The American Journal of Chinese Medicine

The outbreak caused by COVID-19 is causing a major challenge to clinical management and a worldwide threat to public health. So far, there is no specific anti-coronavirus therapy approved for the treatment of COVID-19. Recently, as the efficacy and safety of traditional Chinese medicine (TCM) is widely acknowledged, it has been brought to a crucial status by the public, governments, and World Health Organization (WHO). For a better popularization of TCM, governments have made several advances in regulations and policies for treatment and measures of novel coronavirus pneumonia (NCP). Therefore, on the basis of epidemiology and virology information, we reviewed relevant meta-analysis and clinical studies of anti-coronavirus therapeutics by TCM, in the aspect of mortality, symptom improvement, duration and dosage of corticosteroid, incidence of complications and the like. In addition, we also summarized preclinical rationale for anti-coronavirus activity by TCM in terms of virion assembly and release, as well as viral entry and replication, which could be a useful contribution for figuring out effective Chinese herbal medicine (CHM) for coronavirus, including ingredients from single monomeric compounds, Chinese herbs, Chinese herb extracts and Chinese herb formulas, or potential targets for medicine. We would like to see these relevant studies, ranging from basic researches to clinical application, could provide some idea on effects of CHM to combat COVID-19 or other coronaviruses, and also offer new thinking for the exploration of therapeutic strategies under the guidance of TCM.

Since the outbreak of Corona Virus Disease 2019 (COVID-19) in Hubei province, the epidemic scale has increased rapidly, and no effective antiviral drug therapy has been identified yet. This study aimed to evaluate the adjuvant efficacy of Natural Herbal Medicine (NHM) combined with Western medicine in the treatment of COVID-19. We performed a retrospective, 1:1 matched, case-control study of the first cohort of hospitalized COVID-19-confirmed cases (January 17, 2020 to January 28, 2020). A total of 22 of the 36 confirmed patients were included in this study, split into two groups of 11: the NHM group (NHM combined standard Western medicine treatment) and control group (standard Western medicine treatment alone). All patients received appropriate supportive care and regular clinical and laboratory monitoring. Main evaluation indicators included improvement of clinical symptoms such as fever, cough and diarrhea after hospitalization; pathogen nucleic acid test result of respiratory tract and fecal specimens of the patient after hospitalization, and change of chest CT examination after hospitalization. The duration of fever in the NHM group ($3.4\pm 2.4$ days) was significantly shorter than that in the control group ($5.6\pm 2.2$ days) ($p=0.03$). During the whole hospitalization period, the number of cases with diarrhea in the NHM group (two cases) was less than that in the control group (eight cases) ($p=0.03$). Compared with the control group ($7.5\pm 1.6$), the duration for improvement (DI) of chest CT in the NHM group ($5.6\pm 2.3$) was significantly shorter ($p=0.04$). Our results suggest that NHM could improve the clinical symptoms of COVID-19 patients and may be effective in treating COVID-19; thus, a larger, prospective, randomized, controlled clinical trial should be conducted to further evaluate the adjuvant efficacy of NHM in the treatment of COVID-19.

Acupuncture reduces pain by activating specific areas called acupoints on the patient’s body. When these acupoints are fully activated, sensations of soreness, numbness, fullness, or heaviness called De qi or Te qi are felt by clinicians and patients. There are two kinds of acupuncture, manual acupuncture and electroacupuncture (EA). Compared with non-acupoints, acupoints are easily activated on the basis of their special composition of blood vessels, mast cells, and nerve fibers that mediate the acupuncture signals. In the spinal cord, EA can inhibit glial cell activation by down-regulating the chemokine CX3CL1 and increasing the anti-inflammatory cytokine interleukin-10. This inhibits P38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways, which are associated with microglial activation of the C-Jun N-terminal kinase signaling pathway and subsequent astrocyte activation. The inactivation of spinal microglia and astrocytes mediates the immediate and long-term analgesic effects of EA, respectively. A variety of pain-related substances released by glial cells such as the proinflammatory cytokines tumor necrosis factor $\alpha$, interleukin-1$\beta$, interleukin-6, and prostaglandins such as prostaglandins E2 can also be reduced. The descending pain modulation system in the brain, including the anterior cingulated cortex, the periaqueductal gray, and the rostral ventromedial medulla, plays an important role in EA analgesia. Multiple transmitters and modulators, including endogenous opioids, cholecystokinin octapeptide, 5-hydroxytryptamine, glutamate, noradrenalin, dopamine, $\gamma$-aminobutyric acid, acetylcholine, and orexin A, are involved in acupuncture analgesia. Finally, the “Acupuncture $+$” strategy is introduced to help clinicians achieve better analgesic effects, and a newly reported acupuncture method called acupoint catgut embedding, which injects sutures made of absorbable materials at acupoints to achieve long-term effects, is discussed.

Proanthocyanidins (PAs) are a group of polyphenols enriched in plant and human food. In recent decades, epidemiological studies have upheld the direct relationship between PA consumption and health benefits; therefore, studies on PAs have become a research hotspot. Although the oral bioavailability of PAs is quite low, pharmacokinetics data revealed that some small molecules and colonic microbial metabolites of PAs could be absorbed and exert their health beneficial effects. The pharmacological effects of PAs mainly include anti-oxidant, anticancer, anti-inflammation, antimicrobial, cardiovascular protection, neuroprotection, and metabolism-regulation behaviors. Moreover, current toxicological studies show that PAs have no observable toxicity to humans. This review summarizes the resources, extraction, structures, pharmacokinetics, pharmacology, and toxicology of PAs and discusses the limitations of current studies. Areas for further research are also proposed.

Chrysanthemum indicum L. (C. indicum L.), a member of the Compositae family, is a perennial plant that has been used as a traditional medicine for more than 2000 years in China and is widely used for the treatment of Pemphigus, swelling, pain, and scrofula. To date, more than 190 chemical constituents have been isolated and identified from this plant, including flavonoids, terpenoids, phenylpropanoids, and phenolic acids. Numerous modern studies have shown that extracts or monomeric compounds from C. indicum L. have several pharmacological activities, such as anti-inflammatory anti-oxidation, antipathogenic microorganism, anticancer, immune regulation, and hepatoprotective effects. However, resource availability, the research on the mechanism, and quality control are still insufficient, which deserves further efforts. In this paper, the advances in botany, phytochemistry, and pharmacology of C. indicum L were reviewed. We hope that this review can provide important information for traditional Chinese medicine, phytochemistry, synthetic and medicinal chemistry researchers for making full use of C. indicum L. resource.

In Chinese medicine, fermentation is a highly important processing technology whereby medicinal herbs are fermented under appropriate temperature, humidity, and moisture conditions by means of the action of microorganisms to enhance their original characteristics and/or produce new effects. This expands the scope of such medicines and helps them to meet the stringent demands of clinical application. Since ancient times, Chinese medicine has been made into Yaoqu to reduce its toxicity and increase its efficiency. Modern fermentation technologies have been developed on the basis of traditional fermentation techniques and modern biological technology, and they can be divided into solid fermentation, liquid fermentation, and two-way fermentation technologies according to the fermentation form employed. This review serves as an introduction to traditional fermentation technology and its related products, modern fermentation technologies, and the application of fermentation technology in the field of Chinese medicine. Several problems and challenges facing the field are also briefly discussed.

Chronic insomnia is a disease which brings intense mental pain and disturbing complications to patients worldwide. The oral microbiome exhibits a mechanistic influence on human health. Therefore, it is crucial to understand the oral microbial diversity in insomnia. Tongue diagnosis has been considered a critical basic procedure in insomnia therapeutic decision-making in Traditional Chinese Medicine (TCM). Hence, it is significant to elucidate the various oral microbiome differences in chronic insomnia patients with different tongue features. In this paper, we used 16S rRNA gene sequencing and bioinformatics analysis to investigate dynamic changes in oral bacterial profile and correlations between chronic insomnia patients and healthy individuals, as well as in patients with different tongue coatings. Moreover, the relationship between the severity of insomnia and oral microbiota was explored. Our findings showed that chronic insomnia patients harbored a significantly higher diversity of oral bacteria when compared to healthy controls. More importantly, the results revealed that the diversity and relative abundance of the bacterial community was significantly altered among different tongue coatings in patients but not in healthy individuals. Oral bacteria with a relative abundance $>$1% and $P<0.05$ among different tongue groups were considered remarkable bacteria, which included three phyla Proteobacteria, Bacteroidetes, Gracilibacteria, and four genera, Streptococcus, Prevotella_7, Rothia, and Neisseria. Our findings indicate that changes in oral microbiome correlate with tongue coatings in patients with chronic insomnia. Thus, the remarkable microbiome may provide inspiration for further studies on the correlation between tongue diagnosis and oral microbiome in chronic insomnia patients.

Tetramethylpyrazine has shown neuroprotective and axonal outgrowth-promoting effects and can improve cognitive deficit in a rat model of chronic hypoperfusion. However, the role of tetramethylpyrazine in sevoflurane-induced neurotoxicity is still vague. Therefore, this study was designed to investigate the effects and mechanisms of tetramethylpyrazine on sevoflurane-induced autophagy, apoptosis, and the expression of BACE1 and A$\beta$ in SH-SY5Y cells. We measured the expression levels of the apoptosis protein markers Bax and Bcl-2, autophagy protein markers Atg5 and LC3-II, BACE1, and A$\beta$ in SH-SY5Y cells after sevoflurane treatment and determined the effects of tetramethylpyrazine on sevoflurane-induced expression of these proteins after silencing GPR50 or Atg5 with siRNA in vitro. We found that exposure to 3.4% sevoflurane for 6 h decreased the expression of autophagy protein markers and increased the expression of the apoptosis protein markers, BACE1, and A$\beta$ in SH-SY5Y cells. The number of red puncta (autolysosomes) and yellow puncta (autophagosomes) in each SH-SY5Y cell decreased after transient transfection with the mRFP-GFP-LC3 expression plasmid. Silencing of GPR50 decreased the expression of pCREB, Atg5, and LC3-II, while silencing of Atg5 increased the expression of BACE1 and A$\beta$ in SH-SY5Y cells. Our results demonstrate that tetramethylpyrazine attenuated sevoflurane-induced neurotoxicity by enhancing autophagy through the GPR50/CREB pathway in SH-SY5Y cells.

Inflammation and endoplasmic reticulum (ER) stress have been documented to contribute to the development of atherosclerosis. Ginsenoside Rb2 has been reported to exhibit antidiabetic effects. However, the effects of Rb2 on atherosclerotic responses such as inflammation and ER stress in endothelial cells and monocytes remain unclear. In this study, the expression of inflammation and ER stress markers was determined using a Western blotting method. Concentrations of tumor necrosis factor alpha (TNF$\alpha$) and monocyte chemoattractant protein-1 (MCP-1) in culture media were assessed by enzyme-linked immunosorbent assay (ELISA) and apoptosis was evaluated by a cell viability assay and a caspase-3 activity measurement kit. We found that exposure of HUVECs and THP-1 monocytes to Rb2 attenuated inflammation and ER stress, resulting in amelioration of apoptosis and THP-1 cell adhesion to HUVECs under lipopolysaccharide (LPS) condition. Increased AMPK phosphorylation and heme oxygenase (HO)-1 expression, including GPR120 expression were observed in Rb2-treated HUVECs and THP-1 monocytes. Downregulation of both, AMPK phosphorylation and HO-1expression rescued these observed changes. Furthermore, GPR120 siRNA mitigated Rb2-induced AMPK phosphorylation. These results suggest that Rb2 inhibits LPS-mediated apoptosis and THP-1 cell adhesion to HUVECs by GPR120/AMPK/HO-1-associated attenuating inflammation and ER stress. Therefore, Rb2 can be used as a potential therapeutic molecule for treatment of atherosclerosis.

Our previous report revealed that Gardenia jasminoides (GJ) has protective effects against acute pancreatitis. So, we examined whether aqueous extract of GJ has anti-inflammation and antifibrotic effects even against cerulein-induced chronic pancreatitis (CP). CP was induced in mice by an intraperitoneal injection of a stable cholecystokinin (CCK) analogue, cerulein, six times a day, four days per week for three weeks. GJ extract (0.1 or 1g/kg) or saline (control group) were intraperitoneally injected 1h before first cerulein injection. After three weeks of stimulation, the pancreas was harvested for the examination of several fibrotic parameters. In addition, pancreatic stellate cells (PSCs) were isolated using gradient methods to examine the antifibrogenic effects of GJ. In the cerulein-induced CP mice, the histological features of the pancreas showed severe tissue damage such as enlarged interstitial spaces, inflammatory cell infiltrate and glandular atrophy, and tissue fibrosis. However, treatment of GJ reduced the severity of CP such as pancreatic edema and inflammatory cell infiltration. Furthermore, treatment of GJ increased pancreatic acinar cell survival, and reduced pancreatic fibrosis and activation of PSC in vivo and in vitro. In addition, GJ treatment inhibited the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) in the PSCs. These results suggest that GJ attenuated the severity of CP and the pancreatic fibrosis by inhibiting JNK and ERK activation during CP.

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-$\beta$-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

Codonopsis lanceolata roots have been widely used in Korean cuisine and traditional medicine. This study aimed to investigate the antimetastatic effects of lancemaside A, a major triterpenoid saponin, isolated from the roots of C. lanceolata, in human ovarian cancer cells. Lancemaside A significantly suppressed the migration and invasion and the expression of matrix metalloproteinases (MMPs)-2 and -9 in ovarian cancer A2780 and SKOV3 cells. Treatment with lancemaside A generated reactive oxygen species (ROS) in ovarian cancer cells. However, treatment with anti-oxidant N-acetyl-L-cysteine (NAC) significantly negated the anti-invasive activity of lancemaside A. Additionally, lancemaside A activated p38 MAP kinase, which is mediated by ROS generation. This is the first study, to our knowledge, to reveal that lancemaside A isolated from the roots of C. lanceolata exerts antimetastatic activity through inhibition of MMP expression and cancer cell invasion via activation of the ROS-mediated p38 pathway.