Multi-level advances in databases related to systems pharmacology in traditional Chinese medicine: a 60-year review.

The therapeutic effects of traditional Chinese medicine (TCM) involve intricate interactions among multiple components and targets. Currently, computational approaches play a pivotal role in simulating various pharmacological processes of TCM. The application of network analysis in TCM research has provided an effective means to explain the pharmacological mechanisms underlying the actions of herbs or formulas through the lens of biological network analysis. Along with the advances of network analysis, computational science has coalesced around the core chain of TCM research: formula-herb-component-target-phenotype-ZHENG, facilitating the accumulation and organization of the extensive TCM-related data and the establishment of relevant databases. Nonetheless, recent years have witnessed a tendency toward homogeneity in the development and application of these databases. Advancements in computational technologies, including deep learning and foundation model, have propelled the exploration and modeling of intricate systems into a new phase, potentially heralding a new era. This review aims to delves into the progress made in databases related to six key entities: formula, herb, component, target, phenotype, and ZHENG. Systematically discussions on the commonalities and disparities among various database types were presented. In addition, the review raised the issue of research bottleneck in TCM computational pharmacology and envisions the forthcoming directions of computational research within the realm of TCM.

Modulating activity of PVN neurons prevents atrial fibrillation induced circulation dysfunction by electroacupuncture at BL15.

BACKGROUND: Circulation dysfunction is a major contributing factor to thrombosis in patients with atrial fibrillation (AF) for which effective interventions are lacking. Growing evidence indicates that regulating the paraventricular nucleus (PVN), an autonomic control center, could offer a novel strategy for treating cardiovascular and circulatory diseases. Concurrently, electroacupuncture (EA) at Xinshu (BL15), a form of peripheral nerve stimulation, has shown efficacy in treating several cardiovascular conditions, although its specific mechanism remains unclear. This study aimed to assess the impact of EA at BL15 on circulatory dysfunction in a rat AF model and investigate the pivotal role of PVN neuronal activity. METHODS: To mimic the onset of AF, male SD rats received tail intravenous injection of ACh-CaCl2 and were then subjected to EA at BL15, sham EA, or EA at Shenshu (BL23). Macro- and micro-circulation function were evaluated using in vivo ultrasound imaging and laser doppler testing, respectively. Vasomotricity was assessed by measuring dimension changes during vascular relaxation and contraction. Vascular endothelial function was measured using myograph, and the activation of the autonomic nerve system was evaluated through nerve activity signals. Additionally, chemogenetic manipulation was used to block PVN neuronal activation to further elucidate the role of PVN activation in the prevention of AF-induced blood circulation dysfunction through EA treatment. RESULTS: Our data demonstrate that EA at BL15, but not BL23 or sham EA, effectively prevented AF-induced macro- and micro-circulation dysfunction. Furthermore, EA at BL15 restored AF-induced vasomotricity impairment. Additionally, EA treatment prevented abnormal activation of the autonomic nerve system induced by AF, although it did not address vascular endothelial dysfunction. Importantly, excessive activation of PVN neurons negated the protective effects of EA treatment on AF-induced circulation dysfunction in rats. CONCLUSION: These results indicate that EA treatment at BL15 modulates PVN neuronal activity and provides protection against AF-induced circulatory dysfunction.

[Acupoints compatibility rules of acupuncture for depression disease based on data mining technology].

Based on data mining technology, the acupoints compatibility rules of acupuncture for depression diseases were explored. The randomized controlled trial (RCT) articles regarding acupuncture for depression diseases published from establishment of database to September 2nd, 2022 were searched in CNKI database, Wangfang database, VIP database, SinoMed database, PubMed, EMbase, Web of Science and Cochrane Library. The use frequency of acupoints, meridian tropism, selection of special acupoints and acupoint association rules for five common depression diseases, including primary depression, post-stroke depression, menopausal syndrome, psychoneurosis and anxiety disorder, were analyzed by Python programming language. Cytoscape software was used to analyze the acupoint association and the disease-acupoint co-occurrence network. As a result, totally 387 articles were included, and 319 acupoints prescriptions for the above five common depression diseases were extracted, involving 159 acupoints. The use frequency of acupoints was 2 574 times in total. The frequently-used acupoints were Baihui (GV 20), Sanyinjiao (SP 6), Taichong (LR 3), Neiguan (PC 6), Shenmen (HT 7), Yintang (GV 24+), Zusanli (ST 36), Hegu (LI 4), Sishencong (EX-HN 1) and Taixi (KI 3), etc. The frequently involved meridians were the governor vessel, foot-taiyang bladder meridian, foot-taiyin spleen meridian, and foot-jueyin liver meridian. The frequency of the special acupoints from high to low was crossing points, five-shu points, yuan-primary points, back-shu points, luo-connecting points, and eight confluent points, etc, which were often used in combination with "Baihui (GV 20)-Yintang (GV 24+)" (the highest degree of association). At the same time, the analysis of the co-occurrence network of depression diseases and acupoints showed that the core acupoints group of acupuncture for depression diseases were Baihui (GV 20), Taichong (LR 3), Shenmen (HT 7), Zusanli (ST 36), Neiguan (PC 6) and Sanyinjiao (SP 6). In conclusion, acupuncture treatment for depression diseases has gradually formed a rule of acupoint compatibility, with special acupoint as the main body and "unblocking the governor vessel, and regulating the spirit and qi " as the main therapeutic principle.

Restoring the Autonomic Balance in an Atrial Fibrillation Rat Model by Electroacupuncture at the Neiguan Point.

OBJECTIVES: Autonomic nervous activity imbalance plays an important role in atrial fibrillation (AF). AF can be treated by acupuncture at the Neiguan point (PC6), but the mechanism remains elusive. Here, we investigated autonomic nervous system activity in electroacupuncture (EA) at PC6 in a rat AF model. MATERIAL AND METHODS: In this study, we established a rat AF model via tail vein injection with ACh-CaCl2 for ten consecutive days with or without EA at PC6. AF inducibility and heart rate variability (HRV) were assessed by electrocardiogram. Next, we completed in vivo recording of the activity of cervical sympathetic and vagal nerves, respectively. Finally, the activities of brain regions related to autonomic nerve regulation were assessed by c-Fos immunofluorescence and multichannel recording. RESULTS: EA at PC6 decreased AF inducibility and prevented changes in HRV caused by ACh-CaCl2 injection. Meanwhile, EA at PC6 reversed the increased sympathetic and decreased vagal nerve activity in AF rats. Furthermore, EA treatment downregulated increased c-Fos expression in brain regions, including paraventricular nucleus, rostral ventrolateral medulla, and dorsal motor nucleus of the vagus in AF, while c-Fos expression in nucleus ambiguus was upregulated with EA. CONCLUSION: The protective effect of EA at PC6 on AF is associated with balance between sympathetic and vagal nerve activities.

Enhancing the Contrast of Tumor Imaging for Image-Guided Surgery Using a Tumor-Targeting Probiotic with the Continuous Expression of a Biomarker.

Tumor recurrence commonly results from tumor-positive resection margins and metastatic lesions. The complete removal of tumor-positive margins is particularly essential in clinics. Thus, we designed a strategy based on Escherichia coli Nissle 1917 (EcN) nitroreductase (NTR) with a polyethylene glycol (PEG) polymer coating (PC-EcN-NTR) to specifically target and colonize in tumors for high-contrast tumor imaging by providing a large amount of NTR as biomarkers in situ. NTR is a favorable biomarker for tumor detection and imaging. The nfsB-encoding plasmid with a 16S promoter was transfected into EcN for the continuous and stable expression of NTR (E. coli. NfsB). PC-EcN-NTR can accumulate and proliferate for a long time in tumors to substantially express NTR. When the NTR-activated fluorescence (FL) probe was sprayed on the tumor, the tumor region showed fluorescence signals within 5 min. Compared to the tumor without colonization with bacteria, the PC-EcN-NTR-colonized tumors displayed 3.15× enhanced fluorescence signals. Furthermore, the fluorescence signals of the whole tumor can last at least 3 h, which is suitable for a long and meticulous surgical operation. More importantly, in the PC-EcN-NTR-harboring tumor, obvious FL appeared even at the very edge (approximately 200 µm away from the edge) of the tumor tissue. A TCF-Based near-infrared-II fluorescent probe (probe 2) was designed and synthesized. Results similar to those of probe 1 were observed when probe 2 was used for in vivo tumor imaging, which further proved the generality of the enhancing ability of the tumor-targeting probiotic. This strategy will hopefully guide the surgical resection of tumors via monitoring intense NTR activity. It may spur the use of tumor-targeting probiotic and enzyme-activated fluorescent probes for the processes of tumor diagnosis and image-guided surgery.

Saikosaponin a contributed to CCIN treatment by promoting neutrophil bactericidal activity via activation CBL-dependent ERK pathway.

BACKGROUND: Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical, cancer chemotherapy induced neutropenia (CCIN) infection and infection-related mortality is high for lack of functionally mature neutrophils. Generating functional neutrophils is new therapeutic approaches to reduce CCIN-associated infection and mortality. Saikosaponin a (SSA) is one of the major bioactive components of Radix Bupleuri (RB) and exerts immunoregulatory effects. PURPOSE: The present study aims to investigate the efficacy and mechanism of SSA in CCIN therapy. METHODS: SSA was applied both in vitro and in vivo to assess the efficacy of CCIN therapy. The differentiation of neutrophils was measured by Nitroblue tetrazolium (NBT) reduction assay and Giemsa staining assay. The neutrophil differentiation related real-time transcription factors were detected by quantitative PCR (RT-qPCR) and Western Blot. Bacteria killing assay was used to assess the ability of fighting infection. Network pharmacology was employed to explore the mechanism network, and the predicted pathways were validated by Western Blot. RESULTS: We found that SSA contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology prediction showed 55 pathways were predicted involved in SSA against CCIN. Further validation showed that CBL-ERK1/2 pathway was activated by SSA, which could upregulate PU.1 and CEBPß expression leading to neutrophil differentiation. CONCLUSIONS: Our findings suggest a natural regimen SSA regenerates microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2 pathway, providing a rationale for future therapeutic approaches.

Saikosaponin d contributed to cancer chemotherapy induced neutropenia therapy by promoting neutrophil differentiation via activation CBL-dependent ERK pathway.

Cancer chemotherapy induced neutropenia (CCIN) is one of the most common toxicity caused by cytotoxic anticancer agents. Despite granulocyte colony-stimulating factor (GCSF) is widely used in clinical practice, the infection and infection-related mortality rate is still high for lack of functionally mature neutrophils. Saikosaponin d (SSD) is one of the major bioactive constituents of Radix Bupleuri (RB), which exerts immune-modulatory properties. We explored the function of SSD in CCIN therapy, we found that SSD contributed to generate functional mature neutrophils which capable of fighting infection both in vitro and in vivo. Network pharmacology was employed to explore the mechanism, 61 signal pathways might play an important role in CCIN treatment. Western Blot was employed to further confirm the potential pathway involved. We found CBL-ERK1/2 pathway was activated by SSD, followed by upregulating PU.1 and CEBPß expression and leading to neutrophil differentiation. Our findings suggest a natural regimen SSD which could regenerate microbicidal neutrophils to effectively reduce CCIN-associated infection via activating CBL-ERK1/2, providing a rationale for future therapeutic approaches.

Toxicity of traditional Chinese medicine herbal and mineral products.

Traditional Chinese medicine (TCM) has been used to treat numerous kinds of diseases for more than 2000 years in eastern Asian countries. A portion of the TCM herbal and mineral products are believed to be toxic according to modern standards, and are still widely prescribed in the clinic. However, some TCM products considered to be non-toxic or low-toxic have been reported to possess significant toxicological effects on different organs in both animal and human models. In this review, we define the term "toxic" in TCM, and then we summarize the advances in pharmacology and toxicology research of Toxic Traditional Chinese Medicine (TTCM), including Chinese aconite (Fu Zi), Arsenic Trioxide, Tripterygium wilfordii Hook f. (Thunder God Vine), herbal drugs derived from plants in the Aristolochiaceae Juss. family (Ma Dou Ling), and other TCM products. Finally, the compatibility art of TCM and modern pharmaceutical approaches to manage undesired toxicity of TTCM is discussed. Promoting pharmacology and toxicology studies of TTCM and non-toxic TCM is critical for the further development and safety of TCM in clinical practice.

A genetically encoded fluorescent biosensor for detecting nitroreductase activity in living cancer cells.

Genetically encoded fluorescent biosensors are particularly promising sensors to examine biochemical processes in a complex cellular context. RNA mimics of GFP are RNA-fluorophore complexes that emit green fluorescence comparable in brightness to fluorescent proteins. The fluorophore is non-fluorescent until it binds with specific RNA. We designed and developed a dual activated fluorescent probe based on RNA mimics of GFP for the detection of an intracellular nitroreductase. Our probe only fluoresces in the presence of both the specific RNA and nitroreductase. Since we used RNA to tag cells, our probe only fluoresces when nitroreductase exists in such cells. Our detection system should benefit the study of cell biomarkers in heterogeneous cell populations. More importantly, the strategy of quenching the RNA/DFHBI complex by alkylation of the hydroxyl group in DFHBI opens new possibilities for developing various genetically encoded fluorescent biosensors based on RNA/DFHBI complexes.