Pornthip Waiwut

Aging is a multifactorial biological process characterized by progressive alterations in cellular homeostasis, metabolic regulation, immune function, and neurological integrity, contributing to chronic disease, functional decline, and reduced healthspan. Natural bioactive compounds are increasingly investigated as potential geroprotective agents because of their ability to modulate multiple pathways associated with biological aging. Polyphenols, alkaloids, terpenoids, peptides, and related phytochemicals have demonstrated antioxidant, anti-inflammatory, neuroprotective, metabolic, and immunomodulatory effects. However, modulation of aging-related pathways should be distinguished from direct evidence of lifespan extension. Medicinal plants, traditional medicine, and locally consumed functional foods represent important yet comparatively underexplored sources of bioactive compounds with potential relevance to healthy aging. This review synthesizes molecular, cellular, preclinical, and clinical evidence on medicinal plants and their bioactive constituents, with emphasis on neuroprotection, metabolic homeostasis, and immune regulation. Key mechanisms include modulation of oxidative stress, mitochondrial function, nutrient-sensing pathways, autophagy, cellular senescence, neuroinflammation, and chronic low-grade inflammation. Advances in analytical chemistry, molecular docking, network pharmacology, and multi-omics approaches are also considered for their role in strengthening mechanistic characterization and identifying potential responder profiles. Overall, current evidence supports further investigation of medicinal plants as candidate modulators of biological aging and healthspan-related processes, while emphasizing the need for standardized preparations, robust clinical studies, and mechanistically informed translational research.

Cancer remains a leading cause of mortality worldwide, largely due to dysregulated apoptotic signaling and the persistent activation of oncogenic pathways. However, natural products are a promising source of multi-target anticancer agents. In this study, we investigated the anticancer activity and underlying mechanisms of Clausena harmandiana root extract and its major carbazole alkaloid, 7-methoxyheptaphylline, both in vitro and in vivo. High-Performance Liquid Chromatography (HPLC) chemical fingerprinting confirmed the presence of bioactive coumarins and carbazole alkaloids in the extract. Cytotoxicity assays demonstrated that the extract significantly reduced the viability of human colorectal adenocarcinoma (HT-29), human hepatocellular carcinoma (HepG2), human lung adenocarcinoma (A549–Luc2), and murine Lewis lung carcinoma (3LL–Luc2) cells in a dose- and time-dependent manner. Our mechanistic investigations revealed the activation of JNK signaling, downregulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1), and increased cleaved caspase-3 expression, indicating that mitochondrial apoptosis was induced. Notably, 7-methoxyheptaphylline markedly suppressed STAT3 phosphorylation in a concentration-dependent manner, comparable to the STAT3 inhibitor JSI-124. In a syngeneic 3LL–Luciferase2 lung cancer mouse model, oral administration of C. harmandiana capsules significantly reduced tumor growth and bioluminescence intensity compared with controls. These in vivo findings were consistent with the inhibition of STAT3 signaling and induction of apoptosis observed in vitro. Collectively, our results demonstrate that C. harmandiana exerts broad-spectrum anticancer activity through coordinated modulation of the JNK–STAT3 axis, leading to caspase-dependent apoptosis. These findings highlight its potential as a promising candidate for the development of STAT3-targeted anticancer therapies.

Dihydrocapsaicin (DHC), a prominent capsaicinoid derived from red chili peppers, has shown cytotoxic effects against various cancer cell types. However, its role in modulating cytokine-induced survival and apoptotic signaling in cancer cells remains unclear. In this study, we investigated the effects of DHC on tumor necrosis factor-α (TNF-α)-induced cell cycle arrest and apoptosis in HeLa human cervical cancer cells. Our results demonstrate that DHC significantly enhances TNF-α-induced G1 phase cell cycle arrest and apoptosis by targeting the transforming growth factor-β-activated kinase 1 (TAK1)-mediated prosurvival pathways. DHC inhibited the phosphorylation of TAK1 and downstream effectors including IKKα, NF-κB p65, MAPKs (p38, JNK, ERK), Akt, and EGFR, thereby disrupting key signaling networks that typically confer resistance to TNF-α-induced cytotoxicity. Additionally, DHC suppressed the TNF-α-induced phosphorylation of EGFR at Ser-1046/1047 and Thr-669, sites critical for survival signaling. Co-treatment with DHC and TNF-α led to enhanced apoptotic features, including increased PARP-1 cleavage. These findings suggest that DHC sensitizes cervical cancer cells to cytokine-induced cell death by interfering with TAK1/NF-κB and EGFR signaling axes. Our study positions DHC as a promising candidate for combination therapies aimed at overcoming resistance in cancers with aberrant inflammatory and survival signaling.

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive memory loss, posing a significant risk, particularly within aging populations. Effective treatments to prevent or cure AD have remained elusive with current treatments only able to slow disease progression. Moreover, challenges in drug development for AD therapies are a complex pathology. A multi-target agent gained considerable interest over the single therapy in complex diseases, providing possible insights into therapeutic development by simultaneously targeting multiple pathological mechanisms. Virtual screening (VS) is a potent computational tool for identifying potential drug candidates from vast chemical databases, with subsequent molecular docking providing detailed insights into ligand-protein interactions. The ZINC database, housing millions of chemical compounds, serves as a valuable resource for screenings. Here, we conducted VS of compounds sourced from the ZINC database to identify potential multi-target AD agents. Through the VS analysis and subsequent in-vitro evaluations, our investigation identified one compound, ZINC006067856 (VS3), as a highly promising hit. This compound exhibited multifaceted actions against key AD pathological features, including cholinesterase inhibition, modulation of amyloid beta (Aβ) aggregation, and promotion of Aβ destabilization. Additionally, VS3 demonstrated neuroprotective effects against hydrogen peroxide-induced cell damage, further highlighting its potential as a comprehensive multi-targeted therapeutic agent for AD. Therefore, our findings suggested that VS3 held promise as a candidate for further preclinical and clinical investigations in the treatment of AD. Further elucidation of its mechanisms of action and comprehensive preclinical evaluations are required to assess its safety, efficacy, and therapeutic potential in improving AD clinical outcomes.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer in humans, with an increasing incidence worldwide. The current study aimed to explore the molecular mechanisms that inhibit the proliferation of HepG2 cells, a hepatoblastoma-derived cell line. MSC-derived exosomes (UC-MSCs) were prepared with a median particle size (N50) of 135.8 nm. Concentrations of UC-MSCs ranging from 10 μg/mL to 1000 μg/mL were applied to HepG2 cell cultures and compared to untreated and anticancer drug-treated HepG2 cells. A combined approach was employed, integrating a proteomic analysis of UC-MSCs, metabolomic analysis of HepG2 cells, and transcriptomic profiling of HepG2 cells to decipher the inhibitory mechanisms of UC-MSC exosomes on HepG2 cell growth. Treatment with a high concentration of UC-MSCs led to a notable reduction in HepG2 cell viability, with survival decreasing by 65%. A proteomic analysis of UC-MSCs revealed enriched degranulation processes in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in addition to the known exosomal pathways. Transcriptomic profiling showed distinct changes in the expression of genes related to hepatocellular diseases in UC-MSC-treated HepG2 cells, contrasting with changes observed in HepG2 cells treated with the chemotherapeutic agent doxorubicin (DOX). Combined with a metabolomic analysis, the detailed GO and KEGG pathway analyses indicated that pathways associated with neutrophil extracellular trap formation played a critical role in mediating protein degradation and suppressing central carbon metabolism in cancer cells. Our results revealed that the UC-MSC treatment mimicked molecular mechanisms similar to those involved in neutrophil extracellular trap formation, exhibiting effects on HepG2 cell growth suppression that differed from those of chemical cancer drugs. Notably, the UC-MSC treatment demonstrated that protein degradation in HepG2 cells was regulated through canonical signaling pathways activated by bacterial peptides in neutrophils. This research has provided valuable insights into the potential of MSC-derived exosomes as a therapeutic approach for cancer treatment in the future.

A cytokine known as TNF-related apoptosis-inducing ligand (TRAIL) has the ability to precisely cause the death of cancer cells, while normal cells are left undisturbed. Recent studies show that certain cancer cells are sensitive to the apoptotic effect of TRAIL. In this study, HT29 colorectal adenocarcinoma cells exposed to TRAIL were treated with heptaphylline and 7-methoxyheptaphylline from Clausena harmandiana in an effort to comprehend the mechanisms involved behind this activity. The MTT test was utilized to determine cell survival, and phase contrast microscopy was used to examine cell morphology. Through using real-time RT-PCR, Western blotting, and RT-PCR, the molecular mechanisms were investigated. According to the findings, whilst hepataphylline caused cytotoxicity in normal colon FHC cells, in comparison to healthy colon FHC cells, 7-methoxyheptaphylline inhibited cancer cells in a concentration-dependent manner. Heptaphylline alone or in conjunction with TRAIL showed no discernible effect on TRAL-induced HT29 cell death, but 7-methoxyheptaphylline boosted caspase-3 cleavage. The study showed that the JNK pathway was responsible for the 7-methoxyheptaphylline's enhancement of the DR5 (death receptor 5) mRNA, TRAIL receptor, and protein. The results demonstrated that the 7-methoxyheptaphylline of Clausena harmandiana increased the expression of DR5 via the JNK pathway, intensifying TRAIL-induced HT29 cell death.

The effects of Mesua ferrea Linn flower (MFE) extract on the pathogenic cascade of Alzheimer’s disease (AD) were determined by an in vitro and cell culture model in the search for a potential candidate for the treatment of AD. The 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay exhibited that the MFE extract had antioxidant activities. According to the Ellman and the thioflavin T method’s result, the extracts could inhibit acetylcholinesterase and β-amyloid (Aβ) aggregation. Studies on neuroprotection in cell culture found that the MFE extract could reduce the death of human neuroblastoma cells (SH-SY5Y) caused by H₂O₂ and Aβ. Western blot analysis exhibited that the MFE extract alleviated H₂O₂-induced neuronal cell damage by downregulating the pro-apoptotic proteins, including cleaved caspase-3, Bax, and by enhancing the expression of anti-apoptotic markers including MCl₁, BCl_xl, and survivin. Moreover, MFE extract inhibited the expression of APP, presenilin 1, and BACE, and increased the expression of neprilysin. In addition, the MFE extract could enhance scopolamine-induced memory deficit in mice. Overall, results showed that the MFE extract had several modes of action related to the AD pathogenesis cascade, including antioxidants, anti-acetylcholinesterase, anti-Aβ aggregation, and neuroprotection against oxidative stress and Aβ. Therefore, the M. ferrea L. flower might be a possibility for further development as a medication for AD.

This study was designed to investigate the effects of the root-bark extract of Clausena harmandiana (CH) and its active constituents (nordentatin and 7-methoxyheptaphylline) on pharmacological activities regarding selected targets associated with AD, namely, its antioxidant activity, inhibition of Aβ aggregation, acetylcholinesterase (AChE) activity, and neuroprotective effects. The effect of the CH extract on the cognitive impairment induced by scopolamine was also evaluated in mice. The effects of the CH extract and its active constituents on radical scavenging, Aβ aggregation, and AChE activity were investigated with a 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assay, a thioflavin-T assay, and Ellman’s method. The neuroprotective effects of the extract against hydrogen-peroxide and Aβ toxicity were evaluated with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In addition, the effects on cognitive impairment induced by scopolamine in mice were evaluated using Morris-water-maze and modified-Y-maze test models. The results of the present study demonstrate that the root-bark extract of CH shows multimodal actions relevant to the AD pathological cascade, including antioxidant effects, the inhibition of Aβ aggregation, the inhibition of AChE function, and neuroprotection against oxidative stress and Aβ toxicity. The extracts could improve both the short- and long-term memory deficits induced by scopolamine in mice.