Rotundine (levo-tetrahydropalmatine) / Second Affiliated Hospital of Guangzhou Medical University, National Institute on Drug Abuse, University of Maryland - LARVOL DELTA

Clinical characteristics and predictors of severe toxicity following acute rotundine poisoning: A retrospective study of 37 patients in Vietnam. (PubMed, Toxicol Rep) - "Acute Rotundine poisoning generally has a favorable prognosis but may occasionally cause severe central nervous system depression requiring intensive care and mechanical ventilation. Admission GCS may serve as a simple bedside predictor of severe toxicity, while electrocardiographic monitoring should be considered because QTc prolongation is relatively common."

Journal • Retrospective data • CNS Disorders • Critical care • Depression • Psychiatry

L-tetrahydropalmatine attenuates ketamine reward effect via modulating the miR-27a-3p/MAP2K4 axis. (PubMed, Front Genet) - "Furthermore, inhibition of miR-27a-3p expression using an miR-27a-3p inhibitor in PC12 cells resulted in increased mitogen-activated protein kinase 4 (MAP2K4) expression, indicating that MAP2K4 is a potential functional target of miR-27a-3p in vitro. Our findings demonstrate that l-THP attenuates KET reward effect by modulating the BDNF/TrkB pathway and the miR-27a-3p/MAP2K4 axis, which may be promising targets for the intervene of KET reward effect."

Journal • CNS Disorders • Psychiatry • MAP2K4 • MAPK4 • MIR27A

Fluorescent labeled enzyme immobilized on chitosan-coated magnetic microspheres for potential cyclooxygenase-2 inhibitors screening accompanied with molecular modeling and in situ cell imaging. (PubMed, Mikrochim Acta) - "Under optimal conditions, the prepared nanocomposites screened fourteen potential COX-2 inhibitors from YBTC, which were identified by UHPLC-MS/MS as tetrahydrocolumbamine, protopine, trahydocoptisine, yuanhunine, rotundine, tetrahydroberberine, thalictrimine, palmatine, dehydrocorydaline, mudanpioside D, astringin, nodakenin, paeoniflorin sulfite and ligustilide...Fluorescence cell imaging results indicated that the screened compounds effectively inhibited synovial cell proliferation, suggesting their potential therapeutic efficacy in the treatment of rheumatoid arthritis (RA). The proposed methodology, integrating highly specific screening with in-situ visual imaging, established a robust platform for the efficient and selective screening of plant-derived biologically active molecules."

Journal • Preclinical • Immunology • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology

Design, Synthesis, and Anti-Inflammation Activity of C-12 Arylated Tetrahydropalmatine Derivatives. (PubMed, ChemMedChem) - "The bioactive natural product L-tetrahydropalmatine and its analogs have attracted significant attention due to their potent pharmacological activities...Among these derivatives, compound 4p, bearing a 4-ethenylphenyl moiety, suppressed the production of pro-inflammatory cytokines (TNF-α and IL-1β) in LPS-induced in vitro inflammatory models, indicating that it might be a potential anti-inflammatory agent. This work offers valuable insights into the development of tetrahydropalmatine analogs as novel anti-inflammatory agents."

Journal • Inflammation • IL1B • TNFA

Comprehensive profiling and molecular characterization of alternative splicing regulation in synaptic remodeling associated with neuropathic pain induced by chronic constrictive injury in a rat Model. (PubMed, RNA Biol) - "We analysed 12 RNA-seq datasets (GSE217932) using the SUVA pipeline to identify splicing alterations in Sham, chronic constriction injury (CCI), and CCI treated with L-tetrahydropalmatine (CCI_THP) groups...This study provides a transcriptome-wide view of alternative splicing and RBP dysregulation in NP, and suggests that THP may alleviate neuropathic pain partly by modulating aberrant splicing programs. These findings offer insight into NP mechanisms and identify potential therapeutic targets."

Journal • Preclinical • Neuralgia • Pain • GRN • NEFH

A drug-drug co-amorphous formulation for enhanced solubility and transdermal absorption of rotundine. (PubMed, Int J Pharm ) - "In vivo analgesic evaluations in acetic acid-induced zebrafish nociception and mouse hot-plate models evidenced rapid, sustained pain relief with the co-amorphous system, mitigating RTD's sedative effects while preserving efficacy. This study highlights co-amorphous drug-drug systems as a versatile, excipient-free platform for transdermal delivery of poorly soluble bioactives, offering a promising strategy for improving the efficacy and safety of pain management treatments."

Journal • Pain

Mechanisms of cancer pain and the multitarget therapeutic potential of Traditional Chinese Medicine. (PubMed, Sheng Li Xue Bao) - "For example, bioactive components such as tetrahydroberberine, levo-tetrahydropalmatine, and piperine exert analgesic effects, thereby improving the quality of life of patients by inhibiting inflammatory cascades, regulating neurotransmitter systems, and preserving neural integrity...This review also discusses the current limitations of clinical evidence, such as small sample sizes, short follow-up periods, and limited translation from animal models, alongside major challenges in standardization, mechanistic elucidation, and clinical trial design. Future directions should focus on precise pain phenotyping, integrated multi-target interventions, rigorous efficacy-safety validation, and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management."

Journal • Addiction (Opioid and Alcohol) • Oncology • Osteosarcoma • Pain • Pancreatic Cancer • Peripheral Neuropathic Pain • Sarcoma • Solid Tumor

Synergistic effects of levo-tetrahydropalmatine and low-dose naltrexone on nicotine conditioned place preference in mice: a dual-target strategy based on dopamine and opioid systems. (PubMed, Front Pharmacol) - "These findings indicate that the combination therapy based on dual-action mechanism of l-THP and LDN, targeting both dopamine and opioid pathways, effectively attenuates nicotine-induced CPP in mice, which may offer a potential treatment for nicotine addiction. The combination enhances therapeutic efficacy within the nicotine-induced CPP paradigm and correlates with an elevation of β-endorphin levels."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Nicotine Addiction • Psychiatry

L-tetrahydropalmatine attenuates methamphetamine-induced pulmonary vascular remodeling via CaSR-BMP2/mTOR signaling. (PubMed, Bioorg Chem) - "L-THP reversed MA-induced hemodynamic changes, downregulated the level of CaSR, and inhibited MA-induced autophagy through BMP2/mTOR interaction to reduce the proliferation of PASMCs and prevent pulmonary vascular remodeling. This study is the first to demonstrate that L-THP suppresses MA-induced autophagy in PASMCs through modulation of CaSR, providing experimental evidence supporting L-THP as a potential protective strategy for MA-associated PAH."

Journal • Cardiovascular • Hypertension • Pain • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • BMP2

Integrated metabolomics and gut microbiota analysis to explore the potential mechanism of levo-tetrahydropalmatine against ketamine addiction. (PubMed, Front Pharmacol) - "Moreover, Spearman's correlation analysis showed that discriminative metabolites were closely correlated with special bacteria. The findings demonstrated that l-THP might serve as a promising intervention strategy for KET addiction by regulating serum and urine metabolism and gut microbiota."

Journal • CNS Disorders • Metabolic Disorders • Psychiatry • Substance Abuse

The Effects of Several Natural Protoberberine Alkaloids and Cinnamic Acid Derivatives Used for Traditional Medicine on the Membrane Boundary Potential and Lipid Packing Stress. (PubMed, Int J Mol Sci) - "Here we elucidated the effects of natural protoberberine alkaloids (rotundine, berberine, and nitidine) and cinnamic acid derivatives (ethyl-4-methoxycinnamate and osthole) found in Vietnamese medicinal plants, on the boundary potential of lipid bilayers and phase behavior of membrane lipids...We also revealed that ethyl-4-methoxycinnamate and osthole diminished the melting point of both components of PS transition without the changes in their relative impacts. The observed membrane activity of the tested compounds may be related to their physiological and pharmacological potential."

Journal

L-Tetrahydropalmatine synergizes cytotoxic CD8+ T mediated antitumor and ferroptosis in gastric cancer. (PubMed, Cell Death Discov) - "L-THP reduced the FSP1 stability to trigger the ferroptosis of GC cells. In conclusion, this study shows that L-THP synergizes cytotoxic CD8+ T cell-mediated GC antitumor response and ferroptosis through FSP1, providing potent evidence for GC immunoregulation."

Journal • Gastric Cancer • Oncology • Pain • Solid Tumor • AIFM2 • CD8

Structural and functional insights into targeting hTERT G-quadruplex by levo-Tetrahydropalmatine in the non-small cell lung cancer. (PubMed, Bioorg Med Chem) - "Moreover, these ligands significantly suppressed the hTERT mRNA expression (1.00 for control, 0.43 ± 0.02 for l-THP, 0.19 ± 0.01 for M1, 0.33 ± 0.03 for M2) and showed the potent antitumor activity in A549 cells and lung cancer xenograft model. Collectively, these findings establish l-THP and its derivatives as the promising lead compounds for the development of chemotherapeutics against non-small cell lung cancer as well as provide the plausible mechanism insights into potent antitumor activity."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • TERT

Optimizing Extended-release Formulation of l-tetrahydropalmatine Based on In Vivo Outcomes Using Integrated Modeling Approaches. (PubMed, AAPS PharmSciTech) - "The optimized formulation was estimated to exhibit an early onset of action (0.68 h), remain effective for more than 11.4 h, and be safe with Cmax consistently falling within the therapeutic window. The present approach can be applied to design other drug delivery systems for flexible in vivo outcomes."

Journal • Preclinical • CNS Disorders • Psychiatry

A Novel ingredients recipe derived from Shugan-Hewei Formula targeting chemical carcinogenesis-ROS signaling pathway treated Gastroesophageal reflux disease. (PubMed, J Ethnopharmacol) - "Further analysis pinpointed key compound-target pairs, including Berberine targeting CYP1A1, and Honokiol, Tangeretin, α-Cyperone, 1-O-Acetylbritannilactone, Rotundine B, Cyperolone targeting HMOX1...Our findings offered a comprehensive insight into GERD treatment and herbal intervention, enhancing our understanding of accurate network pharmacology. It suggested that concentrating on a single pathway, specifically the ROS signaling pathway, could serve as a new therapeutic strategy for herbal medicine in GERD treatment."

Journal • CNS Disorders • Depression • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Mood Disorders • Oncology • Psychiatry • CYP1A1 • HMOX1

A concise enzyme cascade enables the manufacture of natural and halogenated protoberberine alkaloids. (PubMed, Nat Commun) - "Through enzyme discovery and engineering, along with systematic optimization of the berberine bridge enzyme to address remaining manufacturing challenges in protoberberine alkaloid biosynthesis, the high production of drug Rotundine is achieved at an impressive gram-scale titer, demonstrating its industrial potential. More importantly, this cascade also enables the efficient biosynthesis of various unnatural halogenated protoberberine alkaloids. Thus, this work not only unlocks the potential of enzyme cascades in overcoming longstanding challenges in the efficient biosynthesis of plant-derived alkaloids, but also opens avenues to introduce structural complexity and diversity into alkaloids through synthetic biology, offering significant potential for drug development."

Journal

Natural products as the therapeutic strategies for addiction. (PubMed, Biomed Pharmacother) - "According to their chemical structure, 43 natural products and 5 herbal combinations with potential to treat addiction were classified, and their sources, pharmacological effects and clinical trials were introduced. It was also found that mitragine, ibogine, L-tetrahydropalmatine and crocin had greater potential for anti-addiction."

Journal • Review • CNS Disorders • Psychiatry • Substance Abuse

Simultaneous Determination of Levo-tetrahydropalmatine and Naltrexone in Rat Plasma by LC-MS/MS and its Application in a Pharmacokinetic Study. (PubMed, Curr Pharm Biotechnol) - "The assay has been used for pharmacokinetic studies of l-THP and naltrexone in the rat."

Journal • PK/PD data • Preclinical

DNA methylation induces subtle mechanical alteration but significant chiral selectivity. (PubMed, Chem Commun (Camb)) - "Methylation also induces significant chiral selectivity towards drug molecules such as d,l-tetrahydropalmatine. Our results precisely quantify the mechanical effect of methylation and suggest that drug design should take methylation into consideration for enhanced selectivity."

Epigenetic controller • Journal

Based on spinal central sensitization creating analgesic screening approach to excavate anti-neuropathic pain ingredients of Corydalis yanhusuo W.T.Wang. (PubMed, J Ethnopharmacol) - "Employing multi types of cells based on spinal central sensitization rather than single cell may allow for more thorough excavation of active substances. Glaucine was firstly found could attenuate neuropathic pain but not other types of pain which indicated that different alkaloids in RC exert distinct analgesic effects on different pain models, and gluacine has the potential to be developed as an analgesic drug specifically for neuropathic pain relieving."

Journal • Neuralgia • Pain

Levo-tetrahydropalmatine ameliorates neuropathic pain by inhibiting the activation of the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis. (PubMed, Phytomedicine) - "This study is the first to indicate that l-THP may exert an analgesic effect through inhibiting neuroinflammation via the Clec7a-MAPK/NF-κB-NLRP3 inflammasome axis, supporting the clinical utility of l-THP in NP therapy."

Journal • Inflammation • Neuralgia • Pain • CLEC7A • NLRP3

Preparation of the Levo-Tetrahydropalmatine Liposome Gel and Its Transdermal Study. (PubMed, Int J Nanomedicine) - "Compared to the emulsion, the liposomes provided greater bioavailability when used transdermally. The liposomes also provided greater stability for l-THP during storage."

Journal

Morphine Withdrawal-Induced Hyperalgesia in Models of Acute and Extended Withdrawal Is Attenuated by l-Tetrahydropalmatine. (PubMed, Int J Mol Sci) - "This indicates that the efficacy of l-THP on pain perception extends beyond its half-life. As a non-opioid treatment for reversing a significant hyperalgesic state during withdrawal, l-THP may be a valuable addition to the currently limited arsenal of opioid detoxification treatments."

Journal • Pain

High-Throughput Sequencing Reveals That Rotundine Inhibits Colorectal Cancer by Regulating Prognosis-Related Genes. (PubMed, J Pers Med) - "Rotundine inhibits the development and progression of colorectal cancer by regulating the expression of these prognosis-related genes. Our findings could further provide new directions for the treatment of colorectal cancer."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CLHC1 • IGF2BP3 • ZNF117

Levo-tetrahydropalmatine promotes apoptosis of human hepatocellular carcinoma through switching energy metabolism phenotype via upregulation of mitochondrial reactive oxygen species (PubMed, Zhongguo Zhong Yao Za Zhi) - "When cells were co-treated with THP and chloroquine(CQ, an autophagy inhibitor), THP further increased mtROS and apoptosis. Meanwhile, THP significantly reduced the proliferation index and mitochondrial membrane potential of HCC cells accompanied by the increased apoptosis. This study demonstrates that the up-regulation of mtROS by THP significantly promotes HCC cell autophagy(protective autophagy) and impairs mitochondrial respiration through reprogramming energy metabolism, ultimately inducing the mitochondria-mediated apoptosis of SMMC-7721 and BEL-7402 cells."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ANXA5