FGF homologous factors are secreted from cells to induce FGFR-mediated anti-apoptotic response.

FGF homologous factors (FHFs) are the least described group of fibroblast growth factors (FGFs). The FHF subfamily consists of four proteins: FGF11, FGF12, FGF13, and FGF14. Until recently, FHFs were thought to be intracellular, non-signaling molecules, despite sharing structural and sequence similarities with other members of FGF family that can be secreted and activate cell signaling by interacting with surface receptors. Here, we show that despite lacking a canonical signal peptide for secretion, FHFs are exported to the extracellular space. Furthermore, we propose that their secretion mechanism is similar to the unconventional secretion of FGF2. The secreted FHFs are biologically active and trigger signaling in cells expressing FGF receptors (FGFRs). Using recombinant proteins, we demonstrated their direct binding to FGFR1, resulting in the activation of downstream signaling and the internalization of the FHF-FGFR1 complex. The effect of receptor activation by FHF proteins is an anti-apoptotic response of the cell.

Byrsonima sericea Ethanol Extract Protected PC12 Cells from the Oxidative Stress and Apoptosis Induced by 6-Hydroxydopamine.

Parkinson's disease is characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway and oxidative stress is one of the main mechanisms that lead to neuronal death in this disease. Previous studies have shown antioxidant activity from the leaves of Byrsonima sericea, a plant of the Malpighiaceae family. This study aimed to evaluate the cytoprotective activity of the B. sericea ethanolic extract (BSEE) against the cytotoxicity induced by 6-hydroxydopamine (6-OHDA) in PC12 cells, an in vitro model of parkinsonism. The identification of phenolic compounds in the extract by HPLC-DAD revealed the presence of geraniin, rutin, isoquercetin, kaempferol 3-O-ß-rutinoside, and quercetin. The BSEE (75-300 µg/mL) protected PC12 cells from toxicity induced by 6-OHDA (25 µg/mL), protected cell membrane integrity and showed antioxidant activity. BSEE was able to decrease nitrite levels, glutathione depletion, and protect cells from 6-OHDA-induced apoptosis. Thus, we suggest that the BSEE can be explored as a possible cytoprotective agent for Parkinson's disease due to its high antioxidant capacity and anti-apoptotic action.

Discovery and optimization of (2-naphthylthio)acetic acid derivative as selective Bfl-1 inhibitor.

Bcl-2 anti-apoptotic protein family suppresses cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Bfl-1 is a relatively understudied member of this family, though it has been implicated in the pathogenesis and chemoresistance of a variety of human cancers. Reported small molecular Bfl-1 inhibitors encountered the issue of either lack in potency or poor selectivity against its most homologous member Mcl-1. In order to tackle this issue, compound library was screened and a hit compound UMI-77 was identified. We modified its chemical structure to remove the characteristic of PAINS (pan-assay interference compounds), demonstrated the real binding affinity and achieved selectivity against Mcl-1 under the guidance of computational modeling. After optimization 15 was obtained as leading compound to block Bfl-1/BIM interaction in vitro with more than 10-fold selectivity over Mcl-1. We believe 15 is of great value for the exploration of Bfl-1 biological function and its potential as therapeutic target.

Intracellular FGF1 protects cells from apoptosis through direct interaction with p53.

Fibroblast growth factor 1 (FGF1) acts by activating specific tyrosine kinase receptors on the cell surface. In addition to this classical mode of action, FGF1 also exhibits intracellular activity. Recently, we found that FGF1 translocated into the cell interior exhibits anti-apoptotic activity independent of receptor activation and downstream signaling. Here, we show that expression of FGF1 increases the survival of cells treated with various apoptosis inducers, but only when wild-type p53 is present. The p53-negative cells were not protected by either ectopically expressed or translocated FGF1. We also confirmed the requirement of p53 for the anti-apoptotic intracellular activity of FGF1 by silencing p53, resulting in loss of the protective effect of FGF1. In contrast, in p53-negative cells, intracellular FGF1 regained its anti-apoptotic properties after transfection with wild-type p53. We also found that FGF1 directly interacts with p53 in cells and that the binding region is located in the DBD domain of p53. We therefore postulate that intracellular FGF1 protects cells from apoptosis by directly interacting with p53.

MOMP in the absence of BH3-only proteins.

The minimum requirement for mitochondrial apoptosis has been controversial ever since the discovery of BCL-2 as a cell death regulator. In this issue ofGenes&Development, O'Neill and colleagues (pp. 973-988) end a long-standing debate by creating a cellular system free of BCL-2 family proteins, thereby identifying the outer mitochondrial membrane rather than BH3-only proteins as the only requirement for BAX/BAK activation and mitochondrial outer membrane permeabilization (MOMP).

Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane.

The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.

Tauroursodeoxycholic Acid (TUDCA) Relieves Streptozotocin (STZ)-Induced Diabetic Rat Model via Modulation of Lipotoxicity, Oxidative Stress, Inflammation, and Apoptosis.

Tauroursodeoxycholic acid (TUDCA) is approved for the treatment of liver diseases. However, the antihyperglycemic effects/mechanisms of TUDCA are still less clear. The present study aimed to evaluate the antidiabetic action of TUDCA in streptozotocin (STZ)-induced type 2 diabetes mellitus (T2DM) in rats. Fifteen adult Wistar albino male rats were randomly divided into three groups (n = five in each): control, diabetic (STZ), and STZ+TUDCA. The results showed that TUDCA treatment significantly reduced blood glucose, HbA1c%, and HOMA-IR as well as elevated the insulin levels in diabetic rats. TUDCA therapy increased the incretin GLP-1 concentrations, decreased serum ceramide synthase (CS), improved the serum lipid profile, and restored the glycogen content in the liver and skeletal muscles. Furthermore, serum inflammatory parameters (such as TNF-α, IL-6, IL-1ß, and PGE-2) were substantially reduced with TUDCA treatment. In the pancreas, STZ+TUDCA-treated rats underwent an obvious enhancement of enzymatic (CAT and SOD) and non-enzymatic (GSH) antioxidant defense systems and a marked decrease in markers of the lipid peroxidation rate (MDA) and nitrosative stress (NO) compared to STZ-alone. At the molecular level, TUDCA decreased the pancreatic mRNA levels of iNOS and apoptotic-related factors (p53 and caspase-3). In conclusion, TUDCA may be useful for diabetes management and could be able to counteract diabetic disorders via anti-hyperlipidemic, antioxidant, anti-inflammatory, and anti-apoptotic actions.

Hydrogen Water: Extra Healthy or a Hoax?-A Systematic Review.

Hydrogen-rich water (HRW) has emerged as a novel approach in the field of health and wellness. It is believed to have therapeutic antioxidant properties that can neutralize harmful free radicals in the human body. It has also been shown to be beneficial in mitigating oxidative stress-induced damage through its anti-inflammatory and anti-apoptotic pathways. We aim to conduct a systematic review to evaluate the potential benefits of hydrogen-rich water. The review protocol was uploaded on PROSPERO. After the initial search criteria, the articles were reviewed by two blinded investigators, and a total of 25 articles were included in the systematic review. The potential benefits of hydrogen-rich water on various aspects of health, including exercise capacity, physical endurance, liver function, cardiovascular disease, mental health, COVID-19, oxidative stress, and anti-aging research, are a subject of growing interest and ongoing research. Although preliminary results in clinical trials and studies are encouraging, further research with larger sample sizes and rigorous methodologies is needed to substantiate these findings. Current research needs to fully explain the mechanisms behind the potential benefits of hydrogen-rich water. Continued scientific exploration will provide valuable insights into the potential of hydrogen-rich water as an adjunctive therapeutic approach in the future.

Mitochondria and Acute Leukemia: A Clinician's Perspective.

Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival. Apoptosis, particularly via the mitochondrial pathway, is crucial for cellular homeostasis and cancer prevention. In acute leukemia, disruption of apoptosis is pivotal in disease development and progression, with elevated levels of anti-apoptotic proteins conferring a survival advantage to leukemia cells and promoting resistance to conventional therapies. Targeting mitochondrial apoptosis using BH3 mimetics and anti-apoptotic protein inhibitors is a viable therapeutic strategy. Alterations in the mitochondrial membrane potential, metabolism, and dynamics also contribute to the pathogenesis of acute leukemia. Continued research is vital for developing novel therapies and enhancing survival outcomes in patients with acute leukemia while minimizing the long-term adverse effects of treatment. In this narrative review, we provide a birds-eye view of the available scientific literature on the importance of mitochondria in acute leukemia, and discuss the role of BH3 mimetics in targeting the mitochondrial internal apoptotic machinery.

Myrrh Essential Oil Mitigates Renal Ischemia/Reperfusion-Induced Injury.

BACKGROUND: Ischemia/reperfusion (I/R)-induced renal injury is a common reason for kidney injury in clinical settings; therefore, continuous investigation of novel nephroprotective agents is crucial. Myrrh, the oleoresin exudates generated by the genus Commiphora, display numerous pharmacological actions. This study tried to assess the preventive effects of myrrh essential oil against I/R-induced renal damage. METHODS: Rats were randomized into five groups. In the sham group, the animals were subjected to bilateral renal artery separation with no occlusion. In the sham + myrrh group; the rats were administered myrrh essential oil and then treated similarly to the sham group. Renal I/R group: the animals were challenged with renal I/R. In the myrrh + renal I/R groups, rats were administered 50 or 100 mg/kg of myrrh essential oil orally for three weeks before being confronted with I/R. RESULTS: Serum levels of renal function tests and renal injury biomarkers, including NGAL, KIM-1, and CysC, were amplified in the renal I/R group. Animals that experienced renal I/R exhibited elevated lipid peroxidation (MDA); declined SOD, CAT, and GPx activity; declined GSH content; augmented TLR4/NFκB gene expression; and subsequent enhancement of inflammatory mediators (TNF-α, IFN-γ, IL-1ß, and IL-6). Myrrh reduced renal function tests and injury biomarkers and amended renal histological alterations. Pretreatment with myrrh reduced MDA, elevated the antioxidant enzymes' activities and GSH content, and reduced the TLR4 and NFκB gene expression, leading to subsequent inflammation and apoptosis alleviation. CONCLUSIONS: The outcomes of the present investigation established the protective effect of myrrh essential oil against renal I/R via pointing out the antioxidant, anti-inflammatory, and anti-apoptotic effects of myrrh.

Effects of Scrophularia buergeriana Extract (Brainon®) on Aging-Induced Memory Impairment in SAMP8 Mice.

Alzheimer's disease (AD) is a worldwide problem. Currently, there are no effective drugs for AD treatment. Scrophularia buergeriana Miquel (SB) is a traditional herbal medicine used in Korea to treat various diseases. Our previous studies have shown that ethanol extract of SB roots (SBE, Brainon®) exhibits potent anti-amnesic effects in Aß1-42- or scopolamine-treated memory impairment mice model and neuroprotective effects in a glutamate-induced SH-SY5Y cell model. In this study, we evaluated the therapeutic effects of Brainon® and its mechanism of action in senescence-accelerated mouse prone 8 (SAMP8) mice. Brainon® (30 or 100 mg/kg/day) was orally treated to six-month-old SAMP8 mice for 12 weeks. Results revealed that Brainon® administration effectually ameliorated cognitive deficits in Y-maze and passive avoidance tests. Following the completion of behavioral testing, western blotting was performed using the cerebral cortex. Results revealed that Brainon® suppressed Aß1-42 accumulation, Tau hyperphosphorylation, oxidative stress, and inflammation and alleviated apoptosis in SAMP8 mice. Brainon® also promoted synaptic function by downregulating the expression of AChE and upregulating the expression of p-CREB/CREB and BDNF. Furthermore, Brainon® restored SAMP8-reduced expression of ChAT and -dephosphorylated of ERK and also decreased AChE expression in the hippocampus. Furthermore, Brainon® alleviated AD progression by promoting mitophagy/autophagy to maintain normal cellular function as a novel finding of this study. Our data suggest that Brainon® can remarkably improve cognitive deficiency with the potential to be utilized in functional food for improving brain health.

l-borneol promotes neurovascular unit protection in the subacute phase of transient middle cerebral artery occlusion rats: p38-MAPK pathway activation, anti-inflammatory, and anti-apoptotic effect.

Our previous study showed l-borneol reduced cerebral infarction in the acute stage after cerebral ischemia, but there is little about the study of subacute phase. We herein investigated the cerebral protective effects of l-borneol on neurovascular units (NVU) in the subacute phase after transient middle cerebral artery occlusion (t-MCAO). The t-MCAO model was prepared by the line embolus method. Zea Longa, mNss, HE, and TTC staining were used to evaluate the effect of l-borneol. We evaluated the mechanisms of l-borneol on inflammation, p38 MAPK pathway, and apoptosis, etc. through various technologies. l-borneol 0.2, 0.1, 0.05 g·kg-1 could significantly reduce cerebral infarction rate, alleviate the pathological injury, and inhibit inflammation reaction. l-borneol could also significantly increase brain blood supply, Nissl bodies, and the expression of GFAP. Additionally, l-borneol activated the p38 MAPK signaling pathway, inhibited cell apoptosis, and maintained BBB integrity. l-borneol had a neuroprotective effect, which was related to activating the p38 MAPK signaling pathway, inhibiting inflammatory response and apoptosis, and improving cerebral blood supply to protect BBB and stabilize and remodel NVU. The study will provide a reference for the use of l-borneol in the treatment of ischemic stroke in the subacute phase.

Asparagus falcatus L. (Asparagaceae) leaf extracts attenuate doxorubicin-induced renal toxicity via antioxidant, anti-inflammatory, and anti-apoptotic pathways.

The search for therapeutic agents that improve kidney function against doxorubicin-induced renal toxicity is important. Herein, the potential nephroprotective activity by Asparagus falcatus L. (AF, Asparagaceae) leaf extracts against doxorubicin-induced renal toxicity (5 mg/kg, ip) in Wistar rats (n = 6/group) after oral administration of hexane (55 mg/kg), ethyl acetate (35 mg/kg), butanol (75 mg/kg), and aqueous (200 mg/kg) extracts of AF for 28 consecutive days was investigated. It was noticed that the treatment with the selected extracts of AF significantly attenuated doxorubicin-induced elevations of serum creatinine, urea nitrogen, ß2-microglobulin, cystatin C, and proteinuria in experimental rats. The histology showed attenuation of the features of acute tubular injury. Treatment regimens significantly reversed the doxorubicin-induced reduction in total antioxidant status, glutathione peroxidase, and glutathione reductase activity in renal tissue homogenates. A suppression in lipid peroxidation was noted with hexane, ethyl acetate, and butanol extracts of AF. Moreover, a reduction in the concentration of the pro-inflammatory mediator TNF-α (p < 0.05), and immunohistochemical expression of COX-2 were observed. The immunohistochemical expression of pro-apoptotic Bax protein was decreased and the anti-apoptotic BCL-2 was increased in renal tissues following the treatments. In conclusion, it was revealed that, hexane, ethyl acetate, butanol, and aqueous extracts of AF attenuate doxorubicin-induced renal toxicity in Wistar rats through antioxidant, anti-inflammatory, and anti-apoptotic pathways. The plant, AF could be recommended as a promising therapeutic agent to minimize renal toxicity induced by doxorubicin in cancer patients, however, subsequent clinical trials are warranted.

Five new compounds from Zingiberis Rhizoma Recens and their anti-apoptotic activity.

Five new compounds, named gingerol A (1a and 1b), gingerol B (2), diphenylheptane glycoside A (3) and diphenylheptane glycoside B (4), were isolated from the acetone extract of Zingiberis Rhizoma Recens. The structures of new compounds were elucidated on the basis of spectroscopic methods including UV, IR, 1D NMR, 2D NMR and HR-ESI-MS. Compounds 2-4 could significantly decrease the apoptosis rate and increase the survival rate of human normal lung epithelial cells (BEAS-2B) at the concentration of 10 µM.

Design, Synthesis, and Potent Anticancer Activity of Novel Indole-Based Bcl-2 Inhibitors.

The Bcl-2 family plays a crucial role in regulating cell apoptosis, making it an attractive target for cancer therapy. In this study, a series of indole-based compounds, U1-6, were designed, synthesized, and evaluated for their anticancer activity against Bcl-2-expressing cancer cell lines. The binding affinity, safety profile, cell cycle arrest, and apoptosis effects of the compounds were tested. The designed compounds exhibited potent inhibitory activity at sub-micromolar IC50 concentrations against MCF-7, MDA-MB-231, and A549 cell lines. Notably, U2 and U3 demonstrated the highest activity, particularly against MCF-7 cells. Respectively, both U2 and U3 showed potential BCL-2 inhibition activity with IC50 values of 1.2 ± 0.02 and 11.10 ± 0.07 µM using an ELISA binding assay compared with 0.62 ± 0.01 µM for gossypol, employed as a positive control. Molecular docking analysis suggested stable interactions of compound U2 at the Bcl-2 binding site through hydrogen bonding, pi-pi stacking, and hydrophobic interactions. Furthermore, U2 demonstrated significant induction of apoptosis and cell cycle arrest at the G1/S phase. Importantly, U2 displayed a favourable safety profile on HDF human dermal normal fibroblast cells at 10-fold greater IC50 values compared with MDA-MB-231 cells. These findings underscore the therapeutic potential of compound U2 as a Bcl-2 inhibitor and provide insights into its molecular mechanisms of action.

Three Major Causes of Metabolic Retinal Degenerations and Three Ways to Avoid Them.

An imbalance of homeostasis in the retina leads to neuron loss and this eventually results in a deterioration of vision. If the stress threshold is exceeded, different protective/survival mechanisms are activated. Numerous key molecular actors contribute to prevalent metabolically induced retinal diseases-the three major challenges are age-related alterations, diabetic retinopathy and glaucoma. These diseases have complex dysregulation of glucose-, lipid-, amino acid or purine metabolism. In this review, we summarize current knowledge on possible ways of preventing or circumventing retinal degeneration by available methods. We intend to provide a unified background, common prevention and treatment rationale for these disorders and identify the mechanisms through which these actions protect the retina. We suggest a role for herbal medicines, internal neuroprotective substances and synthetic drugs targeting four processes: parainflammation and/or glial cell activation, ischemia and related reactive oxygen species and vascular endothelial growth factor accumulation, apoptosis and/or autophagy of nerve cells and an elevation of ocular perfusion pressure and/or intraocular pressure. We conclude that in order to achieve substantial preventive or therapeutic effects, at least two of the mentioned pathways should be targeted synergistically. A repositioning of some drugs is considered to use them for the cure of the other related conditions.

Targeting miR-21 in spinal cord injuries: a game-changer?

Spinal cord injury (SCI) is a devastating neurological state causing physical disability, psychological stress and financial burden. SCI global rate is estimated between 250,000 and 500,000 individuals every year, of which 60% of victims are young, healthy males between 15 and 35 years. A variety of pathological conditions such as neuroinflammation, mitochondrial dysfunction, apoptosis, glial scar formation, blood-spinal cord barrier disruption, and angiogenesis disruption occur after SCI leading to a limitation in recovery. MicroRNAs (miRs) are endogenous and non-coding RNAs consisting of 22 nucleotides that regulate 60% of all human genes and involve several normal physiological processes and pathological conditions. miR-21 is among the most highly expressed miRs and its expression has been shown to increase one day after SCI and this elevation is sustained up to 28 days after injury. Overexpression of miR-21 exerts many protective effects against SCI by inhibiting neuroinflammation, improving blood-spinal cord barrier function, regulating angiogenesis, and controlling glial scar formation. It also exhibits anti-apoptotic effects in SCI by down-regulating the expression of PTEN, Spry2, and PDCD4. This review provides a novel therapeutic perspective for miR-21 in SCI.

Evaluation of the interaction between anti-apoptotic Bcl-2 protein family mRNA expression and autophagy gene Bcl-1 expression in Egyptian SLE patients.

OBJECTIVES: Autophagy is a complex cellular process that maintains homeostasis in systemic lupus erythematosus. Abnormally high expression of Bcl-2 was observed in B and T lymphocytes in the peripheral blood in SLE patients. These may be responsible for the survival of self-reactive lymphocytes and the development of lupus, and the study aims at evaluating interaction between apoptosis and autophagy in Egyptian lupus patients. METHODS: Sixty patients with SLE were diagnosed by fulfilling the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE and sixty healthy age and sex matched control. All patients were subjected to full medical history and clinical examination. Activity was assessed using SLEDAI-2K score. Gene expression of Beclin-1, Bcl-2-L2, and Bcl-2 was measured. RESULTS: The study revealed that the expression of anti-apoptotic Bcl-2 and Bcl-2-L2 was significantly higher in SLE patients than control subjects, as well as the major apoptotic agent (Beclin-1) mRNA, p = 0.03, < 0.001 and 0.02, respectively. The apoptotic Beclin-1 mRNA was positively correlated with SLE disease severity index, r = 0.25; p = 0.0.4; therefore, our results showed that expression of the Beclin-1 was significantly higher in SLE patients than control (p < 0.02). CONCLUSION: Our results showed that expression of the Beclin 1 were significantly higher in SLE patients than control (p < 0.02).

Molecular delineation, expression profiling, immune response, and anti-apoptotic function of a novel clusterin homolog from big-belly seahorse (Hippocampus abdominalis).

Clusterin (CLU) is a glycoprotein that contains α- and ß-chains. CLU exerts multifunctional activities and plays a role in different cell signaling pathways that are associated with various diseases such as proteotoxic and oxidative stress, as well as cell death and survival. However, its role in marine teleost fish remains unclear. Therefore, the present study was carried out to characterize and investigate the immune responses and anti-apoptotic effects of CLU of the big-belly seahorse (Hippocampus abdominalis) (HaCLU) on oxidative stress-induced cell death. The HaCLU open reading frame was 1389 bp long and encoded a protein with 462 amino acids, a molecular weight of 51.28 kDa and an isoelectric point of 5.41. In-silico results demonstrated that HaCLU has a signal peptide in the 1-29 amino acid region, while the α- and ß-chains were in the 34-227 and 228-455 amino acid regions, respectively. Multiple sequence alignment clarified the low homology of the α-chain with other orthologs. The highest HaCLU mRNA expression level was observed in the liver, followed by the heart, spleen, and brain tissues of healthy big-belly seahorses. Further, HaCLU mRNA expression level was elevated in the liver in response to different stimuli, including lipopolysaccharides, polyinosinic:polycytidylic acid, Edwardsiella tarda, and Streptococcus iniae. HaCLU potentiates cell viability and weakens chromatin condensation in the nucleus of FHM cells following H2O2-induced oxidative stress and subsequent cell death. HaCLU overexpression resulted in a reduced Bax/Bcl-2 mRNA expression ratio. This study revealed the role of HaCLU in immune regulation against pathogenic infections and its anti-apoptotic effects on oxidative stress-induced cell death.

Escin attenuates oxidative damage, apoptosis and lipid peroxidation in a model of cyclophosphamide-induced liver damage.

To investigate the effects of escin (ES) on acute damage induced by alkylating agent, experimental rats were injected with cyclophosphamide (CPM) to cause liver damage. The animals were divided into four groups: Control Group, CPM (200 mg/kg), ES (10 mg/kg), CPM, and ES Groups. Immunohistopathological, hepatic histopathological, and biochemical changes were analyzed. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), malondyaldehyde (MDA), glutathion (GSH), total oxidant status (TOS) and total antioxidant status (TAS) in serum were all determined. Serum and immunohistopathology analysis revealed that MDA, ALT, AST, LDH, TOC and OSI, caspase-3 and Bax levels had increased while GSH, TAC, Bcl- 2 and OSI levels decreased in CPM Group when compared to Control Group. These findings appear to account for the severe damage detected. In the CPM + ES treated group, positive improvements were found in biochemical parameters as well as in cell-death and tissue-related damage parameters.The results show that ES considerably protects the rat liver against CPM-induced hepatotoxicity thanks to because of its anti-oxidant and anti-apoptotic properties.