Methotrexate (MTX) is the preferred drug for the treatment of rheumatoid arthritis (RA), but the toxic effects of long-term use limited its widespread clinical practice. The combination therapy of MTX with natural products is an effective strategy to reduce the toxic effects of MTX and enhance the therapeutic efficacy. Monotropein (MON), an iridoid glycosides, has potential therapeutic effects in inflammatory bone loss and osteoarthritis, and liver injury caused by MTX. However, whether MON can increase the therapeutic effects of MTX on RA and the related mechanism is not clear.

This study aimed to clarify the MON enhancement on MTX in the treatment of RA, and also explore the target and mechanism of MON in anti-RA.

The adjuvant-induced arthritis (AA) mice and RA-fibroblast-like synoviocytes (RA-FLSs) were used to evaluate the alleviating effects of MON, MTX and their combination on RA. The network pharmacology analysis, molecular docking and surface plasmon resonance (SPR) were utilized to predict the potential therapeutic targets and mechanism of MON on RA. The interference RNA was used to knockdown the target gene in TNF-α-stimulated FLSs and AA mice to validate the mechanism of MON on RA.

MON synergizes with MTX to suppress synovial inflammation in AA mice and inhibit TNF-α-induced FLSs proliferation, migration, inflammatory factors production, as well as the activation of NF-κB and JAK2/STAT3 signaling pathways. Network pharmacology predicted GSK-3β as a potential target of MON, and the molecular docking, CETSA, and SPR assays exhibited that MON had a good affinity with GSK-3β. Furthermore, GSK-3β knockdown suppressed TNF-α-induced FLSs proliferation, migration, matrix metalloproteinase 2 (MMP2) and MMP3 expression, and the activation of NF-κB and STAT3 signaling, while MON lost its inhibitory effects in GSK-3β knockdown FLSs. In addition, joint tissue-specific GSK-3β knockdown in AA mice alleviated synovial inflammation, decreased paw swelling and arthritis score, suppressed the phosphorylation of p65 and STAT3 of joint tissue in AA mice, while MON lost efficacy in GSK-3β-knockdown mice.

MON synergizes with MTX to inhibit synovial inflammation in AA mice and RA-FLSs inflammation by targeting GSK-3β to suppress NF-κB and STAT3 pathways.

Tamoxifen (TAM) is a commonly used drug for breast cancer treatment, mainly inhibiting estrogen receptors to prevent tumor growth. Although TAM has achieved remarkable effects in clinical treatment, recent studies have shown that TAM can cause drug-induced liver injury. However, it's still unclear whether long-term use of TAM can cause liver fibrosis. This study explores whether long-term administration of TAM can cause liver fibrosis and its mechanism. We found that TAM could induce liver injury in mice and significantly up-regulate the expression of activation markers of stellate cells, activating the TGF-β/smad signaling pathway. Additionally, TAM induced an inflammatory response and activated the NF-κB signaling pathway. More importantly, we demonstrated for the first time in vivo and in vitro that TAM-induced hepatocyte ferroptosis, accompanied by glutathione (GSH) depletion, reactive oxygen species (ROS) accumulation, and intracellular ferrous enrichment, and changes in the expression of ferroptosis-related proteins. Ferroptosis inhibitors such as ferrostatin-1 (Fer-1) and DFO ameliorated ferroptosis in hepatocytes. However, these ferroptotic events did not occur in macrophages and hepatic stellate cells (HSCs). Co-culture experiments showed that TAM-induced hepatocytes could increase expression of liver fibrosis-related proteins in HSCs, but this could be abolished by ferroptosis inhibitors. Bioinformatics analysis suggested TAM may regulate hepatocyte ferroptosis through solute carrier family 1 member 5 (SLC1A5). Downregulation of SLC1A5 could inhibit TAM-induced hepatocyte ferroptosis, thereby alleviating HSCs activation and the increased expression of ECM proteins. Our study suggests that TAM induces hepatocyte ferroptosis through SLC1A5, leading to HSC activation and liver fibrosis.

Different expression levels of circular RNAs (circRNAs) affect the sensitivity of human cells to drugs, thus producing different responses to the therapeutic effects of drugs. Using traditional biomedical experiments to discover and confirm sensitivity relationships is not only time-consuming but also costly. Therefore, developing an effective method to accurately predict new associations between circRNAs and drug sensitivity is crucial and urgent. Therefore, we constructed a heterogeneous graph network MiGNN2CDS on the basis of multi-instance learning (MIL).

We first extracted similar features of circRNAs and drugs and the structural features of drugs to construct a heterogeneous network. To learn the deep embedding features of the heterogeneous network, we designed a heterogeneous graph convolutional network (GCN) architecture. By introducing instance learning, we subsequently designed a pseudo-metapath instance generator and a bidirectional translation embedding projector BiTrans to learn the metapath-level representation of circRNA-drug pairs. Finally, an interpretable multiscale attention network joint predictor was designed to achieve accurate prediction and interpretable analysis of circRNA-drug sensitivity associations.

MiGNN2CDS achieves better prediction accuracy than many state-of-the-art models do. Case studies show that MiGNN2CDS can effectively predict unknown associations, and the model interpretability of MiGNN2CDS is verified by high-confidence meta-path analysis. The code and data are available at https://github.com/nmt315320/MiGNN2CDS.git .

Drug-induced liver injury (DILI) remains an active field of clinical research and investigation with more than 4700 publications appearing in 2023 relating to hepatotoxicity of all causes and injury patterns. As in years past, we have attempted to identify and summarize highlights and controversies from the past year's literature. Several new and novel therapeutic agents were approved by the US Food and Drug Administration (FDA) in 2023, a number of which were associated with significant hepatotoxicity. Updates in the diagnosis and management of DILI using causality scores as well as newer artificial intelligence-based methods were published. Details of newly established hepatotoxins as well as updated information on previously documented hepatotoxic drugs is presented. Significant updates in treatment of DILI were also included as well as reports related to global DILI registries.

Psoriasis is a prevalent inflammatory disease that shares chronic inflammation pathways with the pathophysiology of metabolic syndrome (MetS), type-2 diabetes mellitus and atherosclerosis. A high prevalence of steatosis and advanced liver fibrosis has been described in psoriasis. The influence of MetS and its compounds, patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 gene polymorphisms and the cumulative dose of methotrexate (MTX) in the progression of steatotic disease are still under debate. A suitable new classification for psoriasis-related liver disease, under the umbrella of steatotic liver disease (SLD), might be evaluated due to the potential impact of MTX on liver steatosis. Considering the interplay between the MetS, steatosis and MTX, a new definition for this complex disease might be discussed since it is not entirely addressed under the umbrella of SLD and metabolic-dysfunction associated SLD. Hence, shortly, a discussion could be raised on the feasible term "Met-Drug SLD", metabolic and drug-induced SLD, which comprises both metabolic dysfunction and drug-related SLD. This review aims to report the best evidence to accurately classify liver disease in psoriasis, considering the new definition of SLD, allowing appropriate management once it is carefully defined.

The treatment of pemphigus vulgaris (PV) often requires long-term systemic corticosteroids. Although new biologicals like rituximab are changing the landscape, traditional immunosuppressants still prevail in many underdeveloped areas. One such medication is methotrexate (MTX), which has been widely used in autoimmune and autoinflammatory diseases, but its role in treating pemphigus remains somewhat unclear and controversial. This study aimed to evaluate the effect and safety profile of using low-dose MTX in PV patients receiving glucocorticoids. PV patients who visited the Department of Dermatology, Peking University First Hospital from January 2010 to December 2021 were retrospectively screened. Based on different treatment regimens, patients were automatically divided into a corticosteroid monotherapy group and a corticosteroid combined with low-dose MTX group (MTX was administered at a dose of no more than15 mg per week, with a minimum duration of 8 weeks). All patients were followed up for 1 year. A total of 142 patients with PV were eligible for the study (100 in the corticosteroid monotherapy group and 42 in the corticosteroid combined with low-dose MTX group). The Kaplan-Meier curve indicated that the corticosteroid combined with low-dose MTX group achieved a 50% reduction in glucocorticoid use faster, with a P value of 0.0132, especially among patients who initially received more than 60 mg of steroids per day. The inclusion of MTX reduced the occurrence of hyperpilidemia. There was not sufficient evidence to determine if the addition of MTX was associated with more bacterial infection cases for certain. The inclusion of low-dose MTX in the corticosteroid treatment regimen for patients with PV, particularly those receiving high doses, can facilitate the reduction of glucocorticoid dosages and lower the incidence of hyperlipidemia, without increasing the risk of other adverse effects.

Background/Objectives: Methotrexate is a folate antagonist that has proven efficacy as an anticancer and immunomodulatory agent. However, the possible incidence of overt hepatotoxicity represents a challenge for its clinical use. Up till now, no single remedy has been considered an effective solution to this important adverse effect. Perindopril is an angiotensin-converting enzyme inhibitor that is widely used for the treatment of hypertension. Due to the involvement of the renin-angiotensin system in the pathogenesis of methotrexate-elicited hepatotoxicity, investigating the efficacy of perindopril in this condition may be of particular interest. The current work aimed at an evaluation of the potential effects of perindopril in a rat model of methotrexate-induced hepatotoxicity and tried to precisely determine the molecular mechanisms that may represent the basis of these effects. Methods: In a model of methotrexate-elicited hepatotoxicity in male Wistar rats, the effects of different doses of perindopril were evaluated at the level of the biochemical measurements and the morphological examination. Results: Oral administration of perindopril to methotrexate-injected rats exhibited a dose-dependent significant improvement in daily food intake; the restoration of the functions of hepatocytes; the potentiation of antioxidant defense mechanisms; the abrogation of the different signaling pathways involved in liver inflammation, apoptosis, and fibrosis; and an enhancement in AMPK/mTOR-driven autophagy when compared to animals that received only a methotrexate injection. These events were reflected in the morphological appearance of the different studied groups. Conclusions: This study presents perindopril as a promising remedy for mitigation of the hepatotoxic effects that occur as a consequence of treatment with methotrexate.

Mitochondrial activity is necessary for the maintenance of many liver functions. In particular, mitochondrial fatty acid oxidation (FAO) is required for energy production and lipid homeostasis. This key metabolic pathway is finely tuned by the mitochondrial respiratory chain (MRC) activity and different transcription factors such as peroxisome proliferator-activated receptor α (PPARα). Many drugs have been shown to cause mitochondrial dysfunction, which can lead to acute and chronic liver lesions. While severe inhibition of mitochondrial FAO would eventually cause microvesicular steatosis, hypoglycemia, and liver failure, moderate impairment of this metabolic pathway can induce macrovacuolar steatosis, which can progress in the long term to steatohepatitis and cirrhosis. Drugs can impair mitochondrial FAO through several mechanisms including direct inhibition of FAO enzymes, sequestration of coenzyme A and l-carnitine, impairment of the activity of one or several MRC complexes and reduced PPARα expression. In drug-induced macrovacuolar steatosis, non-mitochondrial mechanisms can also be involved in lipid accumulation including increased de novo lipogenesis and reduced very-low-density lipoprotein secretion. Nonetheless, mitochondrial dysfunction and subsequent oxidative stress appear to be key events in the progression of steatosis to steatohepatitis. Patients suffering from metabolic dysfunction-associated steatotic liver disease (MASLD) and treated with mitochondriotoxic drugs should be closely monitored to reduce the risk of acute liver injury or a faster transition of steatosis to steatohepatitis. Therapies based on the mitochondrial cofactor l-carnitine, the antioxidant N-acetylcysteine, or thyromimetics might be useful to prevent or treat drug-induced mitochondrial dysfunction, steatosis, and steatohepatitis.

Low-dose methotrexate (LD-MTX) is the anchor drug used in the treatment of various rheumatological illnesses. There are a lot of misconceptions associated with the long-term use of MTX in the minds of practitioners. The origin of most of these myths stems from the ill effects associated with high-dose MTX used in cancer chemotherapy. In this review, we have summarised and discussed the latest data regarding the safety of LD-MTX. The current evidence underscores the safety of LD-MTX. It is not associated with liver and lung fibrosis as previously thought. Other major concerns such as bone marrow suppression and increased risk of infection are rare with chronic LD-MTX therapy. Hypersensitivity pneumonitis is a rare acute lung toxicity associated with MTX intake, it does not cause interstitial lung disease and in fact, may be protective against it. There is a slight concern about the increased risk of skin malignancy associated with MTX intake; however, association with no other malignancy has been found. It has taken many decades for researchers to clear the various preconceptions associated with MTX. It is time for the academic community to embrace LD-MTX as a new, separate and reinvented drug.

Methotrexate (MTX) has been used in high doses for cancer therapy and low doses for autoimmune diseases. It is proven that methotrexate-induced hepatotoxicity occurs even at relatively low doses. It is known that garden cress has anti-inflammatory, antioxidant, and hepatoprotective properties. This study investigates the potential alleviating effect of garden cress oil (GCO) against MTX-induced hepatotoxicity in rats. The chemical composition of GCO was assessed using GC/MS analysis. Liver damage was studied using hepatotoxicity biomarkers, molecular, and histological analysis. Also, the effects of GCO on TNF-α and caspase-3 proteins were evaluated through molecular docking studies. The results demonstrated that MTX caused liver damage, as seen by elevated levels of the liver enzymes ALT, AST, and ALP. Likewise, MTX showed clear signs of apoptosis, such as increased mRNA expression levels of BAX, Caspase-3, and P53, and increased liver inflammation indicated by higher levels of TNF-α expression. MTX exhibited significant liver damage, as demonstrated by histological examination. Treatment with GCO effectively alleviated the apoptotic effects of MTX, provided protection against inflammation, and restored histological alterations. GC/MS metabolite profiling of garden cress oil revealed the presence of several phytoconstituents, including tocopherols, erucic acid, sesamolin, linoleic acid, vaccenic acid, oleic acid, stearic acid, and palmitic acid, that showed strong binding affinities toward TNF-α and caspase-3 proteins in molecular docking studies, which could explain the anti-apoptotic and anti-inflammatory potential of GCO.

Experimental animal models are crucial for elucidating the pathophysiology of liver injuries and for assessing new hepatoprotective agents. Drugs and chemicals such as acetaminophen, isoniazid, valproic acid, ethanol, carbon tetrachloride (CCl4), dimethylnitrosamine (DMN), and thioacetamide (TAA) are metabolized by the CYP2E1 enzyme, producing hepatotoxic metabolites that lead to both acute and chronic liver injuries. In experimental settings, acetaminophen (centrilobular necrosis), carbamazepine (centrilobular necrosis and inflammation), sodium valproate (necrosis, hydropic degeneration and mild inflammation), methotrexate (sinusoidal congestion and inflammation), and TAA (centrilobular necrosis and inflammation) are commonly used to induce various types of acute liver injuries. Repeated and intermittent low-dose administration of CCl4, TAA, and DMN activates quiescent hepatic stellate cells, transdifferentiating them into myofibroblasts, which results in abnormal extracellular matrix production and fibrosis induction, more rapidly with DMN and CCL4 than TAA (DMN > CCl4 > TAA). Regarding toxicity and mortality, CCl4 is more toxic than DMN and TAA (CCl4 > DMN > TAA). Models used to induce metabolic dysfunction-associated liver disease (MAFLD) vary, but MAFLD's multifactorial nature driven by factors like obesity, fatty liver, dyslipidaemia, type II diabetes, hypertension, and cardiovascular disease makes it challenging to replicate human metabolic dysfunction-associated steatohepatitis accurately. From an experimental point of view, the degree and pattern of liver injury are influenced by various factors, including the type of hepatotoxic agent, exposure duration, route of exposure, dosage, frequency of administration, and the animal model utilized. Therefore, there is a pressing need for standardized protocols and regulatory guidelines to streamline the selection of animal models in preclinical studies.

In the present study, the effects of coenzyme Q10 (CoQ10), which is widely used in daily life, on the methotrexate (MTX)-induced hepatotoxicity, which is widely used today in malignancies and autoimmune diseases, were examined. Twenty-four female Wistar albino rats were divided into four groups. The group 1 (n = 6) was given 1 mL corn oil by oral gavage (p.o.) during seven days. Group 2 was given 20 mg/kg intraperitoneal (i.p.) MTX only on the first day of the experiment. Group 3 was given 20 mg/kg (i.p.) MTX on the first day of the experiment and 100 mg/kg CoQ10 dissolved in 1 mL corn oil were given by oral gavage during seven days, and group 4 was given 100 mg/kg CoQ10 dissolved in 1 mL corn oil by oral gavage during seven days. At the end of experiment, all animals were euthanized under anesthesia. In the liver tissue, histopathologic analysis on the hematoxylin and eosin (H&E), Masson trichrome, and periodic acid Schiff (PAS) stained sections, apoptotic analysis (% Annexin V positivity) by flow cytometry, and biochemical analysis for oxidative stress markers (GSH, CAT, and TBARS) was performed. According to histopathological analysis, apoptosis, concession, fibrosis, and inflammatory cell infiltration increased in the MTX group and those results significantly decreased in the MTX + CoQ10 groups. As an interesting result, fatty degeneration and TBARS elevation were observed in the MTX + CoQ10 group. As a result, although CoQ10 has protective effects on MTX-induced hepatotoxicity, fatty degeneration due to the combined usage of MTX and CoQ10 should be investigated with further studies.

Management of rheumatoid arthritis (RA) has evolved from simply the direct translation of drug efficacy results from clinical trials to patient care, to a more complex longitudinal process that considers not only drug efficacy but also the safety gestalt of a treatment and patient profiles and preferences, as well as health-economic factors. With numerous DMARDs available to treat RA, knowledge about trial efficacy becomes less important than data that inform an appropriate clinical strategy for their optimal selection and use. Overly ambitious approaches targeting the 'maximum' level of success could, for example, be prone to failure and create frustration, and lead to a large number of patients then being considered as 'difficult to treat'. Safety profiles might be more informative than efficacy profiles for precision medicine approaches. Contemporary RA management strategies might therefore take a more holistic approach, beyond merely efficacy, to the setting of targets that lead to improved compliance rather than aspirational successes, with consideration of each patient's multimorbidity profile and preferences, as well as the safety profile of each treatment. Ultimately, the goal remains unchanged: maximizing health-related quality of life; however, with a focus on optimal balance rather than superlatives.

Morinda officinalis How. is a commonly used traditional Chinese herb with the pharmacological properties of tonifying liver and kidney, and enhancing bone and muscle. Iridoid glycosides are the predominant components of this plant, including monotropein, asperuloside, deacetylasperuloside and deacetylasperulosidic acid with their contents reaching more than 2%. Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA), but liver injury induced by MTX limits its wider use for RA. Morindaofficinalis iridoid glycoside (MOIG) is reported as having anti-RA and hepatoprotective effects, but the exact efficacy on MTX-induced liver injury and the underlying molecular mechanism remain unclear.

To elucidate the mitigating effect of MOIG against liver injury in RA rats treated with MTX, and explore the possible mechanism.

The effect and mechanism of MOIG were investigated in Wistar rats with collagen-induced arthritis (CIA) which were then treated with MTX, and MTX-induced hepatocyte injury in vitro. Network pharmacological and transcriptomic analyses were conducted to predict the possible mechanisms of MOIG in mitigating MTX-induced liver injury, and lipidomic analysis was performed to further verify the regulatory effects of MOIG on lipid metabolism. BRL-3A hepatocytes were used to evaluate the regulatory effects of MOIG against MTX-associated liver injury.

MOIG treatment enhanced the anti-RA effect of MTX, and mitigated oxidative damage, inflammation and apoptosis of liver tissues in CIA rats treated with MTX. Network pharmacological and transcriptomic analyses demonstrated that MOIG attenuated liver injury by regulating autophagy and lipid metabolism. The result of lipidomic analysis showed that MOIG reversed the disturbance of lipid metabolism of the liver tissue in CIA rats after MTX treatment. In addition, MOIG also inhibited the apoptosis, reduced the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ALT) and alanine aminotransferase (AST), regulated oxidative stress, and increased the formation of autophagosome and translocation of LC3 in the nucleus and expression of autophagy regulatory genes Beclin-1, ATG5, LC3Ⅱ, ATG7 and ATG12 in hepatocytes subjected to MTX damage.

Our findings demonstrated that MOIG could ameliorate MTX-induced liver injury in the treatment of RA through increasing hepatocyte autophagy and improving lipid metabolism homeostasis.

Activated macrophages are key effector cells and specific markers in patients with rheumatoid arthritis (RA). Cysteine cathepsin B (CTS-B) is highly expressed in macrophages and positively associated with RA activity and severity. This study aims to evaluate an activity-based multi-modality diagnostic agent, 68Ga-BMX2, which targets CTS-B to visualize the arthritis activity and evaluate the treatment efficacy. A CTS-B activity-based probe, BMX2, was labeled efficiently with 68Ga to produce 68Ga-BMX2 for fluorescent and positron emission tomography (PET) multi-modality imaging. The affinity and specificity of BMX2 binding with the CTS-B enzyme in macrophages were determined by radioactive experiment using RAW 264.7 cell lines, with CA074 and BMX5 as the inhibitors to test the specificity of the binding. Then, PET and fluorescence imaging were acquired on collagen-induced arthritis (CIA) mice. Additionally, the treatment monitoring capability of 68Ga-BMX2 PET/CT imaging was tested with methotrexate (MTX). RAW 264.7 macrophage cells showed significant uptake of 68Ga-BMX2. The binding of BMX2 with CTS-B in RAW 264.7 macrophage cells is time-dependent and could be blocked by CA074 and BMX5. In vivo optical and PET imaging showed high signals in the right hind arthritis in CIA mice from 68Ga-BMX2 and BMX2 accumulated for at least 120 h. Additionally, 68Ga-BMX2 signals were significantly reduced in the MTX-treated CIA mice compared to the control group. The 68Ga-BMX2, a radioactive and fluorescent dual-modality diagnostic agent targeting CTS-B, demonstrated a practical approach for CIA PET and fluorescence imaging. The 68Ga-BMX2 multimodality imaging could significantly monitor the treatment response in the CIA mice.

Psoriatic arthritis (PsA) is an inflammatory joint and entheseal disease associated with significant personal and public health burden. PsA has a prevalence of up to 1%, affecting ~20% of people suffering with psoriasis. PsA is frequently accompanied by metabolic syndrome (MetS), and both conditions are characterised by a chronic pro-inflammatory state, with several key cytokines in PsA (interleukin (IL)-17 and IL-23) also elevated in those with MetS. This narrative review aims to provide an update on MetS in PsA, focusing on its prevalence, pathogenesis, prognosis, treatment interactions and future therapeutic options. MetS is particularly prevalent in PsA compared to other inflammatory arthritides. Cohort studies indicate a higher risk of PsA in individuals with obesity, while Mendelian randomization studies link childhood obesity, insulin resistance, and dyslipidaemia to PsA. Weight loss interventions have been shown to reduce disease activity in PsA. Additionally, MetS negatively impacts the efficacy of tumour necrosis factor inhibitor (TNFi) drugs in treating PsA. Drugs given for PsA may also affect the conditions constituting MetS. Leflunomide has been shown to reduce body weight but also increase blood pressure. TNFi drugs lead to weight gain but reduce cardiovascular risk. Janus kinase inhibitors increase lipid levels and cardiovascular risk among high-risk groups. Anti-IL-17 and anti-IL-12/IL-23 drugs may cause a short-term increase in cardiovascular risk, although the long-term effects have yet to be established. Weight loss represents an unexplored avenue for disease modification in PsA, alongside a plethora of general health benefits. Dietary and exercise modifications are the cornerstone of weight management but vary substantially across individuals. Novel therapies to treat weight loss, such as glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors, may prove useful alongside disease-modifying therapies for those with PsA and MetS and should be investigated as potential therapeutic adjuncts.

Hepatotoxicity associated with methotrexate (MTX) is mainly due to disruption of redox balance and development of oxidative injury to hepatocytes. Melatonin (MLT) is a potent antioxidant and regulates wide range of biological functions, processes and utilized as adjuvant for number of medical applications. The current study investigated the mitigating effect of MLT on the MTX-induced hepatotoxicity.

Adult male rats received MLT (25 mg/kg, orally) for seven days flowed by single injection of MTX (20 mg/kg, ip) then treat with MLT continued for additional 7 days. The present result showed MLT treatment mitigated histopathological changes in the liver that associated with normalization of ALT and AST activity as well as bilirubin, albumin and alfa-fetoprotein levels in serum of MLT + MTX-treated rat to comparable control level. MLT treatment significantly reduced MDA content and myeloperoxidase activity while enhanced the activity of superoxide dismutase, catalase and glutathione content in the liver indicating the empowerment of the antioxidant status. Amelioration of MLT-induced oxidative stress resulted in a reduction in the inflammatory response due to antioxidant restoration and inhibited apoptosis indicated by downregulation of caspase-3 expression. The replenishment of antioxidant content powers the defense system of the hepatocytes. As a result, apoptosis is reduced which might be due to the ability of MLT protect DNA integrity thus maintaining hepatocyte functions and structure. Consequently, liver histology was protected.

In summary, MLT modulates liver function and structure by orchestrating linked processes, including redox balance, inflammatory response, suppression of caspase-3, and DNA damage.

There are established risk factors for liver fibrosis (LF), but data on the impact of methotrexate on LF in patients with psoriasis are lacking.

This cross-sectional study aimed to determine the prevalence of LF in patients with psoriasis and to evaluate the relationship between LF, cumulative methotrexate dose and other LF risk factors.

Adults with a history of moderate-to-severe chronic plaque psoriasis were recruited between June 2020 and March 2021. Patients underwent transient elastography to evaluate LF. Three values for liver stiffness measurement (LSM) were assessed, indicating mild or worse LF (≥ 7 kPa), moderate or worse LF (≥ 7.9 kPa) and advanced LF (≥ 9.5kPa). Cumulative methotrexate dose and other potential risk factors for LF were assessed.

Overall, 240 patients were recruited and 204 participants with valid LSM values were included in the analysis [median age 48 years [interquartile range (IQR) 37-57]; 51% female sex; 56% body mass index (BMI) ≥ 30 (kg m-2) and a median Alcohol Use Disorders Identification Test (AUDIT) score of 4 (IQR 1-7, 23% score ≥ 8)]. In total, 91% had received methotrexate [median duration 36 months (IQR 14-78)]. Prevalence of LF was 36%, 25% and 17% using LSM ≥ 7 kPa, ≥ 7.9 kPa and ≥ 9.5 kPa, respectively. There was no association between cumulative methotrexate dose [median 2.16 (IQR 0.93-5.2)] and continuous LSM values [unstandardized coefficient 0.16, 95% confidence interval (CI) -0.49 to 0.82, P = 0.626] or using the categorical LSM cutoff values: ≥ 7 kPa [unadjusted odds ratio 1.06 (95% CI 0.97-1.15), P = 0.192], ≥ 7.9 kPa [unadjusted odds ratio 1.03 (95% CI 0.94-1.12), P = 0.577] and ≥ 9.5 kPa (unadjusted odds ratio 1.01, 95% CI 0.91-1.12; P = 0.843). The following risk factors were associated with higher LSM values: BMI (P ≤ 0.001), waist circumference (P ≤ 0.001), metabolic syndrome (P ≤ 0.001), AUDIT score (P = 0.020) and FIB-4 score (P = 0.03). BMI ≥ 28, diabetes and metabolic syndrome were shown to be better predictors of LF compared with FIB-4 score.

This study confirms a high prevalence of significant LF in patients with psoriasis. Cumulative methotrexate dose was not associated with LF. Patients with BMI ≥ 28, metabolic syndrome and diabetes are at higher risk for LF. These risk factors may help to identify when a more detailed liver health assessment is needed.

A high prevalence of steatotic liver disease has been described in psoriasis. However, the influence of genetic polymorphisms has yet to be investigated in this scenario. This study aims to determine the frequency of steatosis, advanced liver fibrosis and PNPLA3/TM6SF2 genotypes in individuals with psoriasis and to evaluate the impact of genetic polymorphisms, metabolic parameters and cumulative methotrexate dose on steatosis and fibrosis.

Cross-sectional study that prospectively included psoriasis outpatients, submitted to clinical and laboratory analysis, transient elastography (FibroScan®, Fr) and PNPLA3/TM6SF2 genotyping. Steatosis was defined by CAP ≥275 dB/m and advanced liver fibrosis as transient elastography ≥10 kPa. Logistic regression analysis evaluated the independent variables related to steatosis and fibrosis; p-value< 0.05 was considered significant.

One hundred and ninety-nine patients were enrolled (age 54.6 ± 12.6 years, 57.3% female). Metabolic syndrome (MetS), steatosis and advanced liver fibrosis prevalence were 55.8%, 54.8% and 9%, respectively. PNPLA3 and TM6SF2 genotypes frequencies were CC 42.3%/CG 49.5%/GG 8.2% and CC 88.7%/ CT 11.3%/ TT 0%. MetS (OR3.01 95%CI 1.51-5.98; p = 0.002) and body mass index (OR1.17 95%CI 1.08-1.26; p < 0.01) were independently associated with steatosis. Diabetes Mellitus (T2DM) (OR10.76 95%CI 2.42-47.87; p = 0.002) and harboring at least one PNPLA3 G allele (OR5.66 95%CI 1.08-29.52; p = 0.039) were associated with advanced fibrosis, but not TM6SF2 polymorphism or cumulative MTX dose.

MetS and T2DM confer higher odds for steatosis and advanced fibrosis in individuals with psoriasis. PNPLA3 G allele, but not TM6SF2 polymorphism, impacts a 5-fold odds of advanced liver fibrosis.

The characteristic features of the rheumatoid arthritis (RA) microenvironment are synovial inflammation and hyperplasia. Therefore, there is a growing interest in developing a suitable therapeutic strategy for RA that targets the synovial macrophages and fibroblast-like synoviocytes (FLSs). In this study, we used graphene oxide quantum dots (GOQDs) for loading anti-arthritic sinomenine hydrochloride (SIN). By combining with hyaluronic acid (HA)-inserted hybrid membrane (RFM), we successfully constructed a new nanodrug system named HA@RFM@GP@SIN NPs for target therapy of inflammatory articular lesions. Mechanistic studies showed that this nanomedicine system was effective against RA by facilitating the transition of M1 to M2 macrophages and inhibiting the abnormal proliferation of FLSs in vitro. In vivo therapeutic potential investigation demonstrated its effects on macrophage polarization and synovial hyperplasia, ultimately preventing cartilage destruction and bone erosion in the preclinical models of adjuvant-induced arthritis and collagen-induced arthritis in rats. Metabolomics indicated that the anti-arthritic effects of HA@RFM@GP@SIN NPs were mainly associated with the regulation of steroid hormone biosynthesis, ovarian steroidogenesis, tryptophan metabolism, and tyrosine metabolism. More notably, transcriptomic analyses revealed that HA@RFM@GP@SIN NPs suppressed the cell cycle pathway while inducing the cell apoptosis pathway. Furthermore, protein validation revealed that HA@RFM@GP@SIN NPs disrupted the excessive growth of RAFLS by interfering with the PI3K/Akt/SGK/FoxO signaling cascade, resulting in a decline in cyclin B1 expression and the arrest of the G2 phase. Additionally, considering the favorable biocompatibility and biosafety, these multifunctional nanoparticles offer a promising therapeutic approach for patients with RA.

Abelmoschus manihot (L.) Medik. Seeds (AMS, སོ་མ་ར་ཛ།), a Tibetan classical herbal in China, are rich in flavonoids and phenolic glycosides compounds, such as quercetin and its derivatives. Moreover, it has been found to possess anti-rheumatoid arthritis (RA) effects. Nonetheless, its anti-RA mechanism is yet unknown.

This research aimed to examine the active ingredients of AMS as well as potential pharmacological mechanisms in AMS on RA.

The ultra-performance liquid chromatography-electrospray ionization-tandem multistage mass spectrometry (UPLC-ESI-IT-MSn) technique was used to determine the primary chemical components of AMS that were responsible for the therapeutic effects on RA. In addition, 36 male Wistar rats weighing between 200 and 220 g were classified at random into six groups [normal control group, collagen-induced arthritis (CIA) group, methotrexate group (positive control, 1.05 mg/kg), AMS group (157.5 mg/kg, 315 mg/kg, 630 mg/kg)]. CIA rats were given AMS extract by intragastric administration for 28 days, and their ankles were photographed to observe the degree of swelling. Further, the arthritis score, paws swelling, and body weight changes of CIA rats were determined to observe whether AMS has any effect on RA, and synovial and cartilage tissue injuries were identified by histopathology. Besides, the levels of IL-10, TNF-α, IL-1β, INF-γ, etc. in serum were estimated by ELISA. Western blot experiments were implemented to identify the expression levels of protein involved in the JAK2/STAT3 signaling pathway in the CIA rats' synovial tissues. Moreover, the mechanisms and targets of active ingredient therapy of AMS for RA were predicted using network pharmacology and then verified using molecular docking.

In the present study, 12 compounds were detected by UPLC-ESI-IT-MSn, such as quercetin and its derivative which could be potential active ingredients that contribute to the anti-RA properties of AMS. Our in vivo studies on CIA rats revealed that an AMS-H dose of 630 mg/kg significantly improved joint damage while decreasing the arthritic index and paw swelling. Furthermore, AMS inhibited the INF-γ, IL-6, IL-17, IL-1β, and TNF-α, levels while upregulating the expression of anti-inflammatory cytokines IL-10 and IL-4 in serum. Besides, AMS inhibited the protein Bcl-2/Bax, STAT3, and JAK2 levels, and promoted the expression of Caspase3, SOCS1, and SOCS3 in the JAK2/STAT3 pathway. Additionally, the JAK/STAT signaling pathway was found to perform a remarkable function in the AMS therapy of RA as evidenced by enrichment in GO terms and KEGG pathways. Meanwhile, data from molecular docking experiments indicated that the core targets of PIK3CA, JAK2, and SRC bound stably to the active ingredients of mimuone, 4'-methoxy-bavachromanol, and quercetin.

According to these findings, the AMS could improve joint inflammation in CIA rats, and its underlying mechanism could be linked to the regulation of the JAK2/STAT3 pathway. Therefore, AMS might become a promising agent for alleviating inflammation in RA patients.

Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals.

AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher Imax, u (maximum unbound plasma concentration)/IC50 (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data.

AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.

High-dose methotrexate (HDMTX) therapy poses challenges in various neoplasms due to individualized pharmacokinetics and associated adverse effects. Our purpose is to identify early risk factors associated with HDMTX-induced toxicities, paving the way for personalized treatment.

A systematic review of PubMed and Cochrane databases was conducted for articles from inception to July 2023. Eligible studies included reviews, clinical trials, and real-world analyses. Irrelevant studies were excluded, and manual searches and citation reviews were performed. Factors such as MTX exposure, drug interactions, demographics, serum albumin, urine pH, serum calcium, and genetic polymorphisms affecting MTX transport (e.g. SLCO1B1), intracellular folate metabolism (MTHFR), cell development (ARID5B), metabolic pathways (UGT1A1, PNPLA3), as well as epigenetics were identified.

This comprehensive review aids researchers and clinicians in early identification of HDMTX toxicity risk factors. By understanding the multifaceted risk factors associated with hematologic malignancies, personalized treatment approaches can be tailored to optimize therapeutic outcomes.

Methotrexate (MTX) is the first drug of choice to treat several diseases, including rheumatoid arthritis. However, its administration is accompanied by severe side effects, most commonly hepatotoxicity. Hence, alternative therapies with a lower toxicity and fewer side effects are needed. This study aimed to investigate the antioxidant and hepatoprotective effects of silibinin (SIL, natural agent) against MTX-induced hepatotoxicity in an adjuvant-induced arthritis (AIA) rat model. Arthritic rats were treated with SIL (100 mg/kg) and/or methotrexate (2 mg/kg). Non-arthritic rats, arthritic untreated rats, and arthritic rats who received the vehicle were followed in parallel. SIL alleviated the systemic consequences of arthritis by restoring lost weight, decreasing the erythrocyte sedimentation rate, and ameliorating joint damage, which was evident both micro- and macroscopically. Additionally, SIL prevented the histopathological alterations in the liver and significantly reduced the liver damage caused by MTX and AIA, as shown by a decrease in the markers of liver damage (ALT and AST). Furthermore, SIL relieved the oxidative stress induced by AIA and MTX in liver tissue by decreasing the lipid peroxidation (MDA) levels and enhancing the antioxidant defense system (GSH levels; catalase and superoxide dismutase (SOD) activities). In conclusion, our results suggest that SIL is a potent antioxidant and hepatoprotective agent in arthritic rats. It markedly attenuated the progression and severity of the arthritic disease and eased the oxidative stress in liver tissue by improving the pro-oxidant/antioxidant balance.

Hepatotoxicity is a well-defined reaction to methotrexate (MTX), a drug commonly used for the treatment of rheumatoid arthritis and various tumours. We sought to elucidate the mechanism underlying MTX-induced hepatotoxicity and establish a potentially effective intervention strategy.

We administered MTX to liver cells and mice and assessed hepatotoxicity by cell viability assay and hepatic pathological changes. We determined ferroptosis and ferritinophagy by detecting ferroptosis-related markers and autophagic degradation of ferritin heavy chain 1 (FTH1).

We have shown that hepatocytes treated with MTX undergo ferroptosis, and this process can be attenuated by ferroptosis inhibitors. Interestingly, NCOA4-mediated ferritinophagy was found to be involved in MTX-induced ferroptosis, which was demonstrated by the relief of ferroptosis through the inhibition of autophagy or knockdown of Ncoa4. Furthermore, MTX treatment resulted in the elevation of high-mobility group box 1 (HMGB1) expression. The depletion of Hmgb1 in hepatocytes considerably alleviated MTX-induced hepatotoxicity by limiting autophagy and the subsequent autophagy-dependent ferroptosis. It is noteworthy that glycyrrhizic acid (GA), a precise inhibitor of HMGB1, effectively suppressed autophagy, ferroptosis and hepatotoxicity caused by MTX.

Our study shows the significant roles of autophagy-dependent ferroptosis and HMGB1 in MTX-induced hepatotoxicity. It emphasizes that the inhibition of ferritinophagy and HMGB1 may have potential as a therapeutic approach for preventing and treating MTX-induced liver injury.

B7-H4 is a recently discovered member of B7 family that negatively regulates T-cell immunity, specifically Th1 and Th17 cell responses. However, its role in the pathogenesis of psoriasis has yet to be determined. This study aims to investigate the effect of B7-H4 polymorphism on the efficacy of methotrexate (MTX) and its mechanism in psoriasis. Four single nucleotide polymorphisms of B7-H4 were genotyped in 310 psoriatic patients who received 12-week MTX. The protein expression of B7-H4 in platelets was characterized using immunofluorescence staining, confocal laser scanning microscopy, and flow cytometry techniques. We found that GG genotype carriers of B7-H4 rs1935780 had a lower Psoriasis Area and Severity Index (PASI) 75 response rate and higher weight (p = 0.0245) and body mass index (p = 0.0185) than AA and AG genotype carriers. Multiple regression analysis showed that the PASI score at baseline (p = 0.01) and age at disease onset (p = 0.003) were positively correlated with PASI 75 response rate, while weight (p = 0.005) and the rs1935780 genotype (p = 0.003) were negatively associated with PASI 75 response rate. B7-H4 was expressed in the platelet plasma membrane and cytoplasm. Furthermore, the expression of B7-H4 protein in platelets was lower in good responders than in non-responders and was upregulated considerably after 12-week MTX or in vitro MTX stimulation in good responders. Collectively, these results demonstrate that psoriatic patients with GG genotype of B7-H4 rs1935780 had a poorer response to MTX. Low expression of B7-H4 protein in platelets correlated with better clinical outcomes of MTX in psoriasis.

Modulating the inflammatory microenvironment can inhibit the process of inflammatory diseases (IDs). A tri-cross-linked inflammatory microenvironment-responsive hydrogel with ideal mechanical properties achieves triggerable and sustained drug delivery and regulates the inflammatory microenvironment. Here, this study develops an inflammatory microenvironment-responsive hydrogel (OD-PP@SeNPs) composed of phenylboronic acid grafted polylysine (PP), oxidized dextran (OD), and selenium nanoparticles (SeNPs). The introduction of SeNPs as initiators and nano-fillers into the hydrogel results in extra cross-linking of the polymer network through hydrogen bonding. Based on Schiff base bonds, Phenylboronate ester bonds, and hydrogen bonds, a reactive oxygen species (ROS)/pH dual responsive hydrogel with a triple-network is achieved. The hydrogel has injectable, self-healing, adhesion, outstanding flexibility, suitable swelling capacity, optimal biodegradability, excellent stimuli-responsive active substance release performance, and prominent biocompatibility. Most importantly, the hydrogel with ROS scavenging and pH-regulating ability protects cells from oxidative stress and induces macrophages into M2 polarization to reduce inflammatory cytokines through PI3K/AKT/NF-κB and MAPK pathways, exerting anti-inflammatory effects and reshaping the inflammatory microenvironment, thereby effectively treating typical IDs, including S. aureus infected wound and rheumatoid arthritis in rats. In conclusion, this dynamically responsive injectable hydrogel with a triple-network structure provides an effective strategy to treat IDs, holding great promise in clinical application.

The constant use of disease modifying anti rheumatic drugs affects the functioning of multiple organs inside the body. Some drugs are more toxic than others. The present case control investigation was designed to evaluate the comparative toxicity of methotrexate and leflunomide on multiple organs in rheumatoid arthritis patients. For this purpose, 100 subjects with confirmed rheumatoid arthritis condition were recruited form tertiary care center. Whereas 50 age matched controls were recruited from the local healthy population. Participants of the study were categorized into three groups with equal numbers of subjects in each group (n = 50). Group 1 comprised rheumatoid arthritis patients on methotrexate treatment, group 2 included rheumatoid arthritis patients on leflunomide treatment and group 3 were healthy subjects. Cardiac and respiratory response was evaluated by monitoring blood pressure, pulse and breathing rate and spot oxygen saturation. Stress on liver was estimated by measuring change in liver enzymes (alanine transaminase, aspartate aminotransferase, and alkaline phosphatase) and total bilirubin. While, degree of renal impairment was assessed by calculating glomerular filtration rate, serum creatinine, urinary urea and uric acid. For statistical interpretation, data was subjected to independent student "t" test and analysis of variance (one way ANOVA) for mean variations. Both methotrexate and leflunomide elevated the systolic and diastolic blood pressure and pulse rate. Leflunomide maintained the oxygen saturation at 96.7%, whereas methotrexate exerted serious effect on spot oxygen saturation by reducing it significantly to 93.25% than healthy subjects. Hepatotoxicity manifested by sustained use of leflunomide was perceptible in this study group. Whereas, both methotrexate and leflunomide influenced renal function as indicated by marked increase in blood urea nitrogen (P = 0.001), serum creatinine (P = 0.007) and reduced glomerular filtration rate (P<0.0001). However, use of methotrexate demonstrated significant (P<0.0001) reduction in serum uric acid and urinary urea levels. Methotrexate is more injurious to heart, blood vessels and kidneys than leflunomide but it is less noxious to hepatic parenchyma. Contrarily, leflunomide usage is comparatively better option for respiratory, cardiovascular, and renal health but dangerous to liver. Thus, a single drug can't be prescribed for the treatment of rheumatoid arthritis for longer management of arthritis patients.

Autoimmune diseases (ADs), with significant effects on morbidity and mortality, are a broad spectrum of disorders featured by body's immune responses being directed against its own tissues, resulting in chronic inflammation and tissue damage. Sinomenine (SIN) is an alkaloid isolated from the root and stem of Sinomenium acutum which is mainly used to treat pain, inflammation and immune disorders for centuries in China. Its potential anti-inflammatory role for treating immune-related disorders in experimental animal models and in some clinical applications have been reported widely, suggesting an inspiring application prospect of SIN. In this review, the pharmacokinetics, drug delivery systems, pharmacological mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of SIN, and the possibility of SIN as adjuvant to disease-modifying anti-rheumatic drugs (DMARDs) therapy were summarized and evaluated. This paper aims to reveal the potential prospects and limitations of SIN in the treatment of inflammatory and immune diseases, and to provide ideas for compensating its limitations and reducing the side effects, and thus to make SIN better translate to the clinic.