Zanthoxylum Nitidum Research Articles

Establishment of mouse alveolar macrophage extraction standard and its application in the evaluation of efficacy in lung metastasis of colorectal cancer

Introduction: Alveolar macrophages (AM) are involved in the development and progression of a variety of lung diseases. It is of great significance to explore the pathogenesis of diseases and evaluate the efficacy of drugs. However, there is no standard process for extracting primary AM. Nitidine chloride is an alkaloid extracted from Zanthoxylum nitidum (Roxb.) DC., which has an anti-tumour pharmacological effect. However, there is no evidence that nitidine chloride has a direct effect on CRC cell lung metastasis. The purpose of this study was to establish a standard for the extraction of primary AM from mice and to investigate the pharmacodynamics of nitidine chloride in mice with lung metastases to colorectal cancer. Methods: The standard for the extraction of mouse primary AM by lavage was established. Western blot and PCR were used to detect the regulatory mechanism of nitidine chloride in the treatment of lung metastasis in mice by macrophage phenotype and glycolysis level. Results: The results showed that sufficient quantity and quality of primary AM could be obtained by optimising extraction steps, and AM obtained by this method could accurately reflect disease progression. At the same time, nitidine chloride can effectively reduce colorectal cancer lung metastasis in mice. From the mechanism, nitidine chloride can inhibit the expression of M2 macrophage markers and the levels of mRNA and proteins of the glycolysis-limiting enzyme. Conclusions: Our results show that primary AM that accurately reflect disease and assess pharmacological effects can be obtained using our established criteria. The inhibitory effect of nitidine chloride on colorectal cancer lung metastasis may be attributed to its regulation of macrophage phenotype and glycolysis.

A comparative analysis of the composition of the primary bioactive molecules, antioxidant activities, and anti-inflammation abilities of the roots of Zanthoxylum nitidum harvested at different years of cultivation

Zanthoxylum nitidum is a traditional medicinal herb prevalent in China and Southeast Asia. However, despite being a widely cultivated perennial woody plant, an accurate reference and guide for determining the appropriate harvesting age in lacking. This study employed high-performance liquid chromatography (HPLC) and ultraviolet-visible (UV-Vis) spectrophotometry, along with in vitro antioxidant and in vivo anti-inflammatory assays, to comprehensively analyze and compare the roots of Z. nitidum at 1–9 and 14 years. The results indicated a positive correlation between the increase in age and the root biomass. The highest decoction rates were observed in the roots of the 5- (44.08 %) and 4-year-old plants (40.42 %). However, the total alkaloid content (TAC) and the levels of nitidine chloride (NC), chelerythrine, and sanguinarine chloride initially increased but then decreased; their highest contents were 1.49 % (3-year-old), 0.50 % (7-year-old), 0.50 % (5-year-old), and 0.061 % (6-year-old), respectively. The levels of magnoflorine exhibited a trend of 3-year peaks; the respective contents were 0.36 % (3-year-old), 0.30 % (5-year-old), and 0.33 % (14-year-old). The change in the in vitro antioxidant potency composite index correlated with the wave-like trends in the total flavonoid content (TFC) and total phenolic acid (TPA). The indices for 9-, 5-, and 3-year-olds ranked among the top three and were >90. Extracts of Z. nitidum roots demonstrated a therapeutic effect in dextran sulfate sodium-induced ulcerative colitis mice, with that from the roots of 5-year-old plants showing the highest impact. Overall, the Z. nitidum roots of 4–6-year-old plants can be harvested as high-quality raw materials that meet the Pharmacopoeia of the People's Republic of China standards. This study provides scientific references for aspects such as the rational harvesting of Z. nitidum during artificial cultivation, the optimal utilization of land resources, and clinical use.

Integration of High-Resolution LC-Q-TOF Mass Spectrometry and Multidimensional Chemical-Biological Analysis to Detect Nanomolar-Level Acetylcholinesterase Inhibitors from Different Parts of Zanthoxylum nitidum.

Zanthoxyli radix is a popular tea among the elderly, and it is believed to have a positive effect on Alzheimer's disease. In this study, a highly effective three-step strategy was proposed for comprehensive analysis of the active components and biological functions of Zanthoxylum nitidum (ZN), including high-resolution LC-Q-TOF mass spectrometry (HRMS), multivariate statistical analysis for heterogeneity (MSAH), and experimental and virtual screening for bioactivity analysis (EVBA). A total of 117 compounds were identified from the root, stem, and leaf of ZN through HRMS. Bioactivity assays showed that the order of acetylcholinesterase (AChE) inhibitory activity from strong to weak was root > stem > leaf. Nitidine, chelerythrine, and sanguinarine were found to be the main differential components of root, stem, and leaf by OPLS-DA. The IC50 values of the three compounds are 0.81 ± 0.02, 0.14 ± 0.01, and 0.48 ± 0.01 μM respectively, indicating that they are potent and high-quality AChE inhibitors. Molecular docking showed that pi-pi T-shaped interactions and pi-lone pairs played important roles in AChE inhibition. This study not only explains the biological function of Zanthoxyli radix in alleviating Alzheimer's disease to some extent, but also lays the foundation for the development of stem and leaf of ZN.

Nitidine chloride inhibits mTORC1 signaling through ATF4-mediated Sestrin2 induction and targets IGF2R for lysosomal degradation

AimsNitidine chloride (NC), a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb.) DC, exhibits multiple bioactivities, including antitumor, anti-inflammatory, and other therapeutic effects. However, the primary targets of NC and the mechanism of action (MOA) have not been explicitly defined. MethodsWe explored the effects of NC on mTORC1 signaling by immunoblotting and fluorescence microscopy in wild-type and gene knockout cell lines generated by the CRISPR/Cas9 gene editing technique. We identified IGF2R as a direct target of NC via the drug affinity-responsive target stability (DARTS) method. We investigated the antitumor effects of NC using a mouse melanoma B16 tumor xenograft model. Key findingsNC inhibits mTORC1 activity by targeting amino acid-sensing signaling through activating transcription factor 4 (ATF4)-mediated Sestrin2 induction. NC directly binds to IGF2R and promotes its lysosomal degradation. Moreover, NC displayed potent cytotoxicity against various cancer cells and inhibited B16 tumor xenografts. SignificanceNC inhibits mTORC1 signaling through nutrient sensing and directly targets IGF2R for lysosomal degradation, providing mechanistic insights into the MOA of NC.

Sesquilignans PD from Zanthoxylum nitidum var. tomentosum exerts antitumor effects via the ROS/MAPK pathway in liver cancer cells

Sesquilignans PD is a natural phenylpropanoid compound that was isolated from Zanthoxylum nitidum var. tomentosum. In this study, we assessed the antitumor effect of PD on SK-Hep-1 and HepG2 cells and the underlying molecular mechanisms. The results revealed that PD markedly inhibited the proliferation and migration of both liver cancer cells. Moreover, PD induced apoptosis, autophagy, and reactive oxygen species (ROS) production in liver cancer cells. Notably, PD increased the protein levels of p-p38 MAPK and p-ERK1/2 in liver cancer cells. This is the first report on the anticancer effect of PD, which is mediated via increased ROS production and MAPK signaling activation.

Study on optimal harvesting period and rational medicinal parts of Zanthoxylum nitidum based on statistics of main effective components

To determine the optimal harvesting period and rational medicinal parts of Zanthoxylum nitidum, the main effective components of cultivated Z. nitidum samples, which originate from various growth years, harvesting months, and different parts were analyzed and compared with the wild samples. HPLC was performed on a Kinetex C18 column(4. 6 mm×100 mm, 2. 6 μm) with the gradient elution of 0. 3% phosphoric acid solution-acetonitrile(80 ∶ 20) containing 0. 2% triethylamine. The flow rate was 1. 0 m L·min-1, and the detection wavelength was 273 nm. The column temperature was 30 ℃. Nitidine chloride and chelerythrine, the main effective components, were determined as the markers. The results showed there was no significant difference in the contents of the main effective components among the roots of wild and cultivated Z. nitidum, as well as the roots and roots + stems of cultivated Z. nitidum. The statistical results of HCA and PCA indicated that the roots and stems could be clearly distinguished, but no distinction could be made between wild and cultivated products, which was consistent with the results of the significance analysis. The total contents of nitidine chloride and chelerythrine in roots and stems of Z. nitidum of 1-6 years old were 0. 114%-0. 256% and 0. 030%-0. 133%, respectively. These results suggested a positive correlation between the content of the main effective components and the growth years. No significant difference was observed between the contents of samples harvested in different seasons, indicating that the harvest season had no effect on the content of the main effective components of the Z. nitidum samples. The total contents of nitidine chloride and chelerythrine of the dried Z. nitidum samples(excluding branches) from three plantation bases were 0. 308%±0. 123% in Yunfu, 0. 192%±0. 025% in Maoming, and 0. 197%±0. 052% in Nanning, respectively, and they were all not less than 0. 15%, or in other words, the roots(including fibrous roots, taproots, and underground stems) and stems(aboveground stems) of Z. nitidum transplanted for more than 2. 5 years can meet the medical requirements. This study demonstrates that the cultivated Z. nitidum could be used as a valid substitute for the wild Z. nitidum, which provides a guarantee for the sustainable development and the application of Z. nitidum resources. The stems and roots could be considered medicinal parts of Z. nitidum. It is recommended to revise the medicinal parts of Z. nitidum to dried roots and stems in the next edition of Chinese Pharmacopoeia, and the medicinal parts can be harvested all year round. In order to ensure the content of effective components and clinical effectiveness, the root and stem should be harvested for medical use after the seedlings of Z. nitidum have been transplanted for more than three years.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

The Therapeutic Potential of Four Main Compounds of Zanthoxylum nitidum (Roxb.) DC: A Comprehensive Study on Biological Processes, Anti-Inflammatory Effects, and Myocardial Toxicity.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a traditional Chinese medicinal plant that is indigenous to the southern regions of China. Previous research has provided evidence of the significant anti-inflammatory, antibacterial, and anticancer properties exhibited by Z. nitidum. The potential therapeutic effects and cardiac toxicity of Z. nitidum remain uncertain. The aim of this research was to investigate the potential therapeutic properties of the four main compounds of Z. nitidum in cardiovascular diseases, their impact on the electrical activity of cardiomyocytes, and the underlying mechanism of their anti-inflammatory effects. We selected the four compounds from Z. nitidum with a high concentration and specific biological activity: nitidine chloride (NC), chelerythrine chloride (CHE), magnoflorine chloride (MAG), and hesperidin (HE). A proteomic analysis was conducted on the myocardial tissues of beagle dogs following the administration of NC to investigate the role of NC in vivo and the associated biological processes. A bioinformatic analysis was used to predict the in vivo biological processes that MAG, CHE, and HE were involved in. Molecular docking was used to simulate the binding between compounds and their targets. The effect of the compounds on ion channels in cardiomyocytes was evaluated through a patch clamp experiment. Organ-on-a-chip (OOC) technology was developed to mimic the physiological conditions of the heart in vivo. Proteomic and bioinformatic analyses demonstrated that the four compounds of Z. nitidum are extensively involved in various cardiovascular-related biological pathways. The findings from the patch clamp experiments indicate that NC, CHE, MAG, and HE elicit a distinct activation or inhibition of the IK1 and ICa-L in cardiomyocytes. Finally, the anti-inflammatory effects of the compounds on cardiomyocytes were verified using OOC technology. NC, CHE, MAG, and HE demonstrate anti-inflammatory effects through their specific interactions with prostaglandin-endoperoxide synthase 2 (PTGS2) and significantly influence ion channels in cardiomyocytes. Our study provides a foundation for utilizing NC, CHE, MAG, and HE in the treatment of cardiovascular diseases.

Urea-based deep eutectic solvents enzyme system for high efficiency extraction of alkaloids and flavonoids in plants: Zanthoxylum nitidum (Roxb.) DC. as a case

In this work, an enzymatic digestion urea-based solvent system was developed to extract alkaloids and flavonoids in Zanthoxylum nitidum (Roxb.) DC (ZN). A total of 50 DESs were prepared and their extraction rate were screened, and the enzyme conditions affecting the rate were also evaluated. As a result, it was found that the Ur/Pa based cellulase system owned the best extraction efficiency in ZN with the rate of 34.56 ± 1.09 mg/g, which was higher than the methanol. Optimized using the one factor experiments and response surface methodology (RSM), the best condition was 27 % water content, 35 min extraction time, 39℃ extraction temperature, 25:1 solid/liquid ratio, 1.3 mg/mL enzyme concentration. The scanning electron microscopy (SEM) results showed that the Ur/Pa based cellulase system entirely destroys the cell wall of ZN, with excellent extraction rate. This study developed a new design of DESs in extraction of alkaloids and flavonoids in ZN.

Nitidine Chloride Inhibits Proliferation and Induces Mitochondrial-Mediated Apoptosis of Human Melanoma A375 and A2058 Cells In Vitro

Melanoma is a malignant tumor transforming from normal melanocytes, with strong invasion and low survival rate. Nitidine chloride (NC) is a natural benzophenidine alkaloid extracted from the roots of traditional Chinese medicine zanthoxylum nitidum. In recent years, many studies have found that NC may have strong anti-tumor activity. However, the efficacy of NC against melanoma has rarely been reported, and the potential molecular mechanism remains unknown. Our study explored the effects of NC on the proliferation and apoptosis of human melanoma A375 and A2058 cells. CCK-8 was utilized to detect the effects of different concentrations of NC on the proliferation of A375 and A2058 cells. Within a certain concentration and time range, NC can inhibit the viability of A375 and A2058 cells significantly in a time-dose-dependent manner. In addition, NC-induced apoptosis was confirmed by DAPI staining and flow cytometry analysis of Annexin V-FITC/PI. Moreover, we observed that the ratio of Bax/Bcl-2 in the cytoplasm increases, activating Caspase-3/-9 and ultimately inducing apoptosis via the mitochondrial pathway. Our study indicated that NC has anti-tumor properties against human melanoma cells through inhibiting proliferation and inducing apoptosis. Therefore, the results provide new insights for future work on the utilization of NC in malignant melanoma treatment.

SSR molecular marker developments and genetic diversity analysis of Zanthoxylum nitidum (Roxb.) DC

Zanthoxylum nitidum (Roxb.) is a commonly used traditional Chinese medicine. However, the collection and protection of wild germplasm resources of Z. nitidum are still insufficient, and there is limited research on its genetic diversity and fingerprint. In the present study, 15 simple sequence repeat (SSR) markers were developed by genotyping based on multiplexed shotgun sequencing. The genetic diversity of 51 populations (142 individuals) of Z. nitidum was evaluated using these 15 SSRs. A total of 245 alleles (Na) were detected, with an average value of 16.333, and the average polymorphism information content was 0.756. The genetic distance among 51 populations was 0.164~1.000, with an average of 0.659. Analysis of molecular variance showed low genetic differentiation (40%) and high genetic differentiation (60%) between populations and individuals, respectively. The genetic differentiation coefficient (Fst) of the population was 0.338, indicating that 66.2% of the genetic variation occurred within the population, and the gene flow (Nm) was 0.636, demonstrating that the gene exchange between populations was low. Clustering analysis revealed that the genetic similarity coefficient was 0.30, dividing the 51 populations into 4 groups of 2, 17, 3, and 29 populations. There was no specific relationship between geographical location differences and genetic distance. The genetic diversity level of Z. nitidum is relatively high, and our results provide a theoretical basis for the rapid identification of Z. nitidum germplasm resources and variety selection.

Comparison of the bioactive components and antioxidant activities of wild-type Zanthoxylum nitidum roots from various regions of Southern China

Zanthoxylum nitidum is a traditional Chinese herb, but limited information is available concerning its antioxidant activity of Z. nitidum. In this study, the bioactive components, content, and antioxidant activity of Z. nitidum roots from various regions in southern China were detected and evaluated. The results revealed that the highest nitidine chloride content found in S13. The S1 contained significantly higher concentrations of hesperidin, total flavonoids, and total phenols than other samples. The samples from S13, S1, and S12 had the strongest comprehensive antioxidant activity. Stoichiometric analysis revealed that samples from various regions were effectively identified and classified. This is the first study to investigate the antioxidant activity of wild-type Z. nitidum in southern China. It lays the groundwork for Z. nitidum harvesting, origin identification, sensible use, as well as the quality evaluation of Z. nitidum resources, particularly in vitro antioxidant activity assessment.

Dynamic changes in the levels of metabolites and endogenous hormones during the germination of Zanthoxylum nitidum (Roxb.) DC. Seeds

ABSTRACT Accumulating experimental data have shown that endogenous hormones play important roles in regulating seed dormancy and germination. Zanthoxylum nitidum is a medicinal plant that propagates via seeds, which require a long dormancy period for normal germination, and complex changes in metabolites occur during the germination process. However, the regulatory network of endogenous hormones and metabolites during the germination of Z. nitidum seeds remains unclear. This study investigated the dynamic changes in the levels of metabolites and endogenous hormones during the germination of Z. nitidum seeds. The results revealed an increase in the levels of gibberellin 3 (GA3), 12-oxophytodienoic acid (OPDA), 1-aminocyclopropane-1-carboxylic acid (ACC) and trans-zeatin (TZ) and decrease in the levels of abscisic acid (ABA), jasmonic acid (JA), N-[(-)-jasmonoyl]-(S)-isoleucine (JA-Ile) and trans-zeatin riboside (TZR). Overall, 112 differential metabolites (DAMs) were screened from 3 seed samples (Sa, Sb and Sc), most of which are related to primary metabolism. A total of 16 DAMs (including 3 monosaccharides, 3 phosphate lipids, 3 carboxylic acids, 1 amino acid, 2 pyrimidines, and 4 nucleotides) were identified in the three sample comparison pairs (Sa vs Sb, Sa vs Sc, and Sb vs Sc); these DAMs were significantly enriched in purine metabolism; glycerophospholipid metabolism, citrate cycle (TCA cycle), alanine, aspartate and glutamate metabolism and pyruvate metabolism. OPDA, ACC and GAs were significantly positively correlated with upregulated metabolites, whereas ABA and JA were significantly positively correlated with downregulated metabolites. Finally, a hypothetical metabolic network of endogenous hormones that regulate seed germination was constructed. This study deepens our understanding of the importance of endogenous hormonal profiles that mediate seed germination.

Targeting ABCB6 with nitidine chloride inhibits PI3K/AKT signaling pathway to promote ferroptosis in multiple myeloma.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Full-length transcriptome analysis of Zanthoxylum nitidum (Roxb.) DC.

Zanthoxylum nitidum (Roxb.) DC. (Z. nitidum) is a type of Chinese Dao-di herb, also called Liangmianzhen, which is widely used to treat arthralgia, rheumatic arthralgia, and stomach pain. However, genomic resources for Z. nitidum are still scarce. This study provides transcriptomic resources for Z. nitidum by applying single-molecule real-time (SMRT) sequencing technology. In total, 456,109 circular consensus sequencing (CCS) reads were generated with a mean length of 2,216 bp from Z. nitidum roots, old stems, young branches, leaves, flowers, and fruits. Of these total reads, 353,932 were full-length nonchimeric (FLNC) reads with an average length of 1,996 bp. A total of 16,163 transcripts with a mean length of 1,171 bp were acquired. Of these transcripts, 14,231 (88%) were successfully annotated using public databases. Across all the 16,163 transcripts, we identified 6,255 long non-coding RNAs (lncRNAs) and 22,780 simple sequence repeats (SSRs). Furthermore, 3,482 transcription factors were identified. Among the SSR loci, 1-3 nucleotide repeats were dominant, occupying 99.36% of the total SSR loci, with mono-, di-, and tri-nucleotide repeats accounting for 61.80%, 19.89%, and 5.02% of the total SSR loci, respectively. A total of 36 out of 100 randomly selected primer pairs were verified to be positive, 20 of which showed polymorphism. These findings enrich the genetic resources available for facilitating future studies and research on relevant topics such as population genetics in Z. nitidum.

In silico studies on potential MCF-7 inhibitors of alkaloid and phenolic compounds isolated from Zanthoxylum nitidum: A combination of molecular docking and ADMET analysis

In this study, computational molecular simulation and drug-like properties assessment were used to gain insight into the binding ability of 16 alkaloid and phenolic compounds isolated from Zanthoxylum nitidum on protein tubulin. Amongst studied candidates, compounds 8 and 10 were identified as potential candidates for inhibiting the function of tubulin at the active site regarding binding affinity, dock pose and ADMET properties analysis. These findings shed light on the potential anti-cancer of compounds isolated from Zanthoxylum nitidum.

Comparison of production of bioactive components in Zanthoxylum nitidum taproots from different regions in southern China.

Zanthoxylum nitidum (Roxb.) DC is a traditional Chinese herb from southern China and its 3-4-year old roots are used in medicine. However, there is a scarcity of studies on the differences in the content of different regions of the roots, as well as comprehensive evaluations of Z. nitidum from the main areas of production in China. This study used ultra performance liquid chromatography, triple quadrupole tandem mass spectrometry, HPLC, and Fourier-transform infrared spectroscopy to detect and identify the bioactive components from different parts and eight regions of 4-year-old roots of Z. nitidum. Our results revealed that the types and quantities of compounds extracted were similar in root bark and root wood, although the amount of alkaloids in the former was substantially higher. The contents of four alkaloids in samples from Guangdong were higher than those in Guangxi Province. Meanwhile, hierarchical cluster analysis and principal component analysis showed that the samples from different regions were effectively identified and evaluated based on alkaloids and other bioactive substances. Our findings have significant implications for Z. nitidum harvesting and usage, as well as for origin identification, quality evaluation, and sensible use of Z. nitidum resources.

Assessment of Chinese suitable habitats of Zanthoxylum nitidum in different climatic conditions by Maxent model, HPLC, and chemometric methods

The suitable habitats of medicinal plants have changed as the result of climate change, which may affect quality of herbal medicine. However, as an important traditional herbal medicine, the Zanthoxylum nitidum (Roxb.) DC. lacks relevant research on coping with climate challenges. In this study, through field and online surveys, occurrence records and samples of Z. nitidum were gathered. The various periods’ suitable habitats of Z. nitidum were predicted by using Maxent and ArcGIS software. The high performance liquid chromatography (HPLC) was used to ascertain the samples’ nitidine chloride (NC) content. Chemometric methods was used to conduct hierarchical cluster analysis (HCA) and principal component analysis (PCA) on Z. nitidum samples from different suitable habitats. The results showed that the precipitation and temperature were significant factors in the distribution of Z. nitidum. The suitable habitats of current climate scenarios were predicted to be mainly distributed in south of the Yangtze River. The suitable habitats were predicted to gradually reduce southward under the four future climate scenarios. The contents of NC in suitable habitats were significantly higher than low-suitable habitats. Meanwhile, HCA and PCA showed that the Z. nitidum samples from different suitable habitats were effectively identified and evaluated based on bioactive substances. Overall, the findings of this study are useful references for the identification of suitable areas of Z. nitidum cultivation, as well as suitable habitats identification and quality evaluation of Z. nitidum resources in China.

Novel lignans from Zanthoxylum nitidum and antiproliferation activity of sesaminone in osimertinib-resistant non-small cell lung cancer cells

Seven previously undescribed tetrahydrofuran lignans with different configurations and unusual isopentenyl substitutions, nitidumlignans D-J (corresponding to compounds 1, 2, 4, 6, 7, 9 and 10), along with 14 known lignans, were isolated from Zanthoxylum nitidum. Notably, compound 4 is an uncommon naturally occurring furan-core lignan derived from tetrahydrofuran aromatization. The antiproliferation activity of the isolated compounds (1–21) was determined in various human cancer cell lines. The structure–activity study revealed that the steric positioning and chirality of the lignans exert important effects on their activity and selectivity. In particular, compound 3 (sesaminone) exhibited potent antiproliferative activity in cancer cells, including acquired osimertinib-resistant non-small-cell lung cancer (HCC827-osi) cells. Compound 3 also inhibited colony formation and induced the apoptotic death of HCC827-osi cells. The underlying molecular mechanisms revealed that 3 downregulated the activation of the c-Met/JAK1/STAT3 and PI3K/AKT/mTOR signaling pathways in the HCC827-osi cells. In addition, the combination of 3 and osimertinib exhibited synergistic effects on the antiproliferative activity against HCC827-osi cells. Overall, these findings inform the structure elucidation of novel lignans isolated from Z. nitidum, and sesaminone was identified as a potential compound for exerting antiproliferative effects on osimertinib-resistant lung cancer cells.

A new phenylpropanoic acid congener from Zanthoxylum nitidum

One new phenylpropanoic acid congener, 2R-(5'-methoxy) pandanusphenol B (1), along with 26 known isolates, were isolated from Zanthoxylum nitidum. Their structures were elucidated by comprehensive spectroscopic data and circular dichroism analyses. All compounds, except 4, 7-10, 15, 17, 19 and 25, were reported from Z. nitidum for the first time. Among them, 16 compounds (1–3, 5–6, 12–14, 16, 20–24 and 26–27) were discovered from genus Zanthoxylum for the first time, while 15 compounds (1–3, 5–6, 12–14, 20–24 and 26–27) were isolated from the Rutaceae family for the first time. All isolates were evaluated for their cytotoxicity against five human cancer cell lines and the results showed that compound 27 exhibited significant cytotoxicity toward HepG2 and T24, with IC50 values of 2.49 and 7.0 μM, respectively.