeutic efficacy. Strategic prioritization of OA-specific MQC targets coupled with delivery system optimization may significantly improve both clinical translatability and therapeutic outcomes.

Accumulation of advanced glycation end products (AGEs) and activation of the receptor for AGEs (RAGE) are implicated in the progression of pathologies associated with aging, chronic inflammation, diabetes, and cellular stress. RAGE activation is also implicated in cardiovascular complications of type 2 diabetes, such as nephropathy, retinopathy, accelerated vascular diseases, and cardiomyopathy. Studies investigating the effects of AGE/RAGE axis activation on skeletal muscle oxidative stress and metabolism are more limited. We tested whether a high-fat diet (HFD) would alter circulating AGE concentration, skeletal muscle AGE accumulation, and oxidative stress in wild-type and RAGE-deficient mice. The physiological significance of AGE/RAGE axis activation in HFD-fed mice was evaluated in terms of exercise tolerance and mitochondrial respiratory chain complex activity. HFD elicited adiposity, abnormal fat distribution, and oral glucose intolerance. HFD also induced accumulation of Nε-carboxymethyl-l-lysine, increased protein carbonyl levels, and impaired respiratory chain complex activity in soleus muscle. Ablation of RAGE had no effects on weight gain and oral glucose tolerance in HFD-fed mice. Peak aerobic capacity and mitochondrial cytochrome-c oxidase activity were restored in HFD-fed RAGE-/- mice. We concluded that RAGE signaling plays an important role in skeletal muscle homeostasis of mice under metabolic stress. Novelty HFD in mice induces accumulation of AGEs, oxidative stress, and mitochondrial dysfunction in the soleus muscle. RAGE, the multi-ligand receptor for AGEs, modulates oxidative stress and mitochondrial electron transport chain function in the soleus muscle of HFD-fed mice.

High dietary sugar intake has emerged as a key modulator of systemic inflammation and metabolic dysregulation, both of which are associated with an increased risk of several chronic diseases, including cancer. Although bladder cancer is primarily driven by factors such as smoking and occupational exposures, metabolic dysregulation may also play a contributory role. Experimental studies indicate that elevated glucose levels promote proliferation, epithelial-mesenchymal transition, increase invasion, and reduce autophagy in bladder cancer cells. Epidemiological evidence suggests associations of high dietary glycaemic index/load and high sugar consumption with bladder cancer risk, although findings for these dietary factors remain heterogeneous. Furthermore, epidemiological data consistently demonstrate a positive association between diabetes mellitus and increased bladder cancer incidence and adverse clinical outcomes. Mechanistically, hyperglycaemia and accumulation of advanced glycation end products (AGEs) can activate inflammatory signalling pathways, including NF-κB, MAPK, and the NLRP3 inflammasome, leading to increased cytokine production, immune dysregulation, and oxidative stress. High dietary sugar intake has also been shown to alter gut microbiota composition, typically reducing short-chain fatty acid (SCFA)-producing bacteria and promoting intestinal permeability, endotoxaemia, and sustained immune activation through TLR4-dependent pathways. Within the bladder tumour microenvironment, systemic inflammatory disturbances enhance oncogenic signalling cascades such as COX-2, JAK/STAT3, and NF-κB, thereby fostering epithelial-mesenchymal transition, angiogenesis, and potential resistance to therapy. Evidence suggests that maintaining well-regulated blood sugar levels may help lower the risk of bladder cancer. Adopting lifestyle habits such as whole-food, fibre-rich diets, probiotics, and regular physical activity supports metabolic and microbial homeostasis, SCFA-mediated immune regulation, and inflammation reduction, thereby serving as a preventive strategy. This review aims to synthesise current evidence on the complex interplay between dietary sugar intake, gut microbiota dysregulation, systemic inflammation, and bladder cancer, and to highlight potential preventive dietary interventions.

Osteoarthritis (OA) is a debilitating disease of the joints, impacting over 500 million peopleworldwide. OA affects several load-bearing regions of the body, but specifically within the knee joint, its pathology involves deterioration of several tissues including cartilage, synovium, meniscus, ligaments and bone, ultimately leading to chronic pain, severe inflammation and joint immobility. Despite its large impact on quality of life and the discovery of several disease modifying OA drugs, no clinically approved cure exists. Aging represents the greatest risk for OA as accumulation of advanced glycation endproducts (AGEs) increase cartilage stiffness, causing chondrocytes to exhibit senescent, inflammatory behavior. We simultaneously captured this biomechanical and biochemical response by treating cartilage explants with 100 mM ribose. Using in silico blind docking simulations, we predicted the in vitro efficacy of anti-aging therapeutics resveratrol and curcumin at suppressing AGE formation and cartilage stiffening, whilst maintaining chondrocyte health. Another major OA cause is traumatic joint injury, following which, significant inter-tissue biological crosstalk occurs, resulting in immediate elevation of inflammatory cytokines and cartilage matrix degrading enzymes that rapidly accelerate disease onset. To represent this crosstalk in vitro, we developed co-cultures containing combinations of cartilage, synovium and meniscus tissue. In response to catabolic challenge with interleukin-1 (IL1), the synovium exhibited protective effects by lowering nitrite production. Additionally, in presence of synovium, cartilage matrix loss was further suppressed following single administration of receptor antagonist IL-1Ra. Proteomic analysis revealed IL-4, matrilin-3 and carbonic anhydrase III as proteins which may contribute to endogenous IL-1 inhibitor production, explaining the protective effects of synovium. Finally, achieving long-term benefits of such therapeutics remains challenging due to rapid synovial joint space clearance and an inability of drugs to penetrate through the dense, negatively charged cartilage matrix following their intra-articular administration. Therefore, we synthesized cartilage-targeting and penetrating conjugates using Avidin or Cationic Peptide Carriers for delivering IL-1Ra. A single low dose of each conjugate significantly alleviated long-term IL-1-induced cartilage aggrecan and nitrite release, while rescuing cellular metabolism more effectively than free IL-1Ra. This work can potentially enable clinical translation of various drugs that have failed due to lack of cartilage targeting or systemic toxicity.--Author's abstract

2. The association between lumbar bone mineral density and advanced glycation end products derived from confocal fluorescence microscopy: a prospective investigation of bone biopsies in patients undergoing lumbar spinal fusion surgery

The impact of mitochondrial quality control by Sirtuins on the treatment of type 2 diabetes and diabetic kidney disease

The pathophysiological distinctions between osteoarthritis (OA) and diabetic osteoarthritis (DOA) are critical yet not well delineated. In this study, we employed single-cell RNA sequencing to clarify the unique cellular and molecular mechanisms underpinning the progression of both conditions. We identified a novel subpopulation of chondrocytes in DOA, termed 'Heat Shock' chondrocytes, marked by the expression of distinct molecular markers including HSPA1A, HSPA1B, HSPB1, and HSPA8. Our comprehensive gene expression analysis revealed a pronounced upregulation of inflammatory pathways associated with oxidative stress-namely the MAPK, NF-κB, and PI3K signaling pathways-in the effector and proliferating chondrocyte subpopulations, with a predominance in DOA. Further, our investigation into cell-cell communication demonstrated a significant diminution of intercellular signaling in DOA compared to OA. These insights not only elucidate distinct cellular heterogeneities and potential pathogenic mechanisms differentiating OA from DOA but also enhance our understanding of their molecular pathophysiology, offering novel avenues for targeted therapeutic strategies.

Diabetes mellitus (DM), a metabolic disease of globally health concern, is pathologically attributed to mitochondrial dysfunction, an essential component in disease progression. Mitochondrial quality control (MQC) acts as a critical defense mechanism for metabolic homeostasis, yet its implications in DM and its complications remain incompletely understood. This study thoroughly summarizes emerging evidence that delineates the molecular processes of MQC, with an emphasis on effector protein post-translational regulation, upstream signaling hubs, and interactions with other metabolic processes including ferroptosis and lipid metabolism. We highlight newly discovered processes involving mitochondrial-derived vesicles, licensed mitophagy, and mitocytosis that broaden the regulatory landscape of MQC, going beyond the traditionally recognized process including biogenesis, dynamics and mitophagy. MQC imbalance exacerbates insulin resistance, while impaired insulin signaling reciprocally compromises mitochondrial function, creating a vicious cycle of metabolic deterioration. Despite tissue-specific pathophysiology, diabetic complications exhibit identical MQC impairment including suppressed biogenesis, fission-fusion imbalance, and deficient mitophagy. Emerging therapies including clinical hypoglycemic agents and bioactive phytochemicals demonstrate therapeutic potential by restoring MQC. However, current strategies remain anchored to classical pathways, neglecting novel MQC mechanisms such as mitocytosis. Addressing this gap demands integration of cutting-edge MQC insights into drug discovery, particularly for compounds modulating upstream regulators. Future studies must prioritize mechanistic dissection of MQC novel targets and their translational relevance in halting metabolic collapse of diabetes progression. Since mitochondrial function is a cornerstone of metabolic restoration, synergizing precision MQC modulation with multi-target interventions, holds transformative potential for refine diabetic complications therapeutics.

Diabetes mellitus (DM) is one of the foremost medical and social challenges of the 21st century, and diabetic neuropathy (DN) is one of its most common complications, occurring in 50–60% of patients with long-standing disease. The aim of this study is to systematize current data on the pathophysiological mechanisms of DN and to analyze the role of metabolic, vascular, oxidative, inflammatory, and trophic factors in nerve tissue damage. A systematic literature review (2014–2024) was conducted using international and Russian databases (PubMed, Scopus, Web of Science, RSCI, eLIBRARY.RU) with the following keywords: "diabetes mellitus," "diabetic neuropathy," "hyperglycemia," "polyol pathway," "advanced glycation end-products," "oxidative stress," "nerve growth factor," and their Russian equivalents. The pathogenesis of DN involves the activation of the polyol pathway, the accumulation of advanced glycation end products, mitochondrial and endothelial dysfunction, chronic inflammation, and a deficiency of neurotrophic factors, all of which lead to progressive nerve tissue damage. Understanding these mechanisms offers opportunities for early diagnosis, the development of biomarkers, and pathogenetically-based therapy. A comprehensive approach to treatment can slow the progression of this complication and improve patients' quality of life.

Osteoarthritis (OA) is a major age-related disease, which may be caused by the accumulation of advanced glycation end-products (AGEs). Excessive degradation of type II collagen and aggrecan by matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS) induced by AGEs is a pivotal event in the pathogenesis of osteoarthritis. In addition, activation of the nuclear factor-κB (NF-κB) pathway induces the expression of a cascade of proinflammatory cytokines, such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α). In the present study, we investigated the effects of salicin, one of the main constituents of aspirin and a derivative of Alangium chinense, on AGE-induced degradation of the articular extracellular matrix in SW1353 human chondrocytes. Our findings reveal a novel beneficial role of salicin in rescuing degradation of type II collagen and aggrecan, reducing oxidative stress, attenuating expression of proinflammatory cytokines, and inhibiting activation of the NF-κB proinflammatory signaling pathway in chondrocytes stimulated with AGEs. Salicin may thus have potential as a safe and effective therapy against the development and progression of OA.

The multiform relation between DM and cancer is far away to be definitively understood and all the studies of the next years will have to reckon with the complexity of both DM and neoplasms and consider the heterogeneity of the population involved. But, in the third millenium medicine, all the scientist are called to make an effort in order to give a solution to the emerging health questions of our society.

Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA. The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels. Intraarticular injections of ribose enhanced cartilage AGE levels approximately 5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels. These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.

Patients with peripheral artery disease are at risk for critical limb ischemia and amputation. Accumulation of advanced glycation end products is increased and predictive for coronary and cerebrovascular events in several high cardiovascular risk groups. We hypothesized that accumulation of tissue advanced glycation end products, measured by skin autofluorescence (SAF), predicts amputation in patients with peripheral artery disease. Between October 2007 and June 2008, 252 patients with peripheral artery disease were included at the outpatient clinic. During a 5-year follow-up, 22 (9%) had an amputation because of critical limb ischemia. Competing risks regression analysis showed a subproportional hazard ratio of 3.05 (95% confidence interval [CI], 1.87-4.96); P<0.0001 for amputation per unit incease of SAF. After correction for diabetes mellitus and Fontaine stage, subproportional hazard ratio was 2.72 (95% CI, 1.38-5.39); P=0.004. In patients with Fontaine stage I and II only (n=215), SAF was the only predictor for amputation, subproportional hazard ratio 4.05 (95% CI, 2.09-7.83); P<0.0001. Fontaine stage multiplied by SAF resulted in a significant increase of the area under the curve for prediction of amputation when compared with Fontaine stage only: area under the curve increased from 0.74 (95% CI, 0.63-0.86) to 0.83 (95% CI, 0.74-0.92); P=0.003. Skin autofluorescence, as a measure of tissue advanced glycation end products deposition, predicts amputation in patients with peripheral artery disease during a 5-year follow-up, independent from the presence of diabetes mellitus and Fontaine stage. Even at lower Fontaine stage (I or II), SAF is a strong predictor of amputation. The multiplication of Fontaine stage by SAF results in a good prediction model of amputation.

Advanced glycation end‐products (AGEs) play a crucial role in the pathogenesis of diabetic osteoarthritis (DOA), contributing to cartilage degradation and impaired joint lubrication, which complicate clinical management. However, no therapeutics specifically targeting AGEs are developed for DOA treatment. Here, a composite hydrogel (PTC‐MP) incorporated with polydopamine‐coated tannic cerium (PTC) nanozymes and magnesium ions (Mg2+), implementing a strategy of “restrain‐restore‐reinforce (3R)” for AGEs‐directed DOA therapy is reported. PTC‐MP hydrogel effectively restrains the formation of AGEs by scavenging free radicals, chelating ferrous ions, and competitive hydrophobic site binding. By leveraging mild photothermal therapy (mPTT), PTC‐MP hydrogel restores cartilage homeostasis by reducing AGEs‐induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, Mg2+ in PTC‐MP hydrogel reinforces joint repair by stimulating endogenous hyaluronic acid (HA) secretion to improve lubrication. In a rat DOA model, PTC‐MP hydrogel with mPTT significantly attenuated DOA progression, reduced osteophytes formation and synovial inflammation, and improved motor function. Therefore, the “3R” strategy targeting AGEs provides a promising therapeutic approach for recalcitrant DOA.