Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the progressive loss of specific neuronal cell populations and are associated with protein aggregates. Current therapeutic approaches are still limited due to the complexity and heterogeneity of these diseases, which points toward an urgent need to discover and develop new therapeutic agents. Natural compounds are a promising source of novel bioactive agents targeting multiple mechanisms of action implicated in neurodegeneration. Andrographolide (ANDRO) is a natural compound extracted from Andrographis paniculata, a traditional Chinese herb known for its anti-inflammatory and antioxidant properties, which has emerged as a potential neuroprotective agent due to its ability to cross the blood-brain barrier (BBB). ANDRO can exert neuroprotective effects by modulating numerous transcription factors and signaling pathways across different cell types in the central nervous system (CNS). It has been described that ANDRO reverses cognitive and/or motor impairments in AD and PD study models. However, the cellular and molecular mechanisms behind these protective effects are still being elucidated. In this review, we analyze the most recent findings on ANDRO, a neuroprotective agent with multiple biological targets that could reduce the progression of the most prevalent neurodegenerative diseases, AD and PD.

Rabies is a fatal zoonotic disease caused by infection with the rabies virus (RABV). Anti-RABV serum or antibody is a unique treatment for patients infected by RABV. However, the mortality is almost 100% in the underdeveloped regions due to the high price and the high cost of transportation and preservation of anti-RABV serum or antibody. Therefore, it is urgently needed to develop novel therapies that can effectively fight against RABV infection. Andrographolide (Andro) is a labdane diterpenoid isolated from Andrographis paniculate, which has been used to treat bacterial and viral infections for decades. In this study, we found that Andro dose-dependently inhibited RABV replication in host cells, with a half-maximal effective concentration (EC50) of slightly less than 60 μmol/L. The antiviral effects of Andro were independent of viral strains and cell lines. Pretreatment of RABV with Andro in test tubes for 1 h did not affect virus replication in host cells, implying that Andro did not directly reduce RABV viability. Of interest, Andro treatment showed no influence on either RABV binding to cells or RABV invasion of cells. Also, Andro treatment downregulated the expression of RABV genomic RNA and structural genes in the cells. To investigate the therapeutic efficacy of Andro in vivo, mice were administered Andro via intraperitoneal (i.p.) injection or intragastric (i.g.) gavage. Neither the administration route nor the dosage significantly affected body weight. Notably, Andro protected mice against a lethal challenge with RABV strain challenge virus standard 11 (CVS-11). Specifically, i.p. injection of 100 mg/kg and 1 mg/kg Andro increased survival rates from 20% to 60% and 80%, respectively, while i.g. gavage of 250 mg/kg Andro elevated the survival rate from 30% to 60%. Correspondingly, RABV viral loads in mouse brain tissues were also reduced. The results suggest that Andro has great potential as a novel anti-RABV agent for the treatment of rabies.

Aplastic anemia (AA) is an immune-mediated bone marrow failure (BMF) syndrome characterized by pancytopenia and bone marrow hypocellularity. While natural killer (NK) cell dysfunction contributes to AA pathogenesis, the epigenetic mechanisms linking genomic instability to inflammatory hyperactivation remain poorly defined. Here, we identify the histone methyltransferase Ash1L as a critical regulator of NK cell homeostasis in AA. Ash1L expression was markedly reduced in NK cells from AA patients and correlated with disease severity and elevated proinflammatory cytokines. Ash1L knockdown reduced NK cell viability, induced apoptosis and G1 cell-cycle arrest, and enhanced secretion of IL-6 and TNF-α. Mechanistically, Ash1L deficiency resulted in reduced H3K4 and H3K36 methylation, impairing activation of the ATM-CHK2-p53 signaling pathway, resulting in persistent γH2AX foci accumulation and aberrant activation of the cGAS-STING signaling pathway. Treatment with the natural compound Andrographolide (Andro) suppressed STING signaling, enhanced DNA damage repair efficiency, and partially restored NK cell function. In an immune-mediated BMF mouse model, Andro attenuated inflammatory responses, restored Ash1L expression in NK cells, inhibited STING pathway activation, and improved hematopoiesis. Collectively, these findings suggest that Ash1L acts as an epigenetic safeguard of genomic stability and inflammatory restraint in NK cells and highlight Andro as a potential therapeutic agent for AA and related immune-mediated BMF disorders.