Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis.

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.

Repurposing diacerein to suppress colorectal cancer growth by inhibiting the DCLK1/STAT3 signaling pathway.

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)-1ß 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.

Inhibitory effect of diacerein on diclofenac-induced acute nephrotoxicity in rats via modulating SIRT1/HIF-1α/NF-κB and SIRT1/p53 regulatory axes.

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.

Capped flexosomes for prominent anti-inflammatory activity: development, optimization, and ex vivo and in vivo assessments.

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.

Downregulation of IL-1ß/p38 mitogen activated protein kinase pathway by diacerein protects against kidney ischemia/reperfusion injury in rats.

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-1ß), 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-1ß 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.

Cardioprotective role of diacerein in diabetic cardiomyopathy via modulation of inflammasome/caspase1/interleukin1ß pathway in juvenile rats.

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/interleukin1ß 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 1ß (IL1ß). 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.

Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein.

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.

Efficacy of Interleukin-1ß Inhibitor on Dry Eye Disease in Patients with Degenerative Arthritis.

Purpose: To evaluate diacerein (interleukin-1ß inhibitor) efficacy on ocular surface disease (OSD). Patients and Methods: This prospective observational study included patients who received diacerein for osteoarthritis and had dry eye (DE). The primary outcome was corneal staining score. Secondary outcomes were ocular surface disease index (OSDI) score, tear breakup time (TBUT), tear osmolarity (Osm), Schirmer's test results, interleukin-1α (IL-1α), interleukin-1ß (IL-1ß), and interleukin-1 receptor antagonist (IL-1Ra) levels in tears. All measurements were done at baseline and 2-month follow-up visits. Linear mixed models were used to examine the effect of all parameters, and log-transformed models were used for IL-1α, IL-1ß, and IL-1Ra analyses. Results: Thirty-four patients (31 females and 3 males) were enrolled. The corneal staining score improved by 1.29 points (P=0.022, 95% confidence interval [95% CI] 0.19 to 2.40) after 2 months, and the OSDI score improved by 17.2 points (P<0.001, 95% CI 10.82 to 23.58) but TUBT decreased by 0.66 seconds (P=0.021, 95% CI 0.10 to 1.22). No significant differences were observed in the tear Osm and Schirmer's test. IL-1Ra demonstrated no statistical difference, IL-1α was significantly increased by 80% (P=0.260), and IL-1ß was significantly decreased by 99.21% (P<0.001). Conclusion: Diacerein can improve corneal staining and decrease IL-1ß levels in tears, which reflects better DE symptoms. Diacerein may be a promising alternative treatment for patients with OSD and osteoarthritis.

TLR4/ MyD88/NF-κB signaling pathway involved in the protective effect of diacerein against lung fibrosis in rats.

PURPOSE: Pulmonary fibrosis (PF) is an inescapable problem. Diacerein, a chondro-protective drug, has antioxidant and anti-inflammatory effects. Its effect on PF injury has not yet been fully clarified. Therefore, the current study aimed to detect its protective effect on lung tissue with the explanation of possible underlying mechanisms. METHODS: Adult male albino rats were assigned to four groups: control group, diacerein control group, PF non-treated group, and PF diacerein pretreated group. Lung tissue oxidative stress parameters, inflammatory biomarkers mainly Toll-like receptors-4 (TLR4), and myeloid differentiation factor 88 (MyD88) levels were determined. Histopathological examination of lung tissue and immunohistochemical studies of nuclear factor-kappa B (NF-κB), and transforming growth factor- ß (TGF-ß) were also done. RESULTS: Diacerein pretreatment has the ability to restore the PF damaging effect, proved by the reduction of the oxidative stress and lung tissue inflammation via downregulation of TLR4/NF-κB signaling pathway together with the restoration of TGF-ß level and improvement of the histopathological and immunohistochemical study findings in the lung tissue. CONCLUSION: These results suggested the protective effect of diacerein on PF relies on its antioxidant and anti-inflammatory effects reducing TLR4/NF-κB signaling pathway.

Diacerein mitigates adenine-induced chronic kidney disease in rats: Focus on TLR4/MYD88/TRAF6/NF-κB pathway.

Chronic kidney disease (CKD) is a serious problem which negatively affects human health. AIMS: The purpose of this investigation was to explore the possible beneficial impacts of diacerein on adenine-induced CKD in rats. MAIN METHODS: 32 male Sprague Dawley rats were allocated into 4 groups; normal, diseased (200 mg/kg adenine, orally) and diacerein (25 and 50 mg/kg, orally). KEY FINDINGS: Adenine produced marked reduction in rats' body weights and a substantial increase in kidney/body weight index. Additionally, adenine significantly increased serum creatinine and BUN levels besides proteinuria levels, and also reduced creatinine clearance. Adenine induced oxidative stress as evidenced by increased MDA content and diminished GSH concentration in renal tissues. These biochemical measurements were confirmed by the morphological and histopathological results. Moreover, adenine revealed substantial elevation in renal level and expression of MYD88, TRAF6 and TNF-α, and renal level of IL-1ß in addition to increased expression of TLR4, NF-κB p65 and p-NF-κB p65 while reduced the expression of IκB-α. Diacerein in a dose-dependent manner effectively ameliorated adenine-induced alterations. SIGNIFICANCE: Diacerein could be used as a therapeutic agent to attenuate CKD after further clinical studies.

In vitro antibiofilm and bacteriostatic activity of diacerein against Enterococcus faecalis.

Enterococcus faecalis is one of the main pathogens that causes hospital-acquired infections because it is intrinsically resistant to some antibiotics and often is capable of biofilm formation, which plays a critical role in resisting the external environment. Therefore, attacking biofilms is a potential therapeutic strategy for infections caused by E. faecalis. Current research indicates that diacerein used in the treatment of osteoarthritis showed antimicrobial activity on strains of gram-positive cocci in vitro. In this study, we tested the MICs of diacerein using the broth microdilution method, and successive susceptibility testing verified that E. faecalis is unlikely to develop resistance to diacerein. In addition, we obtained a strain of E. faecalis HE01 with strong biofilm-forming ability from an eye hospital environment and demonstrated that diacerein affected the biofilm development of HE01 in a dose-dependent manner. Then, we explored the mechanism by which diacerein inhibits biofilm formation through qRT-PCR, extracellular protein assays, hydrophobicity assays and transcriptomic analysis. The results showed that biofilm formation was inhibited at the initial adhesion stage by inhibition of the expression of the esp gene, synthesis of bacterial surface proteins and reduction in cell hydrophobicity. In addition, transcriptome analysis showed that diacerein not only inhibited bacterial growth by affecting the oxidative phosphorylation process and substance transport but also inhibited biofilm formation by affecting secondary metabolism, biosynthesis, the ribosome pathway and luxS expression. Thus, our findings provide compelling evidence for the substantial therapeutic potential of diacerein against E. faecalis biofilms.

Investigating the Efficacy and Safety of Diacerein in the Management of Knee Osteoarthritis with reference to its conventional management.

BACKGROUND: Designated as a "priority disease" by World Health Organization, Osteoarthritis is the most common chronic rheumatic disease. Providing a proper treatment for Osteoarthritis is still a major public health challenge. Diacerein has been proposed as a slow acting, symptom modifying or even disease modifying drug used in Osteoarthritis having a risk-benefit ratio far better than conventionally used drugs. However, the evidence of efficacy and safety of use of Diacerein in Osteoarthritis is yet to be explored. Hence, this study attempted to investigate the efficacy and safety of Diacerein in the management of knee osteoarthritis. METHODS: This is an analytical cohort study comparing Diacerein with Non-steroidal anti-inflammatory drugs for two months in the management of knee OA. Efficacy was assessed by scores of Lysholm Knee Scoring Scale, Knee injury and Osteoarthritis Outcome Score - Physical Function Short form and Western Ontario and McMaster Universities Osteoarthritis Index. RESULTS: After two months of treatment, the post- treatment scores were significantly superior to the baseline scores in both the treatment groups (p<0.001). There were no significant differences among the post-treatment scores in two different treatment groups (p>0.05). Discoloration of urine and gastritis were the frequently reported adverse effects in Diacerein treatment group and Non-steroidal anti-inflammatory drugs treatment group respectively. CONCLUSIONS: Our findings have shown Diacerein is as effective as Non-steroidal anti-inflammatory drugs in treating knee OA patients. Diacerein was generally well tolerated, with a good safety profile. These findings indicate the need for further studies with experimental study design in larger scale.

Rapid characterization of the potential active metabolites of diacerein in rat plasma based on UHPLC-Q-exactive orbitrap mass spectrometry and molecular docking.

Diacerein, a competently semisynthetic diacetyl derivative of anthraquinone, is a nonsteroidal anti-inflammatory drug, which has been used for treating osteoarthritis and preventing vascular diseases. However, previous investigation indicated that diacerein metabolites and its metabolic pathway in vivo was still unclear. In this research, an effective method was established based on ultra-high-performance liquid chromatography coupled with Q-Exactive-Orbitrap mass spectrometer and molecular docking to screen and detect the potential active metabolites of diacerein in rat plasma after oral administration. The data acquisition and processing methods including Full MS-ddMS2 combined with parallel reaction monitoring mode, extracted ion chromatogram and diagnostic fragment ions were adopted to detect and identify more infinitesimal and unknown diacerein metabolites in vivo. As a result, a total of 32 metabolites were detected and identified in rat plasma according to retention times, accurate mass, diagnostic fragment ions, and relevant drug biotransformation knowledge, among 31 metabolites were firstly reported in this study. Then, the relevant reactions in vivo such as deacetylation, hydroxylation, methylation, sulfate conjugation, glucuronidation, and their composite reactions, were all detected. Ultimately, the results of molecular docking showed that the metabolites of diacerein might have good affinity with IL-1 receptor in vivo. Among them, the metabolites M21 and M1 have the strongest binding affinity with IL-1 receptors, and could be considered as potential active metabolites of diacerein, which have an efficient effect on exerting pharmacological effects of diacerein in vivo. In conclusion, the study of diacerein metabolites in rat plasma expanded our understanding about the metabolism of diacerein in vivo and provided the significant foundation for further drug efficacy studies.

Diacerein modulates TLR4/ NF-κB/IL-1ß and TRPC1/CHOP signalling pathways in gentamicin-induced parotid toxicity in rats.

The present study aimed to identify the possible protective effect of diacerein (DIA) on gentamicin (GNT)-induced parotid toxicity in rats. DIA was administered in the presence and absence of GNT. Thirty-two Wistar adult male rats were randomly arranged into four groups: control, DIA (50 mg/kg/day), GNT (100 mg/kg) and GNT+DIA groups for 8 days. Parotid oxidative stress parameters, besides inflammatory and apoptotic biomarkers, were evaluated. Salivary flow rate, transient receptor potential canonical 1 (TRCP1), and C/EBP homologous protein (CHOP) in parotid tissue were measured. A parotid histopathological examination and an interleukin-1 beta (IL-1ß) immunohistochemical study were also performed. GNT significantly increased parotid oxidative stress, inflammatory, apoptotic and CHOP biomarkers with decreased salivary flow rate and TRCP1 level. A histopathological picture of parotid damage and high IL-1ß immunoexpression were detected. DIA significantly normalized the distributed oxidative, inflammatory and apoptotic indicators, CHOP and TRCP1, with a prompt improvement in the histopathological picture and a decrease in IL-1ß immunoexpression. These results reported that DIA protects against GNT-induced parotid toxicity via modulation of TLR4/NF-κB/IL-1ß and TRPC1/CHOP signalling pathways.

Role of diacerein on steroidogenesis and folliculogenesis related genes in ovary of letrozole-induced PCOS mice.

Polycystic ovary syndrome (PCOS), an intricate and multifaceted metabolic-endocrine disorder that typically affects 6-20% of women of reproductive age and accounts for 70-80% of all occurrences of infertility globally. In this study we focussed on the effect of diacerein (DIC) on steroidogenesis and follicle development in addition to the basic metabolic and endocrine problems which are associated with PCOS. Eighteen mature female parkes strain mice were separated into three groups at random with 6 animals in a group as follows: Group I, received water and normal diet for 66 days; group II received letrozole (LETZ) (6 mg/kg bw) for the induction of PCOS; Group III received LETZ (6 mg/kg) for 3 weeks followed by the administration of DIC (35 mg/kg) for 45 days. In our study we observed that mice with PCOS had irregular estrous cycle with increased LH/FSH, estrogen level and decline in expression of Kitl, Bmp, Cyp11a1, CYP19a1, Ar, lhr, Fshr and Esr1 as well as decreased SOD and CAT activity in ovary. Moreover, we observed increase in the expression of CYP17a1, as well as increase in serum cholesterol, triglycerides, testosterone, LH, VEGF and insulin levels. All these changes were reversed after the administration of DIC in PCOS mice. Diacerin administration reversed abnormalities in mice with PCOS by modulating the regulation of genes which are related to steroidogenesis and folliculogenesis.

Diacerein versus non-steroidal anti-inflammatory drugs in the treatment of knee osteoarthritis: a meta-analysis.

BACKGROUND: Knee osteoarthritis (KOA) is a common musculoskeletal condition affecting millions of people worldwide and posing a significant challenge to clinicians and researchers. Emerging evidence suggests that the multifaceted symptomatology of KOA may be alleviated by diacerein. With this in mind, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of diacerein in patients with KOA. METHODS: We systematically searched Embase, PubMed, Cochrane Library, Web of Science, Chinese Biomedical Literature Database (CBM), Wanfang Database (WanFang), China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (VIP) from their inception to August 2022 for randomized controlled trials (RCTs) of diacerein intervention on patients with KOA. Two reviewers independently performed the selection of eligible studies and the extraction of relevant data. The meta-analysis was performed using RevMan 5.4 and R 4.1.3 software tools. Depending on the type of outcome indicator selected, summary measures were expressed as mean differences (MD), standardized mean differences (SMD), or odds ratio (OR) with 95% confidence intervals (CI). RESULTS: Twelve RCTs with 1732 patients were included. The results revealed that diacerein had comparable efficacy to non-steroidal anti-inflammatory drugs (NSAIDs) in reducing pain indicators such as Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (SMD = 0.09, 95% CI [-0.10, 0.28], P = 0.34) and visual analogue scale (VAS) (SMD = -0.19, 95% CI [-0.65, 0.27], P = 0.42). However, diacerein outperformed NSAIDs in terms of global efficacy assessment by both patients and investigators (patients: 1.97, 95% CI [1.18, 3.29], P = 0.01; investigator: 2.18, 95% CI [0.99, 4.81], P = 0.05) at the end of treatment and sustained effectiveness in reducing WOMAC score and VAS score at four weeks after treatment. Moreover, there was no significant difference in adverse events incidence between the diacerein and NSAID groups. However, the GRADE evaluation indicated that the majority of the evidence quality was low. CONCLUSIONS: The results of this study suggest that diacerein could potentially be considered as a pharmacological agent with significant efficacy for the treatment of patients suffering from KOA, offering a potential alternative treatment strategy for those patients contraindicated to NSAIDs. However, further high-quality studies with longer follow-up are needed to make more informed decisions about its efficacy in the treatment of KOA.

Diacerein mitigates renal ischemia/reperfusion injury via inhibition of renal inflammation, dendritic cells maturation and apoptosis: the role of TLR4/NF-kB/NLRP3/IL-1beta signaling pathway / La diacereína mitiga la lesión por isquemia/reperfusión renal a través de la inhibición de la inflamación renal, la maduración de las células dendríticas y la apoptosis: el papel de la vía de señalización TLR4/NF-kB/NLRP3/IL-1beta

SUMMARY: One of the reasons for acute kidney damage is renal ischemia. Nevertheless, there are limited protective and therapeutic approaches for this problem. Diacerein is an anti-inflammatory drug characterized by numerous biological activities. We aimed to determine the ameliorative impact of diacerein on renal ischemia/reperfusion injury (I/R) condition, exploring the underlying mechanisms. Twenty-four male rats were allotted into four groups (n= 6): sham group; Diacerein (DIA) group; I/R group, in which a non-crushing clamp occluded the left renal pedicle for 45 min, and the right kidney was nephrectomized for 5 min before the reperfusion process; I/R + diacerein group, injected intraperitoneally with 50 mg diacerein/kg i.m 30 minutes prior to I/R operation. Ischemia/ reperfusion was found to affect renal function and induce histopathological alterations. The flow cytometry analysis demonstrated an elevated expression of innate and mature dendritic cells in I/R renal tissues. Moreover, upregulation in the expression of the inflammatory genes (TLR4, Myd88, and NLRP3), and overexpression of the pro-inflammatory cytokines (IL-1β), apoptotic (caspase-3) and pyroptotic (caspase-1) markers were observed in I/R-experienced animals. The aforementioned deteriorations were mitigated by pre-I/R diacerein treatment. Diacerein alleviated I/R-induced inflammation and apoptosis. Thus, it could be a promising protective agent against I/R.

La isquemia renal es una de los motivos del daño renal agudo. Sin embargo, los enfoques protectores y terapéuticos para este problema son limitados. La diacereína es un fármaco antiinflamatorio caracterizado por numerosas actividades biológicas. Nuestro objetivo fue determinar el impacto de mejora de la diacereína en la condición de lesión por isquemia/ reperfusión renal (I/R), explorando los mecanismos subyacentes. Veinticuatro ratas macho se distribuyeron en cuatro grupos (n= 6): grupo simulado; grupo de diacereína (DIA); grupo I/R, en el que una pinza no aplastante ocluyó el pedículo renal izquierdo durante 45 min, y el riñón derecho fue nefrectomizado durante 5 min antes del proceso de reperfusión; Grupo I/R + diacereína, inyectado por vía intraperitoneal con 50 mg de diacereína/kg i.m. 30 min antes de la operación I/R. Se encontró que la isquemia/ reperfusión afecta la función renal e induce alteraciones histopatológicas. El análisis de citometría de flujo demostró una expresión elevada de células dendríticas innatas y maduras en tejidos renales I/R. Además, se observó una regulación positiva en la expresión de los genes inflamatorios (TLR4, Myd88 y NLRP3) y una sobreexpresión de las citoquinas proinflamatorias (IL-1β), marcadores apoptóticos (caspasa-3) y piroptóticos (caspasa-1) en animales con experiencia en I/R. Los deterioros antes mencionados fueron mitigados por el tratamiento previo a la diacereína I/R. La diacereína alivió la inflamación y la apoptosis inducidas por I/R. Por lo tanto, podría ser un agente protector prometedor contra I/R.

Topical Diacerein Decreases Skin and Splenic CD11c+ Dendritic Cells in Psoriasis.

Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c+ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c+ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.

Diacerein plus glucosamine hydrochloride improves the safety and efficacy and inhibit inflammatory factors in the treatment of knee osteoarthritis.

OBJECTIVES: The aim of this study is to elucidate the safety and efficacy of diacerein (DIA) plus glucosamine hydrochloride (GlcN·HCl) in the treatment of knee osteoarthritis (KOA) and their effect on inflammatory factors (IFs). METHODS: Retrospectively, 116 KOA patients admitted between August 2018 and August 2021 were selected. Among them, 55 cases received DIA monotherapy (control group, Con) and 61 cases received DIA + GlcN·HCl (observation group, Obs). The efficacy, safety, scores of Lequesne Index, and Visual Analogue Scale (VAS), as well as the levels of IFs of the two groups were observed and compared. Further, Cox regression was used to perform an in-depth analysis of factors influencing the occurrence of complications in patients with KOA. RESULTS: The analyses revealed a higher overall response rate and a lower adverse event rate in the Obs group compared with the Con group, with statistical significance. Decreased scores of Lequesne Index and VAS and levels of IFs were determined in the Obs after treatment, which were all significantly lower compared with those of the Con. Cox regression analysis identified that TNF-α, IL-1ß, hs-CRP, and treatment mode affected the occurrence of complications in KOA patients. CONCLUSIONS: DIA + GlcN·HCl can significantly inhibit the inflammation level in KOA, with definite curative effects and a favorable safety profile.

Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein.

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis. DIA has recently been evaluated as an antimicrobial agent for bacterial keratitis. Two ILs based on natural zwitterionic compounds were investigated: L-carnitine C6 alkyl ester bromide (Carn6), and betaine C6 alkyl ester bromide (Bet6). The stabilising, solubilising, and mucoadhesive properties of ILs were investigated, as well as their cytotoxicity to the murine fibroblast BALB/3T3 clone A31 cell line. Two IL-DIA-based eye drop formulations were prepared, and their efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa was determined. Finally, the eye drops were administered in vivo on New Zealand albino rabbits, testing their tolerability as well as their elimination and degradation kinetics. Both Bet6 and Carn6 have good potential as functional excipients, showing solubilising, stabilising, mucoadhesive, and antimicrobial properties; their in vitro cytotoxicity and in vivo ocular tolerability pave the way for their future use in ophthalmic applications.