Deciphering resveratrol's role in modulating pathological pain: From molecular mechanisms to clinical relevance.

Pathological pain, a multifaceted and debilitating ailment originating from injury or post-injury inflammation of the somatosensory system, poses a global health challenge. Despite its ubiquity, reliable therapeutic strategies remain elusive. To solve this problem, resveratrol, a naturally occurring nonflavonoid polyphenol, has emerged as a potential beacon of hope owing to its anti-inflammatory, antioxidant, and immunomodulatory capabilities. These properties potentially position resveratrol as an efficacious candidate for the management of pathological pain. This concise review summaries current experimental and clinical findings to underscore the therapeutic potential of resveratrol in pathological pain, casting light on the complex underlying pathophysiology. Our exploration suggests that resveratrol may exert its analgesic effect by the modulating pivotal signaling pathways, including PI3K/Akt/mTOR, TNFR1/NF-κB, MAPKs, and Nrf2. Moreover, resveratrol appears to attenuate spinal microglia activation, regulate primary receptors in dorsal root sensory neurons, inhibit pertinent voltage-gated ion channels, and curb the expression of inflammatory mediators and oxidative stress responses. The objective of this review is to encapsulate the pharmacological activity of resveratrol, including its probable signaling pathways, pharmacokinetics, and toxicology pertinent to the treatment of pathological pain. Hopefully, we aim to map out promising trajectories for the development of resveratrol as a potential analgesic.

[Quality evaluation and multi-spectral identification of origin herbs of Lonicerae Japonicae Flos based on grey correlation-TOPSIS method].

The grey correlation-TOPSIS method was used to evaluate the quality of the origin herbs of Lonicerae Japonicae Flos, and the Fourier transform near-infrared(NIR) and mid-infrared(MIR) spectroscopy was applied to establish the identification model of origin herbs of Lonicerae Japonicae Flos by combining chemometrics and spectral fusion strategies. The content of neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, caffeic acid, secoxyloganin, isoquercitrin, isochlorogenic acid B, isochlorogenic acid A, and isochlorogenic acid C in six origin herbs of Lonicerae Japonicae Flos was determined by high-performance liquid chromatography(HPLC), and their quality was evaluated by the grey correlation-TOPSIS method. The Fourier transform NIR and MIR spectra of six origin herbs of Lonicerae Japonicae Flos(Lonicera japonica, L. macranthoides, L. hypoglauca, L. fulvotomentosa, L. confuse, and L. similis) were collected. At the same time, principal component analysis(PCA), support vector machine(SVM), and spectral data fusion technology were combined to determine the optimal identification method for the origin herbs of Lonicerae Japonicae Flos. There were differences in the quality of the origin herbs of Lonicerae Japonicae Flos. Specifically, there were significant differences between L. japonica and the other five origin herbs(P<0.01). The quality of L. similis was significantly different from that of L. fulvotomentosa, L. macranthoides, and L. hypoglauca(P=0.008, 0.027, 0.01), and there were also significant differences in the quality of L. hypoglauca and L. confuse(P=0.001). The PCA and SVM 2D models based on a single spectrum could not be used for the effective identification of the origin herbs of Lonicerae Japonicae Flos. The data fusion combined with the SVM model further improved the identification accuracy, and the identification accuracy of the mid-level data fusion reached 100%. Therefore, the grey correlation-TOPSIS method can be used to evaluate the quality of the origin herbs of Lonicerae Japonicae Flos. Based on the infrared spectral data fusion strategy and SVM chemometric model, it can accurately identify the origin herbs of Lonicerae Japonicae Flos, which can provide a new method for the origin identification of medicinal materials of Lonicerae Japonicae Flos.

Comprehensive analysis of the complete mitochondrial genomes of three Coptis species (C. chinensis, C. deltoidea and C. omeiensis): the important medicinal plants in China.

Coptis plants (Ranunculaceae) contain high levels of isoquinoline alkaloids and have a long history of medicinal use. Coptis species are of great value in pharmaceutical industries and scientific research. Mitochondria are considered as one of the central units for receiving stress signals and arranging immediate responses. Comprehensive characterizations of plant mitogenomes are imperative for revealing the relationship between mitochondria, elucidating biological functions of mitochondria and understanding the environmental adaptation mechanisms of plants. Here, the mitochondrial genomes of C. chinensis, C. deltoidea and C. omeiensis were assembled through the Nanopore and Illumina sequencing platform for the first time. The genome organization, gene number, RNA editing sites, repeat sequences, gene migration from chloroplast to mitochondria were compared. The mitogenomes of C. chinensis, C. deltoidea and C. omeiensis have six, two, two circular-mapping molecules with the total length of 1,425,403 bp, 1,520,338 bp and 1,152,812 bp, respectively. The complete mitogenomes harbors 68-86 predicted functional genes including 39-51 PCGs, 26-35 tRNAs and 2-5 rRNAs. C. deltoidea mitogenome host the most abundant repeat sequences, while C. chinensis mitogenome has the largest number of transferred fragments from its chloroplasts. The large repeat sequences and foreign sequences in the mitochondrial genomes of Coptis species were related to substantial rearrangements, changes in relative position of genes and multiple copy genes. Further comparative analysis illustrated that the PCGs under selected pressure in mitochondrial genomes of the three Coptis species mainly belong to the mitochondrial complex I (NADH dehydrogenase). Heat stress adversely affected the mitochondrial complex I and V, antioxidant enzyme system, ROS accumulation and ATP production of the three Coptis species. The activation of antioxidant enzymes, increase of T-AOC and maintenance of low ROS accumulation in C. chinensis under heat stress were suggested as the factors for its thermal acclimation and normal growth at lower altitudes. This study provides comprehensive information on the Coptis mitogenomes and is of great importance to elucidate the mitochondrial functions, understand the different thermal acclimation mechanisms of Coptis plants, and breed heat-tolerant varieties.

Network Pharmacology Prediction and Metabolomics Validation of the Mechanism of Fructus Phyllanthi against Hyperlipidemia.

Hyperlipidemia has become a leading risk factor for cardiovascular diseases and liver injury worldwide. Fructus Phyllanthi (FP) is an effective drug against hyperlipidemia in Traditional Chinese Medicine (TCM) and Indian Medicine theories, however the potential mechanism requires further exploration. The present research aims to reveal the mechanism of FP against hyperlipidemia based on an integrated strategy combining network pharmacology prediction with metabolomics validation. A high-fat diet (HFD)-induced mice model was established by evaluating the plasma lipid levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Network pharmacology was applied to find out the active ingredients of FP and potential targets against hyperlipidemia. Metabolomics of plasma and liver were performed to identify differential metabolites and their corresponding pathways among the normal group, model group, and intervention group. The relationship between network pharmacology and metabolomics was further constructed to obtain a comprehensive view of the process of FP against hyperlipidemia. The obtained key target proteins were verified by molecular docking. These results reflected that FP improved the plasma lipid levels and liver injury of hyperlipidemia induced by a HFD. Gallic acid, quercetin, and beta-sitosterol in FP were demonstrated as the key active compounds. A total of 16 and six potential differential metabolites in plasma and liver, respectively, were found to be involved in the therapeutic effects of FP against hyperlipidemia by metabolomics. Further, integration analysis indicated that the intervention effects were associated with CYP1A1, AChE, and MGAM, as well as the adjustment of L-kynurenine, corticosterone, acetylcholine, and raffinose, mainly involving tryptophan metabolism pathway. Molecular docking ensured that the above ingredients acting on hyperlipidemia-related protein targets played a key role in lowering lipids. In summary, this research provided a new possibility for preventing and treating hyperlipidemia.

Role of potential bioactive metabolites from traditional Chinese medicine for type 2 diabetes mellitus: An overview.

Type 2 diabetes mellitus (T2DM) is a metabolic disease with persistent hyperglycemia primarily caused by insulin resistance (IR). The number of diabetic patients globally has been rising over the past decades. Although significant progress has been made in treating diabetes mellitus (DM), existing clinical drugs for diabetes can no longer fully meet patients when they face complex and huge clinical treatment needs. As a traditional and effective medical system, traditional Chinese medicine (TCM) has a unique understanding of diabetes treatment and has developed many classic and practical prescriptions targeting DM. With modern medicine and pharmacy advancements, researchers have discovered that various bioactive metabolites isolated from TCM show therapeutic on DM. Compared with existing clinical drugs, these bioactive metabolites demonstrate promising prospects for treating DM due to their excellent biocompatibility and fewer adverse reactions. Accordingly, these valuable metabolites have attracted the interest of researchers worldwide. Despite the abundance of research works and specialized-topic reviews published over the past years, there is a lack of updated and systematic reviews concerning this fast-growing field. Therefore, in this review, we summarized the bioactive metabolites derived from TCM with the potential treatment of T2DM by searching several authoritative databases such as PubMed, Web of Science, Wiley Online Library, and Springer Link. For the convenience of readers, the content is divided into four parts according to the structural characteristics of these valuable compounds (flavonoids, terpenoids, alkaloids, and others). Meanwhile, the detailed mechanism and future directions of these promising compounds curing DM are also summarized in the related sections. We hope this review inspires increasingly valuable and significant research focusing on potential bioactive metabolites from TCM to treat DM in the future.

Integrative quantitative and qualitative analysis for the quality evaluation and monitoring of Danshen medicines from different sources using HPLC-DAD and NIR combined with chemometrics.

The root and rhizome of Salvia miltiorrhiza (Danshen in short) is a well-known herbal medicine used to treat cardiovascular diseases in the world. In China, the roots and rhizomes of several other Salvia species (Non-Danshen in short) are also used as this medicine in traditional folk medicine by local herbalists. Differences have been reported in these medicines originating from different sources, and their quality variation needs to be clearly investigated for effective clinical application. This study presented a comprehensive quality evaluation and monitoring for Danshen from 27 sampling sites and Non-Danshen from other 5 Salvia species based on a high-performance liquid chromatography-diode array detector (HPLC-DAD) and near-infrared (NIR), with the combination of chemometric models. The results showed that cryptotanshinone, tanshinone IIA, tanshinone I, salvianolic acid B, salvianic acid A sodium, dihydrotanshinone I, and rosmarinic acid in these medicines from different sources exhibited great variations. Referring to the standards in Chinese Pharmacopoeia (CP), European Pharmacopeia (EP), and United States Pharmacopeia (USP), Non-Danshen from S. brachyloma, S. castanea, S. trijuga, S. bowleyana, and S. przewalskii were assessed as unqualified, and Danshen in the Shandong Province had the best quality due to the high qualified rate. Based on random forest (RF) and partial least-squares discriminant analysis (PLS-DA), NIR technique could successfully monitor the quality of these medicines by discriminating the species and regions with the accuracies of 100.00 and 99.60%, respectively. Additionally, modified partial least-squares regression (MPLSR) models were successfully constructed to investigate the feasibility of NIR fingerprints for the prediction of the quality indicators in these medicines. The optimized models obtained the best results for the total of tanshinone IIA, tanshinone I, and cryptotanshinone (TTC), tanshinone IIA, and salvianolic acid B, with the relative prediction deviation (RPD) of 4.08, 3.92, and 2.46, respectively. In summary, this study demonstrated that HPLC-DAD and NIR techniques can complement each other and could be simultaneously applied for evaluating and monitoring the quality of Danshen medicines.

Recent advances of tanshinone in regulating autophagy for medicinal research.

Initially described as an ancient and highly conserved catabolic biofunction, autophagy plays a significant role in disease pathogenesis and progression. As the bioactive ingredient of Salvia miltiorrhiza, tanshinone has recently shown profound effects in alleviating and treating various diseases by regulating autophagy. However, compared to the remarkable achievements in the known pharmacological effects of this traditional Chinese medicine, there is a lack of a concise and comprehensive review deciphering the mechanism by which tanshinone regulates autophagy for medicinal research. In this context, we concisely review the advances of tanshinone in regulating autophagy for medicinal research, including human cancer, the nervous system, and cardiovascular diseases. The pharmacological effects of tanshinone targeting autophagy involve the regulation of autophagy-related proteins, such as Beclin-1, LC3-II, P62, ULK1, Bax, ATG3, ATG5, ATG7, ATG9, and ATG12; the regulation of the PI3K/Akt/mTOR, MEK/ERK/mTOR, Beclin-1-related, and AMPK-related signaling pathways; the accumulation of reactive oxygen species (ROS); and the activation of AMPK. Notably, we found that tanshinone played a dual role in human cancers in an autophagic manner, which may provide a new avenue for potential clinical application. In brief, these findings on autophagic tanshinone and its derivatives provide a new clue for expediting medicinal research related to tanshinone compounds and autophagy.

An integrated chemical characterization based on FT-NIR, GC-MS and LC-MS for the comparative metabolite profiling of wild and cultivated agarwood.

Agarwood is a well-known and precious traditional Chinese medicine, has been widely applied as drugs and spices for century. The large demand for this material has deeply stimulated the emergence of numerous cultivated products. However, it is difficult to distinguish wild agarwood from cultivated agarwood, and the chemical composition difference between them is not clear. In this study, an integrated method of Fourier transform near-infrared (FT-NIR), gas chromatography-mass spectrometry (GC-MS) and ultraperformance liquid chromatography Quadrupole-Exactive Orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS) was developed to explore chemical variation between wild and cultivated agarwood in combination with multivariate statistical analysis. Twenty-four wild and cultivated agarwood samples were collected from different regions. FT-NIR profiles were used to obtain the holistic metabolic characterization in combination with principal component analysis (PCA). A total of seventy-six and seventy-nine metabolites, including volatile components and 2-(2-phenethyl) chromones derivatives, were successfully identified by GC-MS and UHPLC-Q-Exactive Orbitrap/MS, respectively. Thereafter, the orthogonal-partial least square method-discriminant analysis (OPLS-DA) and variable importance in the projection (VIP) were used to screen potential characteristic chemical components (VIP > 1) in wild and cultivated agarwood, respectively. Finally, eight key chemical markers were putatively identified by two techniques to distinguish agarwood from different origins, which can be found that sesquiterpenes, aromatics, terpenoids, 2-(2-phenylethyl) chromones of the flidersia type (FTPECs) and tetrahydro-2-(2-phenylethyl) chromones (THPECs) are the most important metabolites. Summary, this research presented a comprehensive metabolomic variation between wild and cultivated agarwood on the basis of a multi-technology platform, which laid a foundation for distinguishing the two ecotypes of agarwood and was conducive to the quality control of this resource.

Integrated metabolomics and ligand fishing approaches to screen the hypoglycemic ingredients from four Coptis medicines.

Rhizoma Coptidis, which is mainly originated from the rhizomes of Coptis chinensis, C. deltoidea, C. omeiensis and C. teeta, has been proved to possess a superior anti-diabetic effect in clinic. However, the metabolic characterization and the hypoglycemic ingredients among these Coptis species remain unclear. In this study, we employed an integrated strategy to screen the bioactive ingredients based on metabolomics and ligand fishing approaches. First, the ultra high-performance liquid chromatography coupled to quadruple time-of-flight tandem mass spectrometry (UHPLC-Q-TOF-MS/MS) was used for qualitative identification of four Coptis rhizomes. After prescreening by α-glucosidase inhibition assay, an affinity ultrafiltration system was constructed to fish out hypoglycemic ingredients from the fractions with superior activity, and verified by molecular docking on a virtual platform. The distribution of major compounds suggested the four Coptis rhizomes possess similar metabolic profiles, mainly including alkaloids and phenylpropanoids. Besides, eight compounds (magnoflorine, groenlandicine, jatrorrhizine, epiberberine, columbamine, coptisine, palmatine and berberine) from the n-butanol fraction were specifically bound to α-glucosidase, and considered as hypoglycemic ingredients of Rhizoma Coptidis. Molecular docking revealed that the inhibitors bound to α-glucosidase mainly by hydrophobic interaction, hydrogen bond interaction and π-π interaction. Summary, this research leads a more systematic and comprehensive study on metabolic characterization and hypoglycemic ingredients of Rhizoma Coptidis, which can provide a theoretical basis for the further clinical application.

Full-length transcriptome analysis of Coptis deltoidea and identification of putative genes involved in benzylisoquinoline alkaloids biosynthesis based on combined sequencing platforms.

KEY MESSAGE: The study carry out comprehensive transcriptome analysis of C. deltoidea and exploration of BIAs biosynthesis and accumulation based on UHPLC-MS/MS and combined sequencing platforms. Coptis deltoidea is an important medicinal plant with a long history of medicinal use, which is rich in benzylisoquinoline alkaloids (BIAs). In this study, Ultra performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) and combined sequencing platforms were performed for exploration of BIAs biosynthesis, accumulation and comprehensive transcriptome analysis of C. deltoidea. By metabolism profiling, the accumulation of ten BIAs was analyzed using UHPLC-MS/MS and different contents were observed in different organs. From transcriptome sequencing result, we applied single-molecule real-time (SMRT) sequencing to C. deltoidea and generated a total of 75,438 full-length transcripts. We proposed the candidate biosynthetic pathway of tyrosine, precursor of BIAs, and identified 64 full length-transcripts encoding enzymes putatively involved in BIAs biosynthesis. RNA-Seq data indicated that the majority of genes exhibited relatively high expression level in roots. Transport of BIAs was also important for their accumulation. Here, 9 ABC transporters and 2 MATE transporters highly homologous to known alkaloid transporters related with BIAs transport in roots and rhizomes were identified. These findings based on the combined sequencing platforms provide valuable genetic information for C. deltoidea and the results of transcriptome combined with metabolome analysis can help us better understand BIAs biosynthesis and transport in this medicinal plant. The information will be critical for further characterization of C. deltoidea transcriptome and molecular-assisted breeding for this medicinal plant with scarce resources.

A Multi-Level Strategy Based on Metabolic and Molecular Genetic Approaches for the Characterization of Different Coptis Medicines Using HPLC-UV and RAD-seq Techniques.

Coptis plants (Ranunculaceae) to have played an important role in the prevention and treatment human diseases in Chinese history. In this study, a multi-level strategy based on metabolic and molecular genetic methods was performed for the characterization of four Coptis herbs (C. chinensis, C. deltoidea, C. omeiensis and C. teeta) using high performance liquid chromatography-ultraviolet (HPLC-UV) and restriction site-associated DNA sequencing (RAD-seq) techniques. Protoberberine alkaloids including berberine, palmatine, coptisine, epiberberine, columbamine, jatrorrhizine, magnoflorine and groenlandicine in rhizomes were identified and determined based on the HPLC-UV method. Among them, berberine was demonstrated as the most abundant compound in these plants. RAD-seq was applied to discover single nucleotide polymorphisms (SNPs) data. A total of 44,747,016 reads were generated and 2,443,407 SNPs were identified in regarding to four plants. Additionally, with respect to complicated metabolic and SNP data, multivariable statistical methods of principal component analysis (PCA) and hierarchical cluster analysis (HCA) were successively applied to interpret the structure characteristics. The metabolic variation and genetic relationship among different Coptis plants were successfully illustrated based on data visualization. Summarily, this comprehensive strategy has been proven as a reliable and effective approach to characterize Coptis plants, which can provide additional information for their quality assessment.

Comprehensive quality assessment for Rhizoma Coptidis based on quantitative and qualitative metabolic profiles using high performance liquid chromatography, Fourier transform near-infrared and Fourier transform mid-infrared combined with multivariate statistical analysis.

Rhizoma Coptidis (RC) originated from the dried rhizomes of Coptis herbal species is a widely used traditional Chinese medicine in history. In this study, a comprehensive quality assessment for RC medicines from C. chinensis, C. deltoidea, C. omeiensis and C. teeta species was performed based on quantitative and qualitative metabolic profiles obtained from high performance liquid chromatography (HPLC), Fourier transform near-infrared (FT-NIR) and Fourier transform mid-infrared (FT-MIR) combined with multivariate statistical analysis. Eight alkaloids including magnoflorine, groenlandicine, jatrorrhizine, columbamine, epiberberine, coptisine, palmatine and berberine were simultaneously identified and determined. Epiberberine, berberine, magnoflorine and groenlandicine were identified as possible index components. FT-NIR and FT-MIR profiles presented the holistic metabolic characterization of RC medicines. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were successively performed to clearly illustrate the metabolic variation and taxonomic relationship among four RC medicines. Additionally, taking berberine as an example, spectral quantification potential was investigated by referring HPLC data, using a conventional partial least squares regression (PLSR) algorithm. Data fusion strategy exhibited a better prediction for this compound than a single technique. Summary, these techniques can complement each other and provide a comprehensive and effective quality assessment for RC originated from different Coptis plants.

Quantitative and Qualitative Characterization of Gentiana rigescens Franch (Gentianaceae) on Different Parts and Cultivations Years by HPLC and FTIR Spectroscopy.

Gentiana rigescens Franch (Gentianaceae) is a famous medicinal plant for treatments of rheumatism, convulsion, and jaundice. Comprehensive investigation of different parts and cultivation years of this plant has not yet been conducted. This study presents the quantitative and qualitative characterization of iridoid glycosides from G. rigescens performed by HPLC and FTIR spectroscopy techniques. The accumulations of loganic acid, swertiamarin, gentiopicroside, and sweroside were determined. Results indicated that their content and distribution in different parts and cultivation years exhibit great variations. Gentiopicroside was identified as the most abundant compound among iridoid glycosides and its highest level was observed in the root of 2-year-old plant. With respect to qualitative variation of metabolic profile, the 1800-800 cm-1 band of FTIR spectra successfully discriminated different parts and cultivation years with the aid of PLS-DA. In addition, combined with PLSR, the feasibility of FTIR spectroscopy for determination of gentiopicroside was investigated by selecting characteristic wavelengths (1800-800 cm-1), which presented a good performance with a residual predictive deviation (RPD) of 3.646. Our results suggested that HPLC and FTIR techniques can complement each other and could be simultaneously applied for comparing and analyzing different parts and cultivation years of G. rigescens.