Drug-induced liver injury (DILI) represents a significant clinical challenge characterized by hepatic dysfunction following exposure to diverse medications. Methotrexate (MTX) is a cornerstone in treating various cancers and autoimmune disorders. However, the clinical utility of MTX is overshadowed by its ability to induce hepatotoxicity. The current study aims to elucidate the hepatoprotective effect of the alcoholic extract of Egyptian Araucaria heterophylla resin (AHR) on MTX-induced liver injury in rats. AHR (100 and 200 mg/kg) significantly decreased hepatic markers (AST, ALT, and ALP), accompanied by an elevation in the antioxidant’s markers (SOD, HO-1, and NQO1). AHR extract also significantly inhibited the TGF-β/NF-κB signaling pathway as well as the downstream cascade (IL-6, JAK, STAT-3, and cyclin D). The extract significantly reduced the expression of VEGF and p38 with an elevation in the BCL2 levels, in addition to a significant decrease in the IL-1β and TNF-α levels, with a prominent effect at a high dose (200 mg/kg). Using LC-HRMS/MS analysis, a total of 43 metabolites were tentatively identified, and diterpenes were the major class. This study presents AHR as a promising hepatoprotective agent through inhibition of the TGF-β/NF-κB and JAK/STAT3 pathways, besides its antioxidant and anti-inflammatory effects.

Pregnanes and pregnane glycosides or their esters are well-studied secondary metabolites, many of them exhibit immunomodulator, anticancer, antidiabetic, antarthritic, antiulcer, anti-nociceptive, hypolipidemic, anti-inflammatory, and antibacterial properties. Pregnane glycosides are widely distributed in the families Apocyanaceae and Asclepiadaceae. Plant members of the genus Caralluma R.Br., Apocynaceae, are among the most studied species because of uses in traditional medicine or as food. They are a rich source of pregnane glycosides, as russelioside B. However, the bioactivity profile of this pregnane glycoside has not been reviewed until now. The present review aims to summarize the most important pharmacological and therapeutic applications of russelioside B with specific emphasis on the mechanism of actions associated with its administration in preclinical models. Russelioside B has many pharmacological effects including antidiabetic, anti-obesity, anti-nociceptive, antiulcer, anti-inflammatory, anti-arthritis effects, and antibiofilm, and wound healing activities. Despite its outstanding pharmacotherapeutic potential, russelioside B has never been tested in clinical trials. This review indicates that russelioside B is a potentially promising bioactive candidate, but further deeper mechanistic studies and clinical trials are needed in the future to elucidate its interaction with receptors of specific genes. Graphical abstract

The occurrence of venous diseases among adults is approximately 77% in females and 57% in males. These conditions are prevalent, progressive disorders that significantly affect individuals socially, physically, and psychologically, often resulting in various venous abnormalities that hinder effective blood circulation in the lower limbs. This review provides a comprehensive overview of venous diseases, focusing on their pathophysiology, symptoms, causes, risk factors, diagnosis, and complications. The symptoms associated with venous diseases are diverse and can include pain, heaviness, swelling, ulcers, and skin changes. Risk factors such as age, obesity, hormonal influences, and genetic predispositions are discussed in relation to their contribution to disease progression. The therapeutic modalities for managing venous diseases are explored, with a particular emphasis on natural products in alleviating symptoms and improving vascular health. Natural compounds, i.e., flavonoids, play a vital role in the circulatory system, supporting blood vessels and promoting healthy blood flow, in addition to their vasoprotective, antioxidant, anti-inflammatory, and anti-platelet properties. Overall, the ongoing research efforts on the efficacy of natural products will significantly enhance the management of several venous diseases in the coming years.

The oleoresins of the Araucaria bidwillii Hook. (A.B.) are commonly used for the treatment of several conditions. However, the full phytochemical profile of its active compounds and its mechanism of action to protect the liver from toxicity remain unclear. The purpose of this research was to investigate the complete set of data relating to the A.B. active metabolites and explore the hepatoprotective properties of AB ethanolic extract on MTX-induced liver injury mainly due to its anti-inflammatory role. Hepatic markers, oxidative stress, inflammatory mediators, the NOTCH/NICD signaling cascade, HES1 expression, HMGB1/TLR4, and the PI3K/mTOR axis were assessed. HPLC-HRMS/MS analysis of A.B. led to the annotation of fifteen compounds from different classes, where diterpenes are the dominant class. Additionally, A.B. (100 and 200 mg/kg) significantly decreased hepatic markers, oxidative stress, and inflammatory mediators. Moreover, the extract significantly increased NOTCH pathway stimulation and HES1 expression, accompanied by a significant decline in the NUMB and HMGB1/TLR4 axes. In addition, it significantly inhibited the PI3K/mTOR pathway, with a prominent effect at the higher dose. This study presents A.B. as a promising hepatoprotective agent through stimulation of the NOTCH pathway and inhibition of the HMGB1/TLR4 pathway, as well as the PI3K/mTOR/NF-κB axis, besides its antioxidant and anti-inflammatory effects.