A comprehensive review of the molecular and genetic mechanisms underlying gum and resin synthesis in Ferula species.

Ferula spp. are plants that produce oleo-gum-resins (OGRs), which are plant exudates with various colors. These OGRs have various industrial applications in pharmacology, perfumery, and food. The main constituents of these OGRs are terpenoids, a diverse group of organic compounds with different structures and functions. The biosynthesis of OGRs in Ferula spp., particularly galbanum, holds considerable economic and ecological importance. However, the molecular and genetic underpinnings of this biosynthetic pathway remain largely enigmatic. This review provides an overview of the current state of knowledge on the biosynthesis of OGRs in Ferula spp., highlighting the major enzymes, genes, and pathways involved in the synthesis of different terpenoid classes, such as monoterpenes, sesquiterpenes, and triterpenes. It also examines the potential of using omics techniques, such as transcriptomics and metabolomics, and genome editing tools, such as CRISPR/Cas, to increase the yield and quality of Ferula OGRs, as well as to create novel bioactive compounds with enhanced properties. Moreover, this review addresses the current challenges and opportunities of applying gene editing in Ferula spp., and suggests some directions for future research and development.

A novel isoquinoline alkaloid HJ-69 isolated from Zanthoxylum bungeanum attenuates inflammatory pain by inhibiting voltage-gated sodium and potassium channels.

ETHNOPHARMACOLOGY RELEVANCE: Zanthoxylum bungeanum Maxim. (Z. bungeanum), a member of the Rutaceae family, has a rich history of traditional use in Asia for treating arthritis and toothache conditions. As characteristic chemical components, numerous kinds of alkaloids have been extracted from plants and their diverse biological activities have been reported. However, research on the isoquinoline alkaloid, a specific type of alkaloids, in Z. bungeanum was scarce. AIM OF THE STUDY: The study aimed to isolate a novel isoquinoline alkaloid from Z. bungeanum and explore its pharmacological activity in vitro and analgesic activity in vivo. MATERIALS AND METHODS: Isoquinoline alkaloid isolation and identification from Z. bungeanum were conducted using chromatographic and spectroscopic methods. The whole-cell patch-clamp technique was applied to assess its impact on neuronal excitability, and endogenous voltage-gated potassium (Kv) and sodium (Nav) currents in acutely isolated mouse small-diameter dorsal root ganglion (DRG) neurons. Its inhibitory impacts on channels were further validated with HEK293 cells stably expressing Nav1.7 and Nav1.8, and Chinese hamster ovary (CHO) cells transiently expressing Kv2.1. The formalin inflammatory pain model was utilized to evaluate the potential analgesic activity in vivo. RESULTS: A novel isoquinoline alkaloid named HJ-69 (N-13-(3-methoxyprop-1-yl)rutaecarpine) was isolated and identified from Z. bungeanum for the first time. HJ-69 significantly suppressed the firing frequency and amplitudes of action potentials in DRG neurons. Consistently, it state-dependently inhibited endogenous Nav currents of DRG neurons, with half maximal inhibitory concentration (IC50) values of 13.06 ± 2.06 µM and 30.19 ± 2.07 µM for the inactivated and resting states, respectively. HJ-69 significantly suppressed potassium currents in DRG neurons, which notably inhibited the delayed rectifier potassium (IK) currents (IC50 = 6.95 ± 1.29 µM) and slightly affected the transient outward potassium (IA) currents (IC50 = 523.50 ± 39.16 µM). Furtherly, HJ-69 exhibited similar potencies on heterologously expressed Nav1.7, Nav1.8, and Kv2.1 channels, which correspondingly represent the main components in neurons. Notably, intraperitoneal administration of 30 mg/kg and 100 mg/kg HJ-69 significantly alleviated pain behaviors in the mouse inflammatory pain model induced by formalin. CONCLUSION: The study concluded that HJ-69 is a novel and active isoquinoline alkaloid, and the inhibition of Nav and Kv channels contributes to its analgesic activity. HJ-69 may be a promising prototype for future analgesic drug discovery based on the isoquinoline alkaloid.

Chemical constituents from Notopterygium incisum and their anti-neuroinflammatory activity.

Phytochemical research on an extract of Notopterygium incisum yielded fifteen compounds (1-15), including four previously undescribed compounds (10-13). The structures of the unreported compounds were elucidated by spectroscopic and spectrometric data analysis such as 1D and 2D NMR, IR and HR-ESI-MS. Compounds 1-5 and 10-14 were isolated from N. incisum for the first time. 7S⁎,8R⁎-Phenethyl-(7-methoxy-8-isoeugenol)-ferulate (10), 7S⁎,8R⁎-p-hydroxyphenethyl-(7-methoxy-8-isoeugenol)-ferulate (11), 7S⁎,8R⁎-benzyl-(7-methoxy-8-isoeugenol)-ferulate (12) and p-hydroxyphenethyl-(4-benzoy-3-methoxy)-cinnamate (13) are the undescribed ferulic acid derivatives. Additionly, the anti-neuroinflammatory effects of compounds were evaluated in lipopolysaccharide (LPS)-induced BV2 cells. The pharmacological results showed that 6ß,10ß-epoxy-4α-hydroxy-guaiane (6), teuclatriol (7) and 7S⁎,8R⁎-p-hydroxyphenethyl-(7-methoxy-8-isoeugenol)-ferulate (11) inhibited the production and expression of nitric oxide (NO) in the LPS-induced BV2 cells in a concentration-dependent manner. Acorusnol (4), teucladiol (9), 7S⁎,8R⁎-benzyl-(7-methoxy-8-isoeugenol)-ferulate (12) and p-hydroxyphenethyl-(4-benzoy-3-methoxy)-cinnamate (13) only inhibited the release of NO at concentration of 20 µM. Moreover, 7S⁎,8R⁎-p-hydroxyphenethyl-(7-methoxy-8-isoeugenol)-ferulate (11) reduced the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in LPS-stimulated BV2 cells. The results demonstrated 7S⁎,8R⁎-p-hydroxyphenethyl-(7-methoxy-8-isoeugenol)-ferulate (11) could be a potential anti-neuroinflammatory agent and is worthy of further study.

Rapid evaluation of PHD2 inhibitory activity of natural products based on capillary electrophoresis online stacking strategy.

Prolyl hydroxylase domain 2 (PHD2) is an important enzyme in the human body that perceives changes in oxygen concentration and regulates response in hypoxic environments. Evaluation of PHD2 inhibitory activity of natural products is crucial for drug development of hypoxia related diseases. At present, the detection of low concentration of α-ketoglutaric acid (the substrate of PHD2 enzymatic reaction) requires derivatization reactions or sample pretreatment, which undoubtedly increases the workload of PHD2 inhibitory activity evaluation. In this paper, a direct detection approach of α-ketoglutaric acid was established by using the online stacking strategy of capillary electrophoresis to evaluate the PHD2 inhibitory activity of natural products. Under optimized conditions, detection of a single sample can be achieved within 2 min. By calculation, the intraday precision RSD of the apparent electrophoretic mobility and peak areas of α-ketoglutaric acid are 0.92 % and 0.79 %, respectively, and the interday RSD were 1.27 % and 0.96 % respectively. The recoveries of the present approach were 97.9-105.2 %, and the LOQ and LOD were 2.0 µM and 5.0 µM, respectively. Furthermore, this approach was applied for the evaluation of inhibitory activity of PHD2 for 13 natural products, and PHD2 inhibitory activity of salvianolic acid A was firstly reported. The present work not only realizes evaluation of PHD2 inhibitory activity through direct detection of α-ketoglutaric acid, but also provides technical support for the discovery of potential drug molecules in hypoxia related diseases.

Neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epilepsy in rats and its underlying mechanisms.

INTRODUCTION: Epilepsy is a common neurological disorder that presents with challenging mechanisms and treatment strategies. This study investigated the neuroprotective effects of quinpirole on lithium chloride pilocarpine-induced epileptic rats and explored its potential mechanisms. METHODS: Lithium chloride pilocarpine was used to induce an epileptic model in rats, and the effects of quinpirole on seizure symptoms and cognitive function were evaluated. The Racine scoring method, electroencephalography, and Morris water maze test were used to assess seizure severity and learning and memory functions in rats in the epileptic group. Additionally, immunohistochemistry and Western blot techniques were used to analyze the protein expression levels and morphological changes in glutamate receptor 2 (GluR2; GRIA2), BAX, and BCL2 in the hippocampi of rats in the epileptic group. RESULTS: First, it was confirmed that the symptoms in rats in the epileptic group were consistent with features of epilepsy. Furthermore, these rats demonstrated decreased learning and memory function in the Morris water maze test. Additionally, gene and protein levels of GluR2 in the hippocampi of rats in the epileptic group were significantly reduced. Quinpirole treatment significantly delayed seizure onset and decreased the mortality rate after the induction of a seizure. Furthermore, electroencephalography showed a significant decrease in the frequency of the spike waves. In the Morris water maze test, rats from the quinpirole treatment group demonstrated a shorter latency period to reach the platform and an increased number of crossings through the target quadrant. Network pharmacology analysis revealed a close association between quinpirole and GluR2 as well as its involvement in the cAMP signaling pathway, cocaine addiction, and dopaminergic synapses. Furthermore, immunohistochemistry and Western blot analysis showed that quinpirole treatment resulted in a denser arrangement and a more regular morphology of the granule cells in the hippocampi of rats in the epileptic group. Additionally, quinpirole treatment decreased the protein expression of BAX and increased the protein expression of BCL2. CONCLUSION: The current study demonstrated that quinpirole exerted neuroprotective effects in the epileptic rat model induced by lithium chloride pilocarpine. Additionally, it was found that the treatment not only alleviated the rats' seizure symptoms, but also improved their learning and memory abilities. This improvement was linked to the modulation of protein expression levels of GLUR2, BAX, and BCL2. These findings provided clues that would be important for further investigation of the therapeutic potential of quinpirole and its underlying mechanisms for epilepsy treatment.

Feedback Intervention for the Control of Glucocorticoid Prescription in Primary Care Institutions: A Cluster Randomized Cross-Over Controlled Trial in Southwest China.

Purpose: The purpose of this study is to assess the effect of glucocorticoid prescription feedback intervention in complex primary care institutions for regulating its inappropriate use. Design Setting and Interventions: A six-month cluster randomized cross-over controlled trial was conducted in primary care institutions. A total of 347 physicians from 69 participating institutions were randomly allocated to either group A or group B. Both groups were given feedback interventions or serve as control. The feedback intervention comprised two components: a real-time pop-up warning of inappropriate glucocorticoid prescriptions based on the Hospital Information System and a high-proportion prescription feedback intervention warning system. Outcome Measures: The primary outcome measure was the 10-day inappropriate glucocorticoid prescription rate, while the 10-day glucocorticoid prescription rate served as secondary outcome measure. Results: At baseline, the 10-day inappropriate glucocorticoid prescription rates were 66.63% and 66.57% in group A and group B, respectively, showing no significant difference (p = 0.140). Following the intervention, group A exhibited a significant reduction in 10-day inappropriate glucocorticoid prescription rate at the crossing point by 13.69% (p < 0.001). In contrast, group B, which served as the control group, experienced an increase of 5.93% (p = 0.037) at the same crossover point. After the crossover point, there was a decrease in 10-day inappropriate glucocorticoid prescription rate for both groups. Group B as the intervention group demonstrated a reduction of 28.22% compared to the crossing point (p < 0.001), whereas group A showed a decrease of 12.20% (p = 0.339). The characteristics of physicians did not significantly influence the inappropriate glucocorticoid prescription rate. Conclusion: The real-time pop-up warning of inappropriate glucocorticoid prescriptions based on the Hospital Information System and high-proportion prescription feedback intervention warning system can effectively regulate the inappropriate glucocorticoid prescribing behavior of physicians. Trial Registration: ISRCTN11747547.

Synaptotagmin-7 mediates cardiac hypertrophy by targeting autophagy.

Sustained cardiac hypertrophy damages the heart and weakens cardiac function, often leading to heart failure and even death. Pathological cardiac hypertrophy has become a central therapeutic target for many heart diseases including heart failure. However, the underlying mechanisms of cardiac hypertrophy, especially the involvement of autophagy program, are still ill-understood. Synaptotagmin-7 (Syt7), a multifunctional and high-affinity calcium sensor, plays a pivotal role in asynchronous neurotransmitter release, synaptic facilitation, and vesicle pool regulation during synaptic transmission. However, little is known about whether Syt7 is expressed in the myocardium and involved in the pathogenesis of heart diseases. Here we showed that Syt7 was significantly upregulated in Ang II-treated hearts and cardiomyocytes. Homozygous syt7 knockout (syt7-/-) mice exhibited significantly attenuated cardiac hypertrophy and fibrosis and improved cardiac function. We further found that Syt7 exerted a pro-hypertrophic effect by suppressing the autophagy process. In exploring the upstream mechanisms, microRNA (miR)-93 was identified to participate in the regulation of Syt7 expression. miR-93 protected hearts against Ang II-induced hypertrophy through targeting Syt7-autophagy pathway. In summary, our data reveal a new cardiac hypertrophy regulator and a novel hypertrophy regulating model composed of miR-93, Syt7 and autophagy program. These molecules may serve as potential therapeutic targets in the treatment of cardiac hypertrophy and heart failure.

Trends and Patterns of Systemic Glucocorticoid Prescription in Primary Care Institutions in Southwest China, from 2018 to 2021.

Purpose: The purpose of this study was to investigate the prescribing patterns and usage trends of systemic glucocorticoids in primary care institutions located in Southwest China from 2018 to 2021. Materials and Methods: A retrospective cross-sectional analysis of systemic glucocorticoids prescriptions was conducted in 32 primary care institutions located in Southwest China between 2018 and 2021. Prescriptions of systemic glucocorticoids were classified as appropriate or inappropriate use. Inappropriate use was further classified into (1) inappropriate indications and (2) inappropriate selection of glucocorticoids. Generalized estimation equations were employed to investigate the factors associated with inappropriate utilization of systemic glucocorticoids. The seasonal autoregressive integrated moving average (SARIMA) model was employed to predict the rate of inappropriate glucocorticoids prescriptions. Results: A total of 203,846 (92.89%) prescriptions were included, both the number of systemic glucocorticoids prescriptions and inappropriate prescriptions increased in winter. Diseases of the respiratory system (68.90%) were the most frequent targets of systemic glucocorticoids use. Of all prescriptions, 73.18% exhibited inappropriate indications, while 0.05% demonstrated inappropriate selection. The utilization of systemic glucocorticoids was deemed inappropriate for diseases of the respiratory system (94.19%), followed by diseases of the digestive system (87.75%). Physicians, who were female or younger than 33 years old, possess lower levels of education and professional titles and exhibit a higher likelihood of inappropriately prescribing systemic glucocorticoids. The phenomenon of inappropriate glucocorticoids use was commoner among male patients aged 65 years and older. After conducting model verification, it was determined that the SARIMA model could be used to predict the monthly rate of inappropriate systemic glucocorticoids prescriptions in primary care institutions in southwest China. Conclusion: The inappropriate use of systemic glucocorticoids remains a significant concern in primary care institutions. In this regard, continuing education and professional knowledge training of physicians should be strengthened in the future.

Trends and Patterns of Antibiotic Prescriptions in Primary Care Institutions in Southwest China, 2017-2022.

Purpose: To explore the prescription patterns and usage trends of antibiotics within primary care institutions located in underdeveloped regions of China from 2017 to 2022. Methods: A retrospective analysis of antibiotic prescriptions was conducted from 25 primary care institutions in Guizhou Province during the period of 2017-2022. Antibiotic prescriptions were categorized into appropriate and inappropriate use. Appropriate use is further categorized into preferred medication, and antibiotics can be used or substituted. Inappropriate use is further categorized into unnecessary use, incorrect spectrum of antibiotics and combined use of antibiotics. Factors associated with inappropriate use were investigated using generalized estimation equations. Holt-Winters and SARIMA models were employed to predict the number of inappropriate antibiotic prescriptions as the alternative model. Results: A total of 941,924 prescriptions were included, revealing a decreasing trend in both the number and inappropriate rates of antibiotic prescriptions from 2017 to 2022. Diseases of the respiratory system (70.66%) was the most frequent target of antibiotic use, with acute upper respiratory infections of multiple and unspecified sites representing 52.04% of these cases. The most commonly used antibiotics were penicillins (64.44%). Among all prescriptions, inappropriate antibiotic prescriptions reached 66.19%. Physicians aged over 35, holding the title of associate chief physician and possessing more than 11 years of experience were more likely to prescribe antibiotics inappropriately. The phenomenon of inappropriate antibiotic use was commoner among children aged five or younger. By comparing model parameters, it was determined that the SARIMA model outperforms the Holt-Winters model in predicting the number of inappropriate antibiotic prescriptions among primary care institutions. Conclusion: The number and inappropriate rates of antibiotic prescriptions in southwest China exhibited a downward trend from 2017 to 2022, but inappropriate prescription remains a serious problem in primary care institutions. Therefore, future efforts should focus on strengthening physician education, training, and clinical practice. Additionally, physicians' awareness of common misconceptions about inappropriate antibiotic use must be improved, and the prescribing behavior of physicians who fulfill patients' expectations by prescribing antibiotics needs to be modified.

Gypenoside-14 Reduces Depression via Downregulation of the Nuclear Factor Kappa B (NF-kB) Signaling Pathway on the Lipopolysaccharide (LPS)-Induced Depression Model.

Neuroinflammation is a common pathogenetic sign of depression and is closely linked to the development of depression. Many clinical anti-inflammatory drugs act as antidepressants by reducing the neuroinflammatory response. Previous research found that gypenosides and their bioactive compound gypenoside-14 (GP-14) had neuroprotective effects against hypoxia-induced injury and reduced neuroinflammation-related high-altitude cerebral edema. Here we investigated the effects of GP-14 on the lipopolysaccharide (LPS)-induced depression-like behavior model. LPS (0.5 mg/kg) was injected into mice intraperitoneally for 7 consecutive days to induce depression-like behavior, which is considered a model for the exacerbation of depression. GP-14 in the amount of 100 mg/kg was simultaneously administered by gavage for 7 days. In the LPS-induced depression model, GP-14 not only attenuated depression-like behavior but also improved the anxiety-like behavior of the mice. Additionally, GP-14 treatment mitigated learning and cognitive decline in depressed mice. ELISA and immunofluorescence staining results revealed that GP-14 inhibited the upregulation of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), and suppressed the activation of astrocytes induced with LPS, indicating its potent anti-inflammatory effect. GP-14 pretreatment in C8 cells and primary astrocytes can inhibit the activation of the NF-κB signaling pathway and downregulate the levels of pro-inflammatory factors. In summary, our findings showed that GP-14 had significant anti-inflammation and anti-depression properties; thus, GP-14 could be a promising lead compound for treating depression.

Sesquiterpene coumarins from Ferula sinkiangensis and their anti-pancreatic cancer effects.

Eight previously unreported sesquiterpene coumarins, namely (+)- and (-)-ferulasinkian A (1), (-)-fukanefuromarin M (2), (±)-ferulasinkian C (3), (±)-ferulasinkian D (4), ferulasinkian E (5), ferulasinkian F (7), and ferulasinkian G (8), together with two known compounds, (+)-fukanefuromarin M (2) and 7-hydroxyferprenin (6), have been isolated from the roots of Ferula sinkiangensis (Umbelliferae). The structures of all compounds were elucidated by spectroscopic analysis, along with ECD calculations and optical rotation calculations. Compounds 1-6 are dimers consisting of a chain sesquiterpene and a coumarin with an oxygen-containing six-membered ring connected from coumarin C-3 and C-4. Currently, there are only seven such structures reported in the genus Ferula, and their absolute configurations have not yet been determined. Compounds 7-8 are sesquiterpene coumarin derivatives with a chain sesquiterpene connected with coumarin C-4. In the present study, the chiral separation of compounds (±)-1 and (±)-2 was successfully carried out, and the absolute configurations of compounds (±)-1, (±)-2, 5, 7 and 8 were determined. The isolates were evaluated for their cytotoxic activity against human pancreatic cancer cell lines including CFPAC-1, PANC-1, CAPAN-2 and SW 1990. Compounds (+)-1, (-)-1 and 7 exhibited potent cytotoxicity against pancreatic cancer cells with IC50 values ranging from 4.57 ± 0.94 to 14.01 ± 1.03 µM. Furthermore, the primary mechanistic study of (-)-1 demonstrated that it could induce apoptosis in CFPAC-1 cells.

Bio-Assay-Guided Isolation of Fractions and Constituents with Antioxidant and Lipid-lowering Activity from Allium cepa.

Active fractions and constituents with antioxidant and lipid-lowering activities were investigated using bio-assay-guided isolation and identification. The data showed that the antioxidant fraction of A. cepa was AC50%, the main constituents of which were quercetin and isoquercitrin, by way of both ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) and bio-assay-guided purification and elucidation. Similarly, the lipid-lowering active fraction of A. cepa was AC30% with the main constituents of 3,4-dihydroxybenzoic acid and quercetin 3,4'-O-diglucoside. Also, bio-assay-guided isolation led to the isolation and identification of five known compounds with a purity of more than 98%, and quercetin was both the best free radical scavenger and lipid-lowering constituent. Moreover, the mechanism of the lipid-lowering effect of AC30% might be its reduction in mRNA expression levels of sterol regulatory element binding protein 2 (SREBP2) and FAS gene in lipid synthesis. Otherwise, reducing the mRNA expression level of lipid synthesis genes, including SREBP1, SREBP2, fatty acid synthetase (FASN), ß-Hydroxy ß-methylglutaryl-CoA (HMGCR), stearoyl CoA desaturase 1 (SCD1), and increasing the mRNA expression level of lipid decomposition gene, such as carnitine palmitoyl transferease-1 (CPT1), might be involved in the lipid-lowering activity of quercetin. This study suggested that Allium cepa might be used to prevent and treat oxidative stress and dislipidemia-related disorders, including NAFLD.

Labdane diterpenoids from Lagopsis supina and their anti-neuroinflammatory activity.

In this study, ten labdane-type diterpenoids 1-10 were isolated from a methanol extract of the whole plant Lagopsis supina, including three undescribed compounds 1-3. Their structures were determined by spectroscopic data analyses such as HR-ESI-MS, 1D, and 2D NMR, as well as comparison with literature data. At the same time, the absolute configuration of five compounds 2-5 and 10 was confirmed for the first time by the single crystal X-ray diffraction method. All the compounds were isolated from L. supina for the first time. The CCK-8 assay showed that all compounds had no significant damage to BV-2 microglial cells, and then screened their inhibitory effects of nitric oxide production stimulated by lipopolysaccharide in BV-2 microglial cells. The pharmacological results showed that compound 4 greatly inhibited LPS-stimulated NO release at the concentration of 10 µM, indicating that it has potential anti-neuroinflammatory activity.

[Research advance on structure and function of amides in Zanthoxylum plants].

Zanthoxylum belongs to the Rutaceae family, and there are 81 Zanthoxylum species and 36 varieties in China. Most of the Zanthoxylum plants are used as culinary spice. In recent years, scholars in China and abroad have carried out in-depth research on Zanthoxylum plants, and found that the peculiar numbing sensation of Zanthoxylum plants originates from amides. It is also determined that amides are an important material basis for exerting pharmacological effects, especially in anti-inflammatory analgesia, anesthesia and other aspects. In this paper, 123 amides in 26 Zanthoxylum plants and their pharmacological activity that have been reported were summarized, which provided scientific reference for the clinical application of Zanthoxylum plants and the research and development of new drugs, and also facilitated the sustainable development and utilization of Zanthoxylum plant resources.

Alkylamides from Zanthoxylum armatum DC. and their neuroprotective activity.

Zanthoxylum armatum DC. is an important medicinal plant, and its pericarps are commonly used as a natural spice in Asian countries. In this study, fifteen alkylamides were isolated and elucidated from the pericarps of Z. armatum, including five undescribed alkylamides (1-5) and ten known compounds (6-15). The molecular structures of all compounds were elucidated by 1D and 2D NMR spectroscopic analysis and mass spectrometry, among which the absolute configuration of compound 15 was determined by the Mo2(OAc)4-induced circular dichroism method. Moreover, all compounds were screened for their neuroprotective activity against H2O2-induced oxidative stress in human neuroblastoma SH-SY5Y cells for the evaluation of their neuroprotective activity. Especially, compounds 2-4 expressed potential neuroprotective activity, and further research showed that the cell viability was significantly enhanced in a concentration dependent manner when the cells were treated for 6 h. Moreover, compounds 2-4 could decrease reactive oxygen species accumulation. This paper enriched structure types of alkylamides in Zanthoxylum armatum.

Two Ferulic Acid Derivatives Inhibit Neuroinflammatory Response in Human HMC3 Microglial Cells via NF-κB Signaling Pathway.

Various physiological and pathological changes are related to the occurrence and development of neurodegenerative diseases. Neuroinflammation is a major trigger and exacerbation of neurodegenerative diseases. One of the main symptoms of neuritis is the activation of microglia. Thus, to alleviate the occurrence of neuroinflammatory diseases, an important method is to inhibit the abnormal activation of microglia. This research evaluated the inhibitory effect of trans-ferulic acid (TJZ-1) and methyl ferulate (TJZ-2), isolated from Zanthoxylum armatum, on neuroinflammation, by establishing the human HMC3 microglial cell neuroinflammation model induced by lipopolysaccharide (LPS). The results showed both compounds significantly inhibited the production and expression of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) contents, and increased the level of anti-inflammatory factor ß-endorphin (ß-EP). Furthermore, TJZ-1 and TJZ-2 can inhibit LPS-induced activation of nuclear factor kappa B (NF-κB). It was found that of two ferulic acid derivatives, both had anti-neuroinflammatory effects by inhibiting the NF-κB signaling pathway and regulating the release of inflammatory mediators, such as NO, TNF-α, IL-1ß, and ß-EP. This is the first report that demonstrates that TJZ-1 and TJZ-2 had inhibitory effects on LPS-induced neuroinflammation in human HMC3 microglial cells, which indicates that two ferulic acid derivates from Z. armatum could be used as potential anti-neuroinflammatory agents.

Discovery of Highly Potent and Selective Thyroid Hormone Receptor ß Agonists for the Treatment of Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. While there are currently no approved therapies for NASH, the thyroid hormone receptor ß (THR-ß), primarily expressed in the liver, is emerging as an effective molecular target for the treatment of NASH. However, the adverse cardiac and bone effects mediated by thyroid hormone receptor α (THR-α) need to be minimized. Herein, we reported the discovery of a series of novel THR-ß agonists featuring pyrrolo[3,2-b]pyridin-5-one skeletons based on structure-based drug design. Further optimization led to compound 15, which exhibited higher potency and selectivity for THR-ß over THR-α compared to clinical drug MGL-3196. More significantly, an excellent liver-to-serum ratio of 93:1 was observed for compound 15. We believe that the high hepatic concentration of compound 15 may result in no cardiotoxicity.

Effects of a feedback intervention on antibiotic prescription control in primary care institutions based on a Health Information System: a cluster randomized cross-over controlled trial.

OBJECTIVES: Overuse and misuse of antibiotics are major factors in the development of antibiotic resistance in primary care institutions of rural China. In this study, the effectiveness of a Health Information System-based, automatic, and confidential antibiotic feedback intervention was evaluated. METHODS: A randomized, cross-over, cluster-controlled trial was conducted in primary care institutions. All institutions were randomly divided into two groups and given either a three-month intervention followed by a three-month period without any intervention or vice versa. The intervention consisted of three feedback measures: a real-time pop-up warning message of inappropriate antibiotic prescriptions on the prescribing physician's computer screen, a 10-day antibiotic prescription summary, and distribution of educational manuals. The primary outcome was the 10-day inappropriate antibiotic prescription rate. RESULTS: There were no significant differences in inappropriate antibiotic prescription rates (69.1% vs. 72.0%) between two groups at baseline (P = 0.072). After three months (cross-over point), inappropriate antibiotic prescription rates decreased significantly faster in group A (12.3%, P < 0.001) compared to group B (4.4%, P < 0.001). At the end point, the inappropriate antibiotic prescription rates decreased in group B (15.1%, P < 0.001) while the rates increased in group A (7.2%, P < 0.001). The characteristics of physicians did not significantly affect the rate of antibiotic or inappropriate antibiotic prescription rates. CONCLUSION: A Health Information System-based, real-time pop-up warnings, a 10-day prescription summary, and the distribution of educational manuals, can effectively reduce the rates of antibiotic and inappropriate antibiotic prescriptions.