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

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."

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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."

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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."

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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

Retracted: Levo-Tetrahydropalmatine Attenuates Progression of Abdominal Aortic Aneurysm in an Elastase Perfusion Rat Model via Suppression of Matrix Metalloproteinase and Monocyte Chemotactic Protein-1. (PubMed, Med Sci Monit) - "Med Sci Monit, 2018; 24: 625-660. DOI: 10.12659/MSM.906153."

Journal • Preclinical • Cardiovascular • CCL2 • ELANE

Metabolomic analysis of serum from pure coronary artery ectasia patients based on UPLC-QE/MS technique. (PubMed, Clin Chim Acta) - "This is the first report describing differential serum metabolomic profiles of pure CAE patients compared to mixed CAE and healthy controls, which revealed 10 potential biomarkers that can provide an early diagnosis of pure CAE. These discriminatory metabolites and related metabolic pathways can help to better understand the pathogenesis of pure CAE."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Immunology • Inflammation • Metabolic Disorders • ICAM1

Using fungible biosensors to evolve improved alkaloid biosyntheses. (PubMed, Nat Chem Biol) - "We have developed a combined screening and selection approach that quickly refines the affinities and specificities of generalist transcription factors; using RamR as a starting point, we evolve highly specific (>100-fold preference) and sensitive (half-maximum effective concentration (EC) < 30 μM) biosensors for the alkaloids tetrahydropapaverine, papaverine, glaucine, rotundine and noscapine. These sensors further enabled the evolution of a streamlined pathway for tetrahydropapaverine, a precursor to four modern pharmaceuticals, collapsing multiple methylation steps into a single evolved enzyme. Our methods for evolving biosensors enable the rapid engineering of pathways for therapeutic alkaloids."

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Combined Levo-tetrahydropalmatine and diphenyleneiodonium chloride enhances antitumor activity in hepatocellular carcinoma. (PubMed, Pharmacol Res) - "Importantly, this is realized without causing systemic toxicity to other organs. Collectively, our work shows that the combinatorial therapy of autophagy activator THP and NOX4 inhibitor DPI may be considered as a therapeutic avenue against HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Metabolic Disorders • Oncology • Solid Tumor • NOX4

Establishment and Application of an Index System for the Risk of Drug Shortages in China: Based on Delphi Method and Analytic Hierarchy Process. (PubMed, Int J Health Policy Manag) - "An indexed system for the risk assessment of drug shortages in China was established to guide the graded response to drug shortages in medical institutions and the implementation of differential management strategies to address these shortages."

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Using structurally malleable biosensors to evolve improved alkaloid biosyntheses (ACS-Sp 2022) - "We have developed a unique combined screening and selection approach that quickly refines the affinities and specificities of generalist transcription factors, and using RamR as a starting point we evolve highly specific (>100-fold preference) and sensitive (EC50 <30 μM) biosensors for the alkaloids tetrahydropapaverine, papaverine, glaucine, rotundine, and noscapine...These sensors further enabled the evolution of a streamlined pathway for tetrahydropapaverine, an immediate precursor to four modern pharmaceuticals, collapsing multiple methylation steps into a single evolved enzyme. Our methods for evolving biosensors now enable the rapid engineering of pathways for therapeutic alkaloids."

AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth. (PubMed, Metabolites) - "More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • AMPK

Levo-tetrahydropalmatine inhibits α4β2 nicotinic receptor response to nicotine in cultured SH-EP1 cells. (PubMed, Acta Pharmacol Sin) - "Current FDA-approved medications for smoking cessation are the antidepressant bupropion and the nicotinic partial agonist varenicline, yet both are limited by adverse side effects and moderate efficacy. Interestingly, two putative α4β2-nAChR isoforms, namely sazetidine A-activated, high-sensitive one (α4β2-nAChR) and cytisine-activated, low-sensitive one (α4β2-nAChR) were pharmacologically separated, and the low-sensitive one was more susceptible to l-THP inhibition than the high-sensitive one. In conclusion, we demonstrate that l-THP blocks neuronal α4β2-nAChR function, which may underlie its inhibition on nicotine addiction."

Journal • CNS Disorders • Nicotine Addiction • Psychiatry • Tobacco Cessation

Levo-tetrahydropalmatine: A new potential medication for methamphetamine addiction and neurotoxicity. (PubMed, Exp Neurol) - "L-THP can effectively enhance the plasticity of nerve cells and improve the function of nerve cells where brain-derived neurotrophic factor (BDNF) and its pathways play a protective role. Therefore, l-THP has the potential to become an important therapeutic drug for METH addiction and neurotoxicity."

Journal • CNS Disorders • Pain • Psychiatry • BDNF