OBJECTIVE: To assess the efficacy and safety of diacerein monotherapy in adults with obesity.
METHODS: Forty-two adults with obesity participated in the study and were randomly assigned to receive diacerein or placebo in addition to lifestyle modification for 14 weeks, in a double-blinded fashion. Differences in changes in body weight, body composition, metabolic variables, fatty liver-related indicators, cardiovascular system variables, lifestyle score and metabolic factors were compared.
RESULTS: Post-treatment weight loss percentage from baseline was -6.56% (-8.71%, -4.41%) in the diacerein group and -0.59% (-2.74%, 1.56%) in the placebo group. Compared with the placebo group, the diacerein group showed significant improvements in body composition, metabolic variables and indicators related to fatty liver. In addition, after 14 weeks of treatment, diacerein led to a significant reduction in serum visfatin concentration versus the placebo group. The reductions in total body fat mass and visceral fat area mediated the weight loss induced by diacerein. No significant differences were found between the groups in the number of adverse events and safety variables.
CONCLUSIONS: For adults with obesity, diacerein led to a clinically meaningful weight loss and provided multiple metabolic benefits with acceptable safety. These results support that diacerein is a promising candidate medicine to be developed for obesity management.

This study aimed to formulate diacerein loaded terpene-enriched invasomes (DCN-TINV) to fulfill a fruitful management of osteoarthritis. A 23 factorial design was adopted, including A: cholesterol concentration (%w/v), B: ethanol volume (mL) and C: phosphatidylcholine: drug ratio as the studied factors. Invasomes were constructed using the thin film hydration technique. Herein, percent entrapment efficiency (EE%), particle size (PS), poly-dispersity index (PDI) and zeta potential (ZP) were statistically analyzed using Design-Expert® software to select the optimum formula. The selected criteria for detecting the optimum formula were restricting PS (<350 nm), dismissing PDI, magnifying ZP (as absolute value) and EE%. The selected formula was further scrutinized through multiple in-vitro studies, including Fourier-transform infrared spectroscopy, differential scanning calorimetry, pH measurement, stability study, release profile and transmission electron microscopy. Furthermore, the ex-vivo performance was evaluated through ex-vivo skin permeation and deposition. Finally, it was subjected to an array of in-vivo tests, namely Draize test, histopathology, In-vivo skin penetration, edema size, and nociception inhibition measurements. The optimum formula with desirability (0.913) demonstrated EE% (89.21% ± 2.12%), PS (319.75 ± 10.11 nm), ZP (-55 ± 3.96 mV) and a prolonged release profile. Intriguingly, revamped skin permeation (1143 ± 32.11 µg/cm2), nociception inhibition (77%) and In-vivo skin penetration (144 µm) compared to DCN suspension (285 ± 21.25 µg/cm2, 26% and 48 µm, respectively) were displayed. The optimum DCN-TINV exhibited plausible safety and stability profiles consolidated with auspicious efficacy for better management of osteoarthritis.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN\'s cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes\' resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN\'s cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.

Double cortin-like kinase 1 (DCLK1) exhibits high expression levels across various cancers, notably in human colorectal cancer (CRC). Diacerein, a clinically approved interleukin (IL)-1β inhibitor for osteoarthritis treatment, was evaluated for its impact on CRC proliferation and migration, alongside its underlying mechanisms, through both in vitro and in vivo analyses. The study employed MTT assay, colony formation, wound healing, transwell assays, flow cytometry, and Hoechst 33342 staining to assess cell proliferation, migration, and apoptosis. Additionally, proteome microarray assay and western blotting analyses were conducted to elucidate diacerein\'s specific mechanism of action. Our findings indicate that diacerein significantly inhibits DCLK1-dependent CRC growth in vitro and in vivo. Through high-throughput proteomics microarray and molecular docking studies, we identified that diacerein directly interacts with DCLK1. Mechanistically, the suppression of p-STAT3 expression following DCLK1 inhibition by diacerein or specific DCLK1 siRNA was observed. Furthermore, diacerein effectively disrupted the DCLK1/STAT3 signaling pathway and its downstream targets, including MCL-1, VEGF, and survivin, thereby inhibiting CRC progression in a mouse model, thereby inhibiting CRC progression in a mouse model.

The aim of this study is to explore the potential of repurposing the antiarthritic drug diacerein (DCN) against diclofenac (DCF)-induced acute nephrotoxicity in rats. Rats were divided into four groups: Group I (CTRL) served as the negative control; Group II (DCF) served as the positive control and was injected with DCF (50 mg/kg/day) for three consecutive days (fourth-sixth) while being deprived of water starting on day 5; Group III (DCF + DCN50) and Group IV (DCF + DCN100) were orally administered DCN (50 and 100 mg/kg/day, respectively) for six days and injected with DCF, while being deprived of water as described above. Changes in kidney function biomarkers were assessed. Levels of MDA and GSH along with NO content in kidney tissues were measured as indicators of oxidative stress status. Histopathological changes of the renal cortex and medulla were evaluated. Changes in renal NF-κB and SIRT-1 levels were immunohistochemically addressed. Western blotting was used to estimate the relative expressions of HIF-1α, p53, and active caspase-3. Our results showed that DCN inhibited kidney dysfunction and suppressed oxidative stress, which were reflected in improved kidney architecture, including less tubular degeneration and necrosis in the cortex and medulla. Interestingly, DCN reduced renal HIF-1α, p53, and active caspase-3 expression and NF-κB activation while increasing renal SIRT1 expression. In conclusion, for the first time, DCN counteracts acute kidney injury induced by DCF in rats by its anti-oxidative, anti-inflammatory, antinecrotic, and anti-apoptotic effects in a dose-dependent manner, which are mainly via targeting SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

UNASSIGNED: Tissue engineering is the application system that tries to restore damaged tissues by different approaches, such as cellular therapy, application of cell differential factors, and various materials. One of the important goals in tissue engineering is to guide stem cells directly to the desired tissue, and researchers tried to utilize different molecules as effective factors to improve this technique.
UNASSIGNED: This study aims to demonstrate the effects of diacerein, a slow-acting drug for the treatment of osteoarthritis, on mesenchymal stem cell proliferation and evaluate its potential in the chondrogenesis process.
UNASSIGNED: Stem cells were isolated from adipose tissue, characterized by flow cytometry, and cells were treated with 10-5M diacerein for three weeks. Chondrogenic gene expression of SOX9, COL2A1, ACAN, and TGFB1 were analyzed by qRT-PCR and immunocytochemistry techniques.
UNASSIGNED: Our results showed that diacerein increased the expression of the following genes involved in chondrogenesis: SOX9 (2.9-fold, P < 0.00), COL2A1 (2.2-fold, P < 0.00), ACAN (2.7-fold, P < 0.00), and TGFB1 (2.6-fold, P < 0.00). Immunocytochemistry results also showed increased production of collagen type II as the main protein marker for chondrocytes.
UNASSIGNED: We observed that diacerein alone could initiate and enhance chondrogenesis, and it can be used as a differentiation factor for stem cells to chondrocyte besides its ability to inhibit IL-1β. Knowing the actual function of diacerein, it could be a good candidate for the treatment of osteoarthritis.

This study aimed to formulate diacerein (DCN)-loaded flexosomes for enhanced efficacy against osteoarthritis. A 23 D-optimal design was employed, investigating the impact of surfactant type (A), surfactant concentration (%w/v) (B), and oleylamine amount (mg) (C). Flexosomes were formulated using a rotary evaporator, and Design-Expert® software was utilized to statistically analyze entrapment efficiency (EE%), zeta potential (ZP), poly-dispersity index (PDI), and particle size (PS) to determine the optimum formula. The selection criteria prioritized increased ZP (as absolute value) and EE%, coupled with decreased PDI and PS. Rigorous physicochemical, in vivo, and ex vivo tests were conducted to validate the safety, stability, and activity of the optimal formula. Physicochemical assessments encompassed pH measurement, transmission electron microscopy, differential scanning calorimetry, release profiles, storage effects, and Fourier transform infrared spectroscopy. In vivo tests included permeation studies, histopathology, anti-inflammatory activity, and skin irritancy, while ex vivo tests focused on permeation parameters and skin deposition. The optimum formula demonstrated high desirability (0.931), along with favorable EE% (90.93%), ZP (- 40.4 mV), particle size (188.55 nm), and sustained behavior. Notably, improved in vivo permeation (132 µm), skin deposition (193.43 µg/cm2), and antinociceptive activity (66%) compared to DCN suspension (48 µm, 66.31 µg/cm2, and 26%, respectively) were observed. The optimal formula also exhibited excellent safety and storage characteristics. In conclusion, DCN-loaded flexosomes exhibit significant potential for effectively managing osteoarthritis.

Renal ischemia-reperfusion (I/R) can be precipitated by multiple clinical situations that lead to impaired renal function and associated mortality. The resulting tubular cell damage is the outcome of complex disorders including, an inflammatory process with an overproduction of cytokines. Here, diacerein (DIA), an inhibitor of proinflammatory cytokine interleukin-1 beta (IL-1β), was investigated against renal I/R in rats. DIA was orally administrated (50 mg/kg/day) for ten days before bilateral ischemia for 45 min with subsequent 2 hr. reperfusion. Interestingly, DIA alleviated the renal dysfunction and histopathological damage in the renal tissues. Pretreatment with DIA corrected the oxidative imbalance by prevented reduction in antioxidant levels of GSH and SOD, while it decreased the elevation of the oxidative marker, MDA. In addition, DIA downregulated IL-1β and TNF-α expression in the renal tissues. Consequent to inhibition of the oxidative stress and inflammatory cascades, DIA inhibited the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK). Therefore, downstream targets for p38 MAPK were also inhibited via DIA which prevented further increases of inflammatory cytokines and the apoptotic marker, caspase-3. Collectively, this study revealed the renoprotective role of DIA for renal I/R and highlighted the role of p38 MAPK encountered in its therapeutic application in renal disease.

Diabetes mellitus is a common metabolic disorder affecting different body organs; one of its serious complications is diabetic cardiomyopathy (DCM). Thus, finding more cardiopreserving agents to protect the heart against such illness is a critical task. For the first time, we planned to study the suspected role of diacerein (DIA) in ameliorating DCM in juvenile rats and explore different mechanisms mediating its effect including inflammasome/caspase1/interleukin1β pathway. Four-week-aged juvenile rats were randomly divided into groups; the control group, diacerein group, diabetic group, and diabetic-treated group. Streptozotocin (45 mg/kg) single intraperitoneal (i.p.) dose was administered for induction of type 1 diabetes on the 1st day which was confirmed by detecting blood glucose level. DIA was given in a dose of 50 mg/kg/day for 6 weeks to diabetic and non-diabetic rats, then we evaluated different inflammatory, apoptotic, and oxidative stress parameters. Induction of DCM succeeded as there were significant increases in cardiac enzymes, heart weights, fasting blood glucose level (FBG), and glycosylated hemoglobin (HbA1c) associated with elevated blood pressure (BP), histopathological changes, and increased caspase 3 immunoexpression. Furthermore, there was an increase of malondialdehyde (MDA), inflammasome, caspase1, angiotensin II, nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNFα), and interleukin 1β (IL1β). However, antioxidant parameters such as reduced glutathione (GSH) and total antioxidant capacity (TAC) significantly declined. Fortunately, DIA reversed the diabetic cardiomyopathy changes mostly due to the observed anti-inflammatory, antioxidant, and anti-apoptotic properties with regulation of blood glucose level.DIA has an ability to regulate DCM-associated biochemical and histopathological disturbances.

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.