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Industrialization and urbanization produce hazardous particulate matter (PM), including ammonium compounds like (NH4)2SO4 and NH4NO3, which comprise around 50 % of PM. Despite this, the influence of ammonium on intestinal inflammation remains unclear. We studied an ammonium mixture’s effects on the intestine, finding elevated pro-inflammatory cytokines and oxidative stress in exposed mice, causing small intestine morphological changes. Investigating mitigation strategies, we assessed silibinin, an antioxidant from milk thistle seeds. Silibinin treatment in (NH4)2SO4- and NH4NO3-exposed mice significantly reduced inflammatory markers, alleviated oxidative stress, and preserved intestinal tissue integrity via the PI3K/AKT pathway. Our findings elucidate ammonium’s potential impact on intestinal inflammation and highlight silibinin’s therapeutic impact against PM-induced small intestine damage.

Nonalcoholic steatohepatitis (NASH) represents an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD). The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome triggers pyroptosis, thus propelling the progression from simple steatosis to NASH. Silibinin, a hepatoprotective compound derived from milk thistle, exerts diverse hepatoprotective effects. However, the direct impact of silibinin on NLRP3 inflammasome activation and its ability to mitigate pyroptosis remain uncertain. To address this, we utilized an in vitro model of NASH, employing HepG2 cells treated with deoxycholic acid (DCA) and free fatty acids. Subsequently, we treated these model cells with silibinin for 24 h. Our findings demonstrated that, although there were no significant changes in cellular lipid content, silibinin effectively ameliorated hepatocyte injuries. Silibinin treatment inhibited the activation of the NLRP3 inflammasome and suppressed DCA-induced pyroptosis. Additionally, molecular docking analysis revealed that silibinin exhibited a binding affinity to components of the NLRP3 inflammasome similar to that of MCC950, a selective NLRP3 inhibitor. These results suggest that silibinin may alleviate inflammation in DCA-exposed HepG2 cells by mitigating pyroptosis, possibly through its binding affinity and inhibition of the NLRP3 inflammasome. Overall, our study indicates that silibinin holds promise as a therapeutic agent for NASH by modulating pyroptosis and inhibiting NLRP3 inflammasome activation.

Glioblastoma represents adulthood's most frequent and aggressive primary brain tumor. The gold standard in the treatment remains radical resection followed by concomitant chemo-radiation therapy according to the STUPP protocol. Despite the therapy, the prognosis remains poor. Thus, one main objective in neuro-oncology research is identifying novel therapeutic targets to improve life expectancy. In this regard, recent advances underline the importance of pSTAT3 expression in the Glioblastoma microenvironment in terms of cancer initiation and progression. Therefore, pSTAT3 inactivation due to Silibinin action may prove to be an additional therapeutic option for Glioblastoma patients. Here we report the case of a 52-year-old patient diagnosed with an unresectable right front-temporal-insular Glioblastoma by biopsy. The patient was directed upfront to concomitant chemoradiotherapy treatment with Temozolomide and Silibinin, which had a neoadjuvant effect, obtaining an objective response that made radical surgery possible. The subsequent immunohistochemistry analyses showed a moderate expression of the signal transducer and activator of transcription 3 on reactive astrocytes surrounding tumor cells. To our knowledge, this is the first report concerning the activity of Silibinin as conversion therapy in concomitance to standard treatment and could lay the foundation for the design of prospective trials aimed at validating this scheme as a standardized neoadjuvant option for unresectable Glioblastoma patients.

Arsenic toxicity is one of the most trending reasons for several malfunctions, particularly reproductive toxicity. The exact mechanism of arsenic poisoning is a big question mark. Exposure to arsenic reduces sperm count, impairs fertilization, and causes inflammation and genotoxicity through interfering with autophagy, epigenetics, ROS generation, downregulation of essential protein expression, metabolite changes, and hampering several signaling cascades, particularly by the alteration of NF-ĸB pathway. This work tries to give a clear idea about the different aspects of arsenic resulting in male reproductive complications, often leading to infertility. The first part of this article explains the implications of arsenic poisoning and the crosstalk of the NF-ĸB pathway in male reproductive toxicity. Silymarin is a bioactive compound that exerts anti-cancer and anti-inflammatory properties and has demonstrated hopeful outcomes in several cancers, including colon cancer, breast cancer, and skin cancer, by downregulating the hyperactive NF-ĸB pathway. The next half of this article thus sheds light on silymarin's therapeutic potential in inhibiting the NF-ĸB signaling cascade, thus offering protection against arsenic-induced male reproductive toxicity.

The proceeding pandemic of coronavirus disease 2019 is the latest global challenge. Like most other infectious diseases, inflammation, oxidative stress, and immune system dysfunctions play a pivotal role in the pathogenesis of COVID-19. Furthermore, the quest of finding a potential pharmaceutical therapy for preventing and treating COVID-19 is still ongoing. Silymarin, a mixture of flavonolignans extracted from the milk thistle, has exhibited numerous therapeutic benefits. We reviewed the beneficial effects of silymarin on oxidative stress, inflammation, and the immune system, as primary factors involved in the pathogenesis of COVID-19. We searched PubMed/Medline, Web of Science, Scopus, and Science Direct databases up to April 2022 using the relevant keywords. In summary, the current review indicates that silymarin might exert therapeutic effects against COVID-19 by improving the antioxidant system, attenuating inflammatory response and respiratory distress, and enhancing immune system function. Silymarin can also bind to target proteins of SARS-CoV-2, including main protease, spike glycoprotein, and RNA-dependent RNA-polymerase, leading to the inhibition of viral replication. Although multiple lines of evidence suggest the possible promising impacts of silymarin in COVID-19, further clinical trials are encouraged.

The bacterial cell division protein FtsZ has been considered a potential therapeutic target due to its rapid treadmilling that induces cellular wall construction in bacteria. The current study discovered a novel antimicrobial compound, silibinin, a natural flavonolignan and its impact on the recombinant S. aureus FtsZ (SaFtsZ). Silibinin inhibited S. aureus Newman growth in a dose-dependent manner. The IC 50 and MIC values for silibinin were 75 μM and 200 μM, respectively. It had no cytotoxicity against HEK293 cells in vitro. Silibinin also enlarged the bacterial cell morphology by ~40 folds and showed antibiofilm property. It perturbed the S. aureus membrane potential both at IC 50 conc. and at MIC conc. Further, it inhibited both the polymerization and GTPase activity of SaFtsZ. It did not inhibit tubulin assembly, a eukaryotic FtsZ homolog. A fluorescence quenching study yielded the K d value for SaFtsZ-Silibinin interaction and binding stoichiometry 0.857 ± 0.188 μM and 1:1, respectively. Both in silico study and competition assay indicated that silibinin binds at the GTP binding site on SaFtsZ. The K i value for the silibinin-mediated inhibition of SaFtsZ was 8.8 μM. Therefore, these findings have comprehensively shown the antimicrobial behavior of silibinin on S. aureus Newman cells targeting SaFtsZ., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Silymarin contains a group of closely-related flavonolignan compounds including silibinin, and is extracted from Silybum marianum species, also called milk thistle. Silymarin has been shown to protect the liver in both experimental models and clinical studies. The chemopreventive activity of silymarin has shown some efficacy against cancer both in vitro and in vivo. Silymarin can modulate apoptosis in vitro and survival in vivo, by interfering with the expression of cell cycle regulators and apoptosis-associated proteins. In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity. The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in gastrointestinal cancers. This review examines the recent studies and summarizes the mechanistic pathways and down-stream targets of silymarin in the therapy of gastrointestinal cancer.

Radiotherapy is one of the most commonly used cancer therapies with many benefits including low toxicity to healthy tissues. However, a major problem in radiotherapy is cancer radioresistance. To enhance the effect of this kind of therapy several approaches have been proposed such as the use of radiosensitizers. A combined treatment of radiotherapy and radiosensitizing drugs leads to a greater effect on cancer cells than anticipated from the addition of both responses (synergism). In this study, high-definition FT-IR imaging was applied to follow lipid accumulation in prostate cancer cells as a response to X-ray irradiation, radiosensitizing drugs, and a combined treatment of X-rays and the drugs. Lipid accumulation induced in the cells by an increasing X-ray dose and the presence of the drugs was analyzed using Principal Component Analysis and lipid staining. Finally, the synergistic effect of the combined therapy (X-rays and radiosensitizers) was confirmed by calculations of the integral intensity of the 2850 cm -1 band., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Silibinin is effective in significantly inhibiting the growth of cancer cells which shown significant anti-neoplastic effects in a variety of in vitro and in vivo cancer models, including skin, breast, lung, colon, bladder, prostate and kidney carcinomas. So, development of a new method to its biomedical analysis in clinical samples in highly demanded. In this study, an innovative electroanalysis method for the accurate, sensitive and rapid recognition of silibinin in human plasma samples was proposed and validated. The sensing platform was designed using silver nanoparticles (AgNPs) dispersed on the polymeric layer of β-cyclodextrin (β-CD). AgNPs with cubic shape providing a large effective surface area for β-CD electropolymerization. So, a layer with high electron conductivity boosting the detection electrochemical signals. Also, poly(β-CD) providing an efficient substrate with cavities to interact with silibinin and its oxidation. Differential pulse voltammetry technique was conducted to measure silibinin concentration in human real samples. Under optimized conditions, proposed sensor indicated linear relationship between the anodic peak current and concentration of silibinin in the range of 0.0103–10.3 µM on the standard and human plasma samples. Based on obtained results, proposed sensor is an efficient platform to efficient therapy of cancer based on recognition of silibinin in clinical samples.

Cancer stem cells (CSCs) are the promising targets for cancer chemotherapy that cannot be eliminated by conventional chemotherapy. In this study cationic liposomes of cabazitaxel (CBX) and silibinin (SIL) were prepared with an aim to kill cancer cells and CSCs for prostate cancer. CBX act as cancer cell inhibitor and SIL as CSC inhibitor. Hyaluronic acid (HA), an endogenous anionic polysaccharide was coated on cationic liposomes for targeting CD44 receptors over expressed on CSCs. Liposomes were prepared by ethanol injection method with particle size below 100 nm and entrapment efficiency of more than 90% at 10% w/w drug loading. Liposomes were characterized by dynamic light scattering, transmission electron microscopy, 1H nuclear magnetic resonance and scanning electron microscopy-energy dispersive x-ray spectroscopy. Liposomes were evaluated for their anticancer action in androgen independent human prostate cancer cell lines (PC-3 and DU-145). HA coated liposomes showed potential cytotoxicity over other groups with low IC50, significantly inhibited cell migration and induced apoptosis. Synergistic cytotoxic effect was also observed with HA coated liposomes that resulted in colony formation inhibition and G2/M phase arrest. Proficient cytotoxicity against CD44+ cells (14.87 ± 0.41% in PC-3 and 33.95 ± 0.68% in DU-145 cells) indicated the efficiency of HA coated liposomes towards CSC targeting. Hence, the outcome of this combinational therapy with CD44 targeting indicates the suitability of HA coated CBX and SIL co-loaded liposomes as a potential approach for eradicating prostate cancer and herein might provide a insight for future studies.

During persistent hyperglycaemia, albumin, one of the major blood proteins, can undergo fast glycation. It can be expected that timely inhibition of protein glycation might be add quality years to diabetic patients' life. Therefore, this study was designed to analyse the role of silibinin to reduced or delay amadori adduct formation at early glycation and its beneficial effect to improve the glycated albumin structure and conformation. We also analysed cytotoxic effect of amadori-albumin in the presence of silibinin on murine macrophage cell line RAW cells by MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay. Formation of early glycated product (furosine) in all samples was confirmed by LCMS. Albumin incubated with glucose only showed presence of furosine like structure. Albumin treated with silibinin in the presence of glucose did not show such furosine like peak. This LCMS result showed the silibinin play a protective role in the formation of early glycated product. HMF contents were also reduced in the presence of silibinin, when albumin was incubated with increasing concentrations of silibinin (100 and 200 μM) in the presence of glucose. ANS binding fluorescence decrease by increasing silibinin concentrations with amadori-albumin. SDS-PAGE was also showed that no significant difference in the band mobility of albumin treated with silibinin as compared to native albumin. The secondary conformational alteration in amadori-albumin due to silibinin were confirmed by FTIR. This spectrum showed slight shift in amide I and Amide II band in albumin co-incubated with glucose and silibinin as compared to albumin incubated with glucose only. We further discussed about cytotoxic effect of amadori albumin and its prevention by silibinin. MTT assay results demonstrated that amadori-albumin showed cytotoxic effect on RAW cells but silibinin showed protective role and increased the cell viability. Moreover, the results showed that silibinin has anti-glycating potential and playing a role to prevent the formation of Amadori-albumin in-vitro. Silibinin possesses strong anti-glycating capacity and can improve albumin structure and function at early stage. It might be useful in delaying the progression of diabetes mellitus and its secondary complications at early stage., Competing Interests: Declaration of competing interest There is no conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Acetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity., Methods: We have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model., Results: Data demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment., Conclusion: The results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient’s outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation.

The estrogen receptor alpha (ERα) has been proven to be one of the most important therapeutic targets in breast cancer over the last 30 years. Previous studies pointed out that a natural flavonoid, silibinin, induced apoptosis in human breast cancer MCF-7 cells. In the present study we report that exposure of MCF-7 cells to silibinin led to cell death through the down-regulation of ERα expression. Silibinin-induced apoptosis of MCF-7 cells through up-regulation of caspase 6 due to ERα signalling repression was further boosted by ERα antagonist. Moreover, up-regulation of autophagy induced by silibinin accounted for apoptotic exacerbation, being further enhanced by ERα inhibition. Upon ERα activation, series of downstream signalling pathways can be activated. We found that silibinin reduced the expressions of Akt/mTOR and extracellular-signal-related kinase (ERK), which respectively accounted for the induction of autophagy and apoptosis. These effects were further augmented by co-treatment with ERα inhibitor. We conclude that the treatment with silibinin of ERα-positive MCF-7 cells down-regulates the expression of ERα, and subsequently mTOR and ERK signaling pathways, ERα downstream, finally resulting in induction of autophagy and apoptosis.

The flavonolignan silybin (isolated from the fruits of the milk thistle, Silybum marianum), is a mixture of two diastereoisomers and has anticancer, chemoprotective, hepatoprotective and dermatoprotective properties. This compound is largely used in various functional foods, nutraceutics and food supplements. The pharmacokinetic profiles of optically pure silybins (silybin A and silybin B) were monitored in rat plasma after the intragastric administration (200 mg⋅kg−1 of body weight) of each diastereoisomer. Free (unconjugated) and total (free + conjugated) silybins were monitored for 6 hours by HPLC-PDA. The metabolic profiles of each silybin diastereoisomer were completely different. Our results clearly demonstrate that silybin B (Cmax = 14.50 µg⋅mL−1, Tmax = 2.6 hours, T1/2 = 2.9 hours; total silybin B) was absorbed faster and in a substantially higher amount than silybin A (Cmax = 1.05 µg⋅mL−1, Tmax = 3.9 hours, T1/2 = 2.2 hours; total silybin A). The oral bioavailability of silybin B was estimated to be 0.3%. The AUC 0→6 h (area under the curve) value of total silybin B was 20-fold higher than that of silybin A. SPE-UPLC-MS/MS (solid phase extraction-ultra performance liquid chromatography) was used to identify glucuronides and sulfates (in several isomeric forms) as dominant metabolites of silybin B in rat plasma. Silybin B-7-O-β-glucuronide was the major plasma metabolite of silybin B.

Ischemic stroke is regarded one of the most common causes of brain vulnerability. Silibinin (SIL), extracted from the seeds of Silybinisus laborinum L., has been found to exhibit obvious therapeutic effects on neurodegenerative diseases. GAS6 has been proven to have significant neuroprotective effects; however, the role of SIL and GAS6 in ischemic stroke remains unclear. This study aimed to investigate the protective effects of SIL against cerebral ischemia-reperfusion injury in neuroblastoma N2a cells, as well as the mechanisms involved. Firstly, the toxicity of SIL was evaluated, and safe concentrations were chosen for subsequent experiments. Then, SIL exerts significant neuroprotection against hypoxia/reoxygenation (HR) injury in N2a cells, as manifested by increased cell viability, decreased apoptotic rate, LDH, and ROS generation. Additionally, SIL was found to inhibit HR-induced apoptosis, mitochondria dysfunction, and oxidative stress. However, silencing of GAS6 inhibited the neuroprotective effects of SIL. To sum up, these results suggest that SIL may be a promising therapeutic agent for the treatment of ischemic stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Ferroptosis, an iron-dependent cell death, is caused by lipid peroxidation. Noteworthily, accumulation of iron and lipid peroxidation are found in the proximity of the neuritic plaque, a hallmark of Alzheimer's disease (AD), but the relationship between ferroptosis and neuroinflammation in AD is unclear. Silibinin, extracted from the Silybum marianum, is possibly developed as an agent for AD treatment from its neuroprotective effect, but the effect of silibinin on sporadic AD that accounts for more than 95% of AD remains unclear. To determine whether silibinin alleviates the pathogenesis of sporadic AD and investigate the underlying mechanisms, STZ-treated HT22 murine hippocampal neurons and intracerebroventricular injection of streptozotocin (ICV-STZ) rats, a sporadic AD model, were used in this study. Results show that silibinin not only promotes survival of STZ-treated HT22 cells, but also ameliorates the cognitive impairment and anxiety/depression-like behavior of ICV-STZ rats. We here demonstrate that silibinin evidently inhibits the protein level of p53 as well as upregulates the protein level of cystine/glutamate antiporter SLC7A11 and ferroptosis inhibitor GPX4, but not p21, leading to the protection against STZ-induced ferroptotic damage. Immunofluorescent staining also shows that accumulation of lipid peroxidation induced by ferroptotic damage leads to increased fluorescence of 8-oxo-deoxyguanosine (8-OHDG), a maker of oxidized DNA. The oxidized DNA then leaks to the cytoplasm and upregulates the expression of the stimulator of interferon gene (STING), which triggers the production of IFN-β and other inflammatory cascades including NF-κB/TNFα and NLRP3/caspase 1/IL-1β. However, the treatment with silibinin blocks the above pathological changes. Moreover, in HT22 cells with/without STZ treatment, GPX4-knockdown increases the protein level of STING, indicating that the ferroptotic damage leads to the activation of STING signaling pathway. These results imply that silibinin exerts neuroprotective effect on an STZ-induced sporadic AD model by downregulating ferroptotic damage and thus the downstream STING-mediated neuroinflammation., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Type 2 diabetes (T2DM) is induced by the abundance of glucose and lipids, which causes glucolipotoxicity to the pancreatic β-cells. Silibinin is a natural flavonoid possessing the regulatory activity on insulin production and therapeutic activity in diabetic mice; however, its effect on glucolipotoxicity is not fully explained. This in vitro study investigates the effects of silibinin on palmitic acid (PA) and high glucose (HG)-induced cell loss and ferroptosis of rat insulinoma INS-1 cells. In the cells treated with PA and HG, expressions of glucose transporter 4 (Glut4) and carnitine acyltransferase I (CPT1) for β-oxidation of fatty acids are reduced. Mitochondria are the metabolic organelles for glucose and fatty acids. The mitochondrial membrane potential (MMP) and ATP production were decreased, while the ROS level was elevated in the cells treated with PA and HG, indicating an induction of mitochondrial disorder. Cell loss was partially rescued by ferroptosis inhibition, suggesting an involvement of ferroptosis in the cells treated with PA and HG. More importantly, the increases in total iron, lipid ROS, MDA and COX-2, and the decrease in ferroptosis inhibitory molecules GSH, GPX4 and FSP1 appeared in the cells treated with PA and HG, confirming the occurrence of ferroptosis. Moreover, PINK1/parkin-mediated mitophagy, a vital process for selective elimination of damaged mitochondria, was blocked. Interestingly, silibinin rescued the mitochondria, restricted the ferroptosis and restored the mitophagy. By using the pharmacological stimulator and inhibitor of mitophagy, and si-RNA transfection to silence PINK1 expression, silibinin's protective effect against ferroptosis caused by PA and HG treatment was found to depend on mitophagy. Collectively, our current study reveals the new mechanisms for the protection of silibinin against the injury of INS-1 cells treated with PA and HG, elucidates the participation of ferroptosis in glucolipotoxicity, highlighting the involvement of mitophagy in defense against ferroptotic cell death., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Serious side effects of chemotherapy drugs greatly limited the anticancer performance, while targeted drug delivery could improve the therapeutic effect and reduce side effects. In this work, biodegradable hydrogel was fabricated from pectin hydrazide (pec-H) and oxidized carboxymethyl cellulose (DCMC) for localized Silibinin delivery in lung adenocarcinoma treatment. The self-healing pec-H/DCMC hydrogel showed blood compatibility and cell compatibility both in vitro and in vivo, and could be degraded by enzymes. The hydrogel also formed fast fit for injectable applications and showed sustained drug release characteristic sensitive to pH based on acylhydrzone bond cross-linked networks. The Silibinin, as a specific lung cancer inhibiting drug targets TMEM16A ion channel, was loaded into the pec-H/DCMC hydrogel to treat the lung cancer in mice model. The results showed that the hydrogel loaded Silibinin significantly enhanced the anti-tumor efficiency in vivo and greatly reduced the toxicity of the Silibinin. Based on the dual effect of improving efficacy and reducing side effects, the pec-H/DCMC hydrogel with Silibinin loading have broad application prospects to inhibit lung tumor growth in clinic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The global prevalence of diabetes has increased sharply, with the number of cases expected to rise from 424.9 million in 2017 to 628.6 million by 2045. Flavonoids are plant derived molecules with well-established antioxidant potential in addition to other therapeutic properties. Silibinin is a naturally occurring flavonoid with antioxidant and antidiabetic properties. However, its rapid metabolism and low bioavailability limit its therapeutic effects., Aims & Objectives: In this study, we have synthesized the nanoformulation of silibinin and compared its antiglycating and antidiabetic potential with the soluble form., Methodology: The inhibitory effect was tested on carbohydrate-hydrolyzing enzymes as well as glycation of human serum albumin (HSA). The structural and biochemical changes in HSA were assessed by spectroscopic analyses and different assays., Key Findings: The nanoforms were found to be better inhibitors of α-amylase and α-glucosidase compared to the bulk forms. Glycation of HSA in the presence of nano-silibinin resulted in the formation of lower level of early and advanced glycation products. This was also confirmed by spectroscopic studies and by estimating protein oxidation and free lysine residues. Molecular docking studies further supported the experimental outcomes. These results indicate that the nano form has significantly stronger antidiabetic and antiglycating effects than the bulk form. Nano-silibinin could therefore be recommended as a dietary supplement for diabetics to help control glycation and other associated complications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The in vitro and in vivo bioactivities of silibinin (SB), paclitaxel (PTX) and SB and PTX in combination (SB+PTX) against murine metastatic mammary 4T1 cancer cell line were investigated. Isobologram and combination index (CI) analyses showed that SB and PTX can function synergistically in the inhibition of 4T1 cell proliferation with a CI value

Arsenic toxicity is one of the most trending reasons for several malfunctions, particularly reproductive toxicity. The exact mechanism of arsenic poisoning is a big question mark. Exposure to arsenic reduces sperm count, impairs fertilization, and causes inflammation and genotoxicity through interfering with autophagy, epigenetics, ROS generation, downregulation of essential protein expression, metabolite changes, and hampering several signaling cascades, particularly by the alteration of NF-ĸB pathway. This work tries to give a clear idea about the different aspects of arsenic resulting in male reproductive complications, often leading to infertility. The first part of this article explains the implications of arsenic poisoning and the crosstalk of the NF-ĸB pathway in male reproductive toxicity. Silymarin is a bioactive compound that exerts anti-cancer and anti-inflammatory properties and has demonstrated hopeful outcomes in several cancers, including colon cancer, breast cancer, and skin cancer, by downregulating the hyperactive NF-ĸB pathway. The next half of this article thus sheds light on silymarin's therapeutic potential in inhibiting the NF-ĸB signaling cascade, thus offering protection against arsenic-induced male reproductive toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We evaluated deguelin and silibinin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene (BP) for their ability to inhibit pulmonary adenoma formation and growth. Animals were treated with either deguelin (5.0 or 10.0 mg/kg body weight, by gavage) or silibinin at doses of 0.05% and 0.1% in the diet, approximately 10 days before a single intraperitoneal dose of BP. We found that oral administration of deguelin reduced tumor multiplicity by 56% and tumor load by 78%, whereas silibinin treatment at doses of 0.05% and 0.1% in the diet did not show any significant efficacy on either tumor multiplicity or tumor load. The result indicates that deguelin significantly inhibits pulmonary adenoma formation and growth in A/J mice. Finding new and effective agents that can prevent lung cancer is urgently needed because cancer of the lungs remains the principal cause of cancer deaths in the United States and because effective chemoprevention of this cancer type remains elusive. Thus, deguelin appears to be a promising new preventive agent for lung cancer and may be considered for further studies in other animal models and in clinical trials.

Silibinin (SIL) has been used extensively for its hepatoprotective properties and antioxidant properties, including bone health. Iron overload can inhibit osteogenic proliferation and differentiation and promote bone loss. However, whether SIL can reverse the harmful effects of iron overload inovariectomized (OVX) rats and the mechanism is not clear. Therefore, this study intends to investigate the effect of SIL on bone mass and bone metabolism in iron overload rats and also explore the role of SIL on osteogenic differentiation of MC3T3-E1.RT-qPCR was used to measure the transcribe of target genes. Furthermore, alizarin red staining, alkaline phosphatase staining, immunofluorescence and CCK-8 assay were conducted to detect cell viability and target protein expression, osteogenic function. The OVX rat model with iron overload was set up to investigate bone reconstruction.Our results demonstrated that SIL promotes the proliferation and differentiation of osteoblasts, increases the ALP secretion and mineralization ability of osteoblasts, and enhances the transcribe and expression of target genes including OC, Runx-2, SOD2 and SIRT1 in an iron overload environment. In addition, it was confirmed that systemic SIL administration inhibits bone loss in OVX rats with iron overload and changes bone metabolism and oxidative stress status. Further study has shown that iron overload exerts its harmful function by accelerating bone turnover-mediated changes in higher bone metabolism to worsen osteoporosis. SIL can inhibit the unfriendly effects of iron overload, and by modifying bone metabolism and oxidative stress levels, the results contribute to clinical prevention and treatment of the progression of postmenopausal osteoporosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Aluminum chloride (AlCl3) and its accumulation in the brain are associated with neurodegenerative disease. Recent investigations have illustrated that silibinin is known to have neuroprotective properties. The present study investigates the neuroprotective effects of silibinin-loaded nanostructured lipid carriers (Sili-NLCs) against AlCl3-induced neurotoxicity in male mice. Sili-NLCs were prepared using the emulsification-solvent evaporation method and subjected to particle size, zeta potential, and entrapment efficiency (% EE) analysis. Mice were treated with AlCl3 (100 mg/kg/day, p.o.) and with the same concentration of silibinin and Sili-NLCs (50,100, and 200 mg/kg/day, p.o.) for 30 days in different groups. After treating animals, behavioral studies were assessed. Also, the brain tissue samples were collected from all mice to evaluate oxidative damage and histological changes. The particle size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of prepared Sili-NLCs found 239.7 ± 4.04 nm, 0.082 ± 0.003, - 16.33 ± 0.15 mV, and 72.65 ± 2.03 %, respectively. Brain uptake studies showed that Sili-NLCs had a 5.7-fold greater uptake in the mice brain than the free drug. The AlCl3 caused significant cognitive impairment and increased the level of lipid peroxidation accompanied by decreasing antioxidant enzyme activity in the brain tissue. These findings correlated well with the histopathological experiments. Furthermore, treatment with Sili-NLCs significantly improved the AlCl3-induced cognitive impairment, neurochemical anomalies, and histopathological changes. Given these results, silibinin, when delivered using NLCs, is potentially more effective than free silibinin in decreasing AlCl3- induced neurotoxicity., (Copyright © 2022. Published by Elsevier B.V.)

Background: Silibinin (SIL) has been extensively studied for its therapeutic effects on various liver diseases. However, its effect on acute liver injury was limited for poor solubility and low bioavailability. Thus, we prepared SIL and bovine serum albumin (SIL/BSA) nanoparticles and further evaluated their therapeutic efficacy against acute liver injury in mouse models., Methods: SIL/BSA nanoparticles were prepared via a nanoprecipitation method. Both in vitro cell culture model and in vivo mouse models of acetaminophen (APAP) and lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute liver injury were used to evaluate the therapeutic effect of SIL/BSA nanoparticles and potential mechanisms., Results: The SIL/BSA nanoparticles with hydrophilic diameters of 90 ± 29 nm were stably suspended. SIL/BSA nanoparticles presented better biocompatibility and more liver distribution in vivo than SIL microparticles. SIL/BSA nanoparticles significantly alleviated APAP and LPS/D-GalN induced acute liver injury in mice. Similarly, SIL/BSA nanoparticles remarkably enhanced the viability of hepatocytes in vitro against both APAP and LPS/D-GalN induced hepatocyte damage. Moreover, SIL/BSA nanoparticles exhibited antioxidant effects against intracellular oxidative stress via upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant responsive element (ARE) pathway, decreasing ROS and regulating antioxidant enzyme reactivity. And the downstream of mitochondria damage and caspase 9/3 related apoptosis pathway was also inhibited CONCLUSION: SIL/BSA nanoparticles were successfully prepared to enhance the liver availability of SIL. Both in vivo and in vitro, SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer., Statement of Significance: In our study, we prepared small-size, stable and well-dispersed silibinin/bovine serum albumin (SIL/BSA) nanoparticles via using simple and cost-effective nanoprecipitation techniques. Their physicochemical and pharmacokinetic characteristics were analyzed. We systematically studied the hepatoprotective and antioxidant efficacy of SIL/BSA both in vivo and in vitro, using two acute liver injury models. These findings revealed that SIL/BSA nanoparticles exerted ideal hepatoprotective and antioxidant efficacy against acute liver injury, suggesting the promising future in clinical transfer., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests related to this publication., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lead (Pb) is an environmental neurotoxin that can lead to toxicity. It has shown that tissues can be exposed to oxidative stress in lead poisoning. Since silymarin is a natural agent with antioxidant effects, this study aimed to investigate the antioxidant and chelation effects of silibinin and nano-silibinin on the oxidative stress status in lead-poisoned rats. Sixty male Wistar rats randomly divided into ten groups (n = 6). Control and Pb groups treated with or without silibinin and nano-silibinin for six days. Following measuring of weight and blood lead levels, biochemical antioxidant parameters evaluated. Finally, a histopathological examination of the liver performed. In this experiment, silibinin and more efficiently nano-silibinin prevented weight loss and blood lead level elevation induced by lead. Also, they increased the attenuated levels of superoxide dismutase (SOD) activity, catalase (CAT), total thiol molecules (TTM), glutathione (GSH), and total antioxidant capacity (TAC). Lead-induced elevation of lipid peroxidation products (MDA) and nitric oxide (NO) normalized to the standard level in silibinin and especially nano-silibinin groups. These data suggested that silibinin and especially nano-silibinin can decrease blood lead levels and prevent weight loss and oxidative stress in the lead-poisoned rat's model., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Nanotechnology has taken novel approaches to advance cancer therapeutic efficacy employing multifunctional nanocarriers with drug delivery and imaging function. In this work, we designed a biocompatible and affordable fluorescence nanocarrier called chitosan (CS)-carbon dot (CD) hybrid nanogel for cell imaging. The green CDs were synthesized using tomato juice through a simple single-step hydrothermal method. Chitosan polymer was used as a carrier for co-delivery CDs and the anti-cancer drug with low solubility, silibinin (Sil), to design the Sil-chitosan carbon dots hybrid nanogels (CCHNs) system. After optimizing the physicochemical properties of nanostructure by DLS, FTIR, FESEM, TEM, and UV-visible techniques, the successful uptake of the fluorescent nanoparticle conjugates into MCF-7 breast cancer cells occurred. Then we embedded CDs in chitosan nanogel. The resultant CCHNs demonstrated optical properties similar to free-CDs, a desirable size distribution (55.22 nm) with a positive surface charge, a suitable loading capacity for Sil (35%), and drug release vulnerable to pH changes. The fluorescent nanocarrier could transfer Sil to MCF-7 cancer cells without remarkable toxicity. The results of the fluorescent microscope indicated that after 4 h, the solid fluorescent signal was received from cells containing CCHNs compared to free CDs and confirmed the ability of hybrid nanogels to high cellular uptake. This study demonstrates a multifunctional nanocarrier containing therapeutic compounds and fluorescent agents that provide cellular imaging to enhance therapeutic efficacy., (Copyright © 2022. Published by Elsevier B.V.)

BNIP3 is found to eliminate cancer cells via causing mitochondrial damage and endoplasmic reticulum stress, but it remains elusive of its role in regulating DNA double strand breaks (DSBs). In this study, we find that silibinin triggers DNA DSBs, ROS accumulation and expressional upregulation of BNIP3 in glioma cells. Mitigation of ROS with antioxidant GSH significantly inhibits silibinin-induced DNA DSBs and glioma cell death. Then, we find knockdown of BNIP3 with SiRNA obviously prevents silibinin-induced DNA DSBs and ROS accumulation. Mechanistically, BNIP3 knockdown not only reverses silibinin-triggered depletion of cysteine and GSH via maintaining xCT level, but also abrogates catalase decrease. Notably, silibinin-induced dephosphorylation of mTOR is also prevented when BNIP3 is knocked down. Given that activated mTOR could promote xCT expression and inhibit autophagic degradation of catalase, our data suggest that BNIP3 contributes to silibinin-induced DNA DSBs via improving intracellular ROS by inhibition of mTOR., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a common neurodegenerative disease of the central nervous system. Due to its complex pathogenesis and the difficulty of drugs to cross the blood brain barrier (BBB), no effective clinical drugs are currently available that prevent the development of the course of AD. Silibinin (Slb) is known to exert dual therapeutic effects on reducing amyloid-β (Aβ) aggregation and deactivating astrocytes to improve behaviour and cognitive performance in subjects with Alzheimer's disease (AD). However, the poor brain targeting ability and low bioavailability limit its wide application. We aimed to encapsulate Slb in macrophage-derived exosomes (Exo-Slb) to improve its brain targeting ability. After entering the brain, exosomal Slb selectively interacted with Aβ monomers to reduce its aggregation. At the same time, Exo-Slb was internalized in astrocytes to inhibit their activation and alleviate astrocyte inflammation-mediated neuronal damage. Finally, Exo-Slb potently ameliorated cognitive deficits in AD mice., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Silibinin offers potential anticancer effect with less aqueous solubility and high permeability. The present study aimed to develop biocompatible magnetic-core-based nanopolymeric carriers of poly (D, l-lactide-co-glycolic) acid (PLGA) encapsulated silibinin for the sustained release action on renal cancerous cell., Main Methods: The synthesized iron oxide nanoparticles were prepared by precipitation method via encapsulation of silibinin in PLGA network using double emulsion method. The nanoparticle formulations were characterized for morphological, physicochemical properties (HRTEM, FTIR, Raman Spectroscopy and VSM), in vitro drug release and cytotoxicity study on kidney cancer cells (A-498). The safety of magnetic-core-based silibinin nanopolymeric carriers was conducted by i.v. administration at a dose of 50 mg/kg in mice., Key Findings: The mean particle size, zeta potential and % encapsulation efficiency of magnetic-core-based silibinin nanopolymeric carriers were found to be 285.9 ± 0.28 nm, -14.71 ± 0.15 mV and 84.76 ± 1.29%, respectively. The saturation magnetization of magnetic core and optimized nanoparticles were reported as 36.35 emu/g and 12.78 emu/g, respectively. HRTEM analyses revealed the spherical shapes of the particles with uniform size distribution. The in vitro release profile of silibinin from the nanoparticles exhibited a sustained delivery for 15 days and displayed better cytotoxicity against human kidney cancer cells (A-498) than silibinin. In vivo study showed the safety of magnetic-core-based silibinin nanopolymeric carriers in mice., Significance: The magnetic-core-based silibinin nanopolymeric carriers will act as a potential carrier for targeted transportation of actives in cancer therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)