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Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by excessive accumulation of extracellular matrix, leading to irreversible fibrosis. Emerging evidence suggests that endoplasmic reticulum (ER) stress, mitochondrial stress, and oxidative stress pathways play crucial roles in the pathogenesis of IPF. ER stress occurs when the protein folding capacity of the ER is overwhelmed, triggering the unfolded protein response (UPR) and contributing to protein misfolding and cellular stress in IPF. Concurrently, mitochondrial dysfunction involving dysregulation of key regulators, including PTEN-induced putative kinase 1 (PINK1), Parkin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and sirtuin 3 (SIRT3), disrupts mitochondrial homeostasis and impairs cellular energy metabolism. This leads to increased reactive oxygen species (ROS) production, release of pro-fibrotic mediators, and activation of fibrotic pathways, exacerbating IPF progression. The UPR-induced ER stress further disrupts mitochondrial metabolism, resulting in altered mitochondrial mechanisms that increase the generation of ROS, resulting in further ER stress, creating a feedback loop that contributes to the progression of IPF. Oxidative stress also plays a pivotal role in IPF, as ROS-mediated activation of TGF-β, NF-κB, and MAPK pathways promotes inflammation and fibrotic responses. This review mainly focuses on the links between ER stress, mitochondrial dysfunctions, and oxidative stress with different signaling pathways involved in IPF. Understanding these mechanisms and targeting key molecules within these pathways may offer promising avenues for intervention., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Aims: Pathological cardiac hypertrophy is a characteristic feature in many cardiovascular diseases (CVDs). Aloin is an anthraquinone glycoside from Aloe species, and the effect of aloin on cardiac hypertrophy and associated fibrotic changes have not been elucidated. This study investigated the effect of aloin against the isoproterenol (ISO)-induced cardiac hypertrophy in rats., Main Methods: Cardiac hypertrophy experimental model was induced in rats by subcutaneous injection of ISO for 14 days. Meanwhile, the animals were administered orally with aloin at doses of 25 and 50 mg/kg/day. On the 15th day, cardiac echocardiography was performed, the heart was collected and subjected for histopathological, gene expression, and immunoblot studies. Additionally, the effect of aloin on ISO-induced hypertrophic changes in H9c2 cells was investigated., Key Findings: Aloin markedly alleviated ISO-induced heart injury, reduced cardiac hypertrophy, improved cardiac function, and histological alterations in the heart. Mechanistically, aloin attenuated ISO-induced fibrosis via inhibition of the levels of collagen I, α-smooth muscle actin (α-SMA), fibronectin, transforming growth factor-β (TGF-β) and pSmad2/3 proteins in the heart. Aloin alleviated ISO-induced myocardial oxidative damage and up-regulated the levels of antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins. Moreover, aloin treatment attenuated ISO-induced hypertrophic changes and the generation of reactive oxygen species (ROS) in H9c2 cells in vitro., Significance: Our findings demonstrated that aloin alleviated ISO-induced cardiac hypertrophy and fibrosis via inhibiting TGF-β/pSmad2/3 signaling and restoring myocardial antioxidants, and therefore has promising therapeutic potential against cardiac hypertrophy and fibrosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is among the deadliest cancer in human malignancies. It is the most common and severe type of primary liver cancer. However, the molecular mechanisms underlying HCC pathogenesis remain poorly understood. Long non-coding RNAs (lncRNAs), a new kind of RNA and epigenetic factors, play a crucial role in tumorigenesis and the progression of HCC. LncRNAs are capable of promoting the autophagy, proliferation, and migration of tumor cells by targeting and modulating the expression of downstream genes in signaling pathways related to cancer; these transcripts modify the activity and expression of various tumor suppressors and oncogenes. LncRNAs could act as biomarkers for treatment approaches such as immunotherapy, chemotherapy, and surgery to effectively treat HCC patients. Improved knowledge regarding the aetiology of HCC may result from an advanced understanding of lncRNAs. Enhanced oxidative stress in the mitochondrial and Endoplasmic reticulum leads to the activation of unfolded protein response pathway that plays a crucial role in the pathophysiology of hepatocellular carcinoma. The mutual regulation between LncRNAs and Endoplasmic reticulum (ER) stress in cancer and simultaneous activation of the unfolded protein response (UPR) pathway determines the fate of tumor cells in HCC. Mitochondria-associated lncRNAs work as essential components of several gene regulatory networks; abnormal regulation of mitochondria-associated lncRNAs may lead to oncogenesis, which provides further insight into the understanding of tumorigenesis and therapeutic strategies. [Display omitted] [ABSTRACT FROM AUTHOR]

Adiponectin plays key roles in energy metabolism and ameliorates inflammation, oxidative stress, and mitochondrial dysfunction via its primary receptors, adiponectin receptors −1 and 2 (AdipoR1 and AdipoR2). Systemic depletion of adiponectin causes various metabolic disorders, including MASLD; however adiponectin supplementation is not yet achievable owing to its large size and oligomerization-associated complexities. Small-molecule AdipoR agonists, thus, may provide viable therapeutic options against metabolic disorders. Using a novel luciferase reporter-based assay here, we have identified Apigenin-6-C-glucoside (ACG), but not apigenin, as a specific agonist for the liver-rich AdipoR isoform, AdipoR2 (EC 50 : 384 pM) with >10000X preference over AdipoR1. Immunoblot analysis in HEK-293 overexpressing AdipoR2 or HepG2 and PLC/PRF/5 liver cell lines revealed rapid AMPK, p38 activation and induction of typical AdipoR targets PGC-1α and PPARα by ACG at a pharmacologically relevant concentration of 100 nM (reported cMax in mouse; 297 nM). ACG-mediated AdipoR2 activation culminated in a favorable modulation of key metabolic events, including decreased inflammation, oxidative stress, mitochondrial dysfunction, de novo lipogenesis, and increased fatty acid β-oxidation as determined by immunoblotting, QRT-PCR and extracellular flux analysis. AdipoR2 depletion or AMPK/p38 inhibition dampened these effects. The in vitro results were recapitulated in two different murine models of MASLD, where ACG at 10 mg/kg body weight robustly reduced hepatic steatosis, fibrosis, proinflammatory macrophage numbers, and increased hepatic glycogen content. Together, using in vitro experiments and rodent models, we demonstrate a proof-of-concept for AdipoR2 as a therapeutic target for MASLD and provide novel chemicobiological insights for the generation of translation-worthy pharmacological agents. [Display omitted] • ACG activates AdipoR2 with an EC 50 of 384 pM. • ACG specifically activates AdipoR2 with >10000X selectivity over AdipoR1. • ACG ameliorates lipotoxicity via AdipoR-associated signaling pathways. • ACG ameliorates MASLD in genetically dyslipidemic mice fed a Western diet. • ACG ameliorates MASLD in a diet-induced rodent model. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is an inflammatory condition primarily affecting the joints. Nuciferine (NCF), a key bioactive aporphine alkaloid biosynthesized in lotus leaves, exhibits promising anti-inflammatory and antioxidant properties. In this study, we investigated whether NCF could alleviate inflammatory arthritis conditions in a complete Freund's adjuvant (CFA)-mediated arthritis model in rats. The arthritis model was established through intradermal injection of CFA (100 μL) in the sub-plantar region of the right hind paw. The arthritic animals were treated orally with NCF at 5 and 10 mg/kg and indomethacin (Indo) at 5 mg/kg body weight as reference control. NCF treatment remarkably alleviated inflammatory joint swelling and arthritic index. The radiological and histological analysis revealed evidence of the beneficial effects of NCF. NCF treatment decreased the content of pro-inflammatory cytokines (TNF-α and IL-1β) and myeloperoxidase (MPO) activity and restored the anti-inflammatory cytokine (IL-10) in the paw joints. The serum levels of pro-inflammatory cytokines were also markedly reduced in the NCF (10 mg/kg) treatment group. Moreover, the arthritis-induced inflammatory mediators, including cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) and the toll-like receptor (TLR)-4, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling proteins were substantially decreased in the NCF treatment groups. NCF treatment also restored the antioxidant defense enzymes and abrogated lipid peroxidation in the paw tissue. Our findings strongly suggest that NCF is a promising therapeutic molecule for rheumatoid arthritis, inspiring further research, and development in this area. [Display omitted] • Nuciferine alleviated adjuvant-induced arthritis in rats. • Nuciferine substantially decreased inflammation in the paw joints. • Nuciferine interferes with TLR-4/MAPK/NF-κB signaling proteins in the paw tissues. • Nuciferine treatment restored the antioxidant defense in the paw tissue. • Nuciferine could be a promising therapeutic molecule for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Cytochrome P450 2E1 (CYP2E1) is an enzyme, primarily involved in the metabolism of xenobiotics and procarcinogens. The present study was designed to investigate the potential role of CYP2E1 triggered endoplasmic reticulum stress in the progression of HCC through inhibition of apoptosis. In vitro CYP2E1 promotes HepG2 cell migration, reduced chromatin condensation, enhanced intracellular ROS accumulation and induce cell cycle progression. Conversely this effect was averted by CYP2E1 siRNA, selective inhibitor Diallyl sulphide (DAS) and antioxidants (vitamin C and E). In vivo Diethylnitrosamine (DEN) induced HCC rats showed decreased body weight and increased relative liver weight. Moreover, macro trabecular-massive HCC (MTM-HCC) histological subtyping showed pathological features like well-differentiated tumors, micro-trabecular and pseudo glandular patterns, megakaryocytes and cholestasis. Masson's trichrome staining revealed an intensive accumulation of collagen fibers in the extracellular matrix (ECM). Increased CYP2E1, VEGF and PCNA enhance the carcinogenicity as revealed in immunohistochemistry results. Immunoblot analysis showed reduced expression of copper-zinc superoxide dismutase (CuZnSOD) and manganese superoxide dismutase (MnSOD) in cytosolic as well as mitochondrial fraction of rat liver tissue respectively. Also, increased level of CYP2E1 stimulated the upregulation of unfolded proteins response (UPR) and ER stress-related proteins such as Glucose regulatory protein 78 (GRP78), activating transcription factor 6 (ATF6) and CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP). Meanwhile, CYP2E1 stimulated ER-stress reduces BCL2 and downregulates the cleaved caspase 3 thus suppresses apoptosis. in. Furthermore, immunofluorescence revealed increased expression level of α-SMA in the HCC rat liver tissue. The level of CYP2E1 mRNA was significantly increased. Altogether, these findings indicate that CYP2E1 has a dynamic role in the pathogenesis of HCC and might be a budding agent in liver carcinogenesis therapy. [Display omitted] • CYP2E1 retards chromatin condensation through activation of anti-apoptotic proteins and enhances intracellular ROS accumulation through ER-stress. • CYP2E1 mediated ER-stress regulates cell cycle progression. • Activation of CYP2E1 led to the disruption of liver function and histology. • CYP2E1 promotes tumorigenicity of HCC through modulation of the GRP78/ATF6/CHOP signaling axis. • Targeting the CYP2E1 could be a potential therapeutic approach for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Alternanthera brasiliana L. is a flowering plant belonging to the family Amaranthaceae and is popularly known as "penicillin". It is used in folk medicine to treat infections, coughs, wound healing, and inflammatory diseases. Aim of the study : We investigated the effect of Alternanthera brasiliana L. leaves hydroalcoholic extract (AB) against oxidative stress, inflammation, and fibrotic changes in an experimental model of carbon tetrachloride (CCl 4)-induced liver injury and fibrosis in mice. Thirty-six male Balb/C mice were randomized into five groups: normal control, AB control, CCl 4 control, CCl 4 + AB-200 mg/kg, and CCl 4 + AB-400 mg/kg. In mice, liver injury was induced by intraperitoneal injection of CCl 4 (20% in corn oil, 5 ml/kg body weight) thrice a week for six consecutive weeks. AB extract at two doses (200 mg/kg and 400 mg/kg body weight) was administered orally for six consecutive weeks. Liver injury-related serum markers (ALT, AST, ALP), antioxidants (GSH, GST, SOD, and vitamin C), pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-18, ultrasonographic and histological alterations, proteins of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase-1 (TIMP-1), nuclear factor-κB (p65) (NF-κB), nod-like receptor protein 3 (NLRP3), and TGF-β/Smad signaling were accessed. LC-Q-TOF-MS/MS analysis of AB was performed. AB treatment significantly decreased the CCl 4 -induced rise in serum ALT, AST, and ALP activities and improved the histological alterations. Compared with the CCl 4 -treated group, treatment with AB significantly restored the hepatic antioxidants and reduced the pro-inflammatory cytokines in the liver. The antioxidant activity of AB may be attributed to its terpenoid constituents, which was confirmed by LC-Q-TOF-MS/MS analysis. The CCl 4 -induced rise in expression of MMP-2 and MMP-9 and decrease in TIMP-1 were markedly restored in the AB-treated groups. Further findings revealed a significant reduction in the protein levels of phospho–NF–κB (p65), NLRP3, TGF-β, pSmad2/3, collagen I, and α-smooth muscle actin (α-SMA) in the AB treatment groups. The hepatoprotective effect of AB may be attributed to the high content of terpenoid compounds and alleviates liver injury and associated fibrotic changes through modulating MMPs, NF-κB (p65), and the TGF-β/Smad axis. [Display omitted] • Alternanthera brasiliana extract (AB) exhibits hepatoprotective effect in mice. • LC-Q-TOF-MS/MS analysis reveals terpenoids (38.7%) are major constituents in AB. • AB restores antioxidants and reduces pro-inflammatory cytokines in the liver. • AB treatment impedes the MMP2/MMP9/TIMP-1 and the TGF-β/Smad signaling axis. [ABSTRACT FROM AUTHOR]

Lung cancer is an aggressive malignancy and the leading cause of cancer-related deaths. Benzo[ a ]pyrene (B[ a ]P), a polycyclic hydrocarbon, plays a pivotal role in lung carcinogenesis. Uncovering the molecular mechanism underlying the pathophysiology of B[ a ]P induced malignancy is crucial. Male Sprague Dawley rats were induced with B[ a ]P to generate a lung cancer model. The B[ a ]P administered rats show increased body and lung weight, loss of normal pulmonary architecture, and decreased survival. This study demonstrated that B[ a ]P upregulates activating transcription factor-6 (ATF6) and C/EBP Homologous Protein (CHOP) and induces endoplasmic reticulum (ER) stress. B[ a ]P also dysregulated mitochondrial homeostasis by upregulating, PTEN-induced putative kinase-1 (PINK1) and Parkin. B[ a ]P affected the levels of superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA), and increased oxidative stress. B[ a ]P exposure downregulated Kelch-like ECH-associated protein 1 (Keap1) and upregulated nuclear factor erythroid 2–related factor 2 (Nrf2) and Heme oxygenase-1(HO1). The metabolomic study identified that biosynthesis of nucleotide, amino acids, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and glutathione metabolism were up-accumulated. On the other hand, lower accumulation of fatty acids e.g., palmitic acid, stearic acid, and oleic acid were reported in the B[ a ]P induced group. Overall, the results of this study indicate that B[ a ]P treatment affects several signaling and metabolic pathways, whose dysregulation might be involved in lung cancer induction. Summary: Molecular mechanism of B [ a ]P-induced lung cancer and its link to altered metabolism. [Display omitted] • B [ a ]P increases ATF6, CHOP, and Parkin, PINK1 to induce ER and mitochondrial stress. • It alters antioxidant levels and increases oxidative stress. • B [ a ]P increases the cytosolic level of Nrf2. • B [ a ]P modulates several cellular pathways, which might contribute to lung cancer development. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) with underlying interstitial fibrosis is often associated with end-stage renal disease (ESRD). In the present study, we investigated the renoprotective and antifibrotic potential of nootkatone (NTK), a bioactive sesquiterpene, in an experimental model of renal fibrosis. Unilateral ureteral obstruction (UUO) model was performed to induce renal fibrosis in Balb/C mice. The animals were randomly assigned into 5 groups: sham, NTK control, UUO control, UUO and NTK 5 mg/kg, and UUO and NTK 10 mg/kg. Animals received NTK at a dose of 5 mg/kg and 10 mg/kg orally for the next 14 consecutive days. UUO induced histological alterations, accumulation of extracellular matrix (ECM) components including collagens, fibronectin, and alpha-smooth muscle actin (α-SMA), activation of the transforming growth factor-β (TGF-β)/Smad signaling and oxidative damage in the obstructed kidneys. Our study revealed that NTK (10 mg/kg) inhibits UUO mediated kidney fibrosis in vivo. Administration of NTK (10 mg/kg) prevented the activation of the TGF-β/Smad signaling, expression of ECM components, markedly attenuated the renal tubular injury and fibrosis area (% area: 6.66 ± 1.45% vs UUO: 26.33 ± 2.90%). Administration of NTK at 10 mg/kg significantly restored the endogenous antioxidants and prevented the reactive oxygen species generation (25.31 ± 1.65% vs UUO: 45.01 ± 4.85%) and reduced the level of tumor necrosis factor (TNF)-α (95.22 ± 12.39 vs UUO: 215.57 ± 60.45 pg/mg protein) in the kidneys. Altogether, our findings suggest that NTK might be a budding therapeutic candidate for renal fibrosis. [ABSTRACT FROM AUTHOR]