Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear. AIM OF THE STUDY: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. MATERIALS AND METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

Cotransplantation of NSCs and ethyl stearate promotes synaptic plasticity in PD rats by Drd1/ERK/AP-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine views kidney shortage as a significant contributor to the aetiology of Parkinson's disease (PD), a neurodegenerative condition that is closely linked to aging. In clinical, patients with Parkinson's disease are often treated with Testudinis Carapax et Plastrum (Plastrum Testudinis, PT), a traditional Chinese medication that tonifies the kidney. Previous research has demonstrated that ethyl stearate (PubChem CID: 8122), an active component of Plastrum Testudinis Extracted with ethyl acetate (PTE), may encourage neural stem cells (NSCs) development into dopaminergic (DAergic) neurons. However, the effectiveness and mechanism of cotransplantation of ethyl stearate and NSCs in treating PD model rats still require further investigation. AIM OF THE STUDY: PD is a neurodegenerative condition marked by the loss and degradation of dopaminergic neurons in the substantia nigra of the midbrain. Synaptic damage is also a critical pathology in PD. Because of their self-renewal, minimal immunogenicity, and capacity to differentiate into dopaminergic (DAergic) neurons, NSCs are a prospective treatment option for Parkinson's disease cell transplantation therapy. However, encouraging transplanted NSCs to differentiate into dopaminergic neurons and enhancing synaptic plasticity in vivo remains a significant challenge in improving the efficacy of NSCs transplantation for PD. This investigation seeks to examine the efficacy of cotransplantation of NSCs and ethyl stearate in PD model rats and its mechanism related to synaptic plasticity. MATERIALS AND METHODS: On 6-hydroxydopamine-induced PD model rats, we performed NSCs transplantation therapy and cotransplantation therapy involving ethyl stearate and NSCs. Rotating behavior induced by apomorphine (APO) and pole climbing tests were used to evaluate behavioral changes. Using a variety of methods, including Western blotting (WB), immunofluorescence analysis, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction (qRT-PCR), we examined the function and potential molecular mechanisms of ethyl stearate in combined NSCs transplantation therapy. RESULTS: In the rat PD model, cotransplantation of ethyl stearate with NSCs dramatically reduced motor dysfunction, restored TH protein levels, and boosted dopamine levels in the striatum, according to our findings. Furthermore, the expression levels of SYN1 and PSD95, markers of synaptic plasticity, and BDNF, closely related to synaptic plasticity, were significantly increased. Cotransplantation with ethyl stearate and NSCs also increased the expression levels of Dopamine Receptor D1 (Drd1), an important receptor in the dopamine neural circuit, accompanied by an increase in MMP9 levels, ERK1/2 phosphorylation levels, and c-fos protein levels. CONCLUSIONS: According to the results of our investigation, cotransplantation of ethyl stearate and NSCs significantly improves the condition of PD model rats. We found that cotransplantation of ethyl stearate and NSCs may promote the expression of MMP9 by regulating the Drd1-ERK-AP-1 pathway, thus improving synaptic plasticity after NSCs transplantation. These findings provide new experimental support for the treatment of PD with the kidney tonifying Chinese medicine Plastrum Testudinis and suggest a potential therapeutic strategy for PD based on cotransplantation therapy.

Transcriptome analysis provides insights into coumarin biosynthesis in the medicinal plant Angelica dahurica cv. Yubaizhi.

Angelica dahurica roots have a long history of use in traditional Chinese medicine due to their high coumarin content. To address the increasing demand for these roots, a synthetic biology approach has been proposed. Nevertheless, our comprehension of coumarin biosynthesis and its regulation remains limited. In this study, we utilized Hiseq2500 sequencing to analyze the transcriptomes of A. dahurica at different growth stages while concurrently quantifying coumarin content. Differentially expressed gene (DEG) analysis was employed to identify key genes involved in coumarin and terpenoid backbone biosynthesis. Weighted gene co-expression network analysis (WGCNA) was applied to identify gene modules strongly associated with coumarin content, elucidating the regulatory relationships between transcription factors (TFs) and pathway genes. Furthermore, KEGG enrichment analysis was used to explore essential pathways governing coumarin biosynthesis, with the identification of hub genes. Our results indicated that total coumarin content was highest in the roots, followed by leaves and stems, across all three developmental stages. Transcriptome analysis identified a total of 92,478 genes, among which 215 and 30 genes were implicated in coumarin and terpenoid backbone biosynthesis, respectively. Within the 73 identified gene modules by WGCNA, three modules-namely aquamarine1 (comprising two OMTs, one CSE, one AACT, one HDS, two PSs, one 2OGO, four UGTs, and seven CYP450s), darkmagenta (containing one UGT and one HDR), and navajowhite2 (consisting of one HCT, three UGTs, one CYP71A25, one OMT, one CSE, one HDS, and one PT)-were strongly associated with imperatorin, oxypeucedanin, and isoimperatorin content, respectively. KEGG enrichment analysis highlighted significant enrichment of cytochrome P450, transporter, and ubiquitin system pathways. Moreover, TF-gene regulatory analysis unveiled the complexity of coumarin biosynthesis, with 17 TF families regulating 17 genes in the aquamarine1 module, 8 TF families regulating 2 genes in the darkmagenta module, and 8 TF families regulating 7 genes in the navajowhite2 module. These comprehensive findings provide valuable insights into coumarin biosynthesis in A. dahurica, facilitating future research and potential applications in traditional Chinese medicine and synthetic biology strategies.

A Synthetic External Control Study Comparing the Clinical Efficacy of Wendan Decoction and 19 Antidepressants.

BACKGROUND: Wendan decoction (WDD) has been used as a treatment for depression in China since the Tang Dynasty. However, high-quality evidence for this is lacking. This study proposed a novel synthetic external control method to evaluate its clinical efficacy. METHODS: We searched public databases for clinical trials of WDD for major depression. The rate of change of the Hamilton Depression Scale score from baseline was used as an efficacy indicator, and a model-based meta-analysis was performed to analyze the clinical efficacy of WDD. To establish a reference standard for efficacy, the antidepressant efficacy distributions of a placebo and 19 antidepressants were virtually synthesized based on the same conditions as the clinical trial characteristics of WDD. RESULTS: This study included 5 clinical trials with 177 participants. WDD showed a slow onset, with a time to reach the maximum effect of 9.71 weeks. At 8 weeks, the rate of change in the Hamilton Depression Scale score from baseline was 66.4% (95% CI = 62.3%-70.3%) in the WDD group. The pure effect value of WDD, after deducting the placebo effect, was 26.9% (95%CI = 23.0%-30.9%), which was comparable with 5 types of antidepressants and significantly higher than the others. CONCLUSION: The proposed external synthetic control method provides a solution to the bottleneck problem of clinical efficacy evaluation in real-world research on traditional Chinese medicine. WDD has high clinical development value for the treatment of depression, and large-scale randomized controlled trials are recommended to confirm its antidepressant effect.

Association of traditional Chinese medicine body constitution and cold syndrome with leukocyte mitochondrial functions: An observational study.

Body constitution in traditional Chinese medicine (TCM) refers to the holistic and relatively durable state of an individual, based on the qi and blood assessment, and TCM syndrome is defined as the theoretical abstraction of disease-symptom profiles. The biological basis as related to mitochondria, which produce most of the cellular energy, has not been well studied. This study aimed to elucidate the association of mitochondrial function with TCM body constitution and cold syndrome. Body constitution and cold syndrome in TCM were assessed using the Constitution in Chinese Medicine Questionnaire (CCMQ). The mitochondrial function of peripheral leukocytes was evaluated based on oxygen consumption rate (OCR) and enzyme activity; OCR reflects mitochondrial activity and the capacity to produce adenosine triphosphate (ATP). Cellular adenosine nucleotides and malondialdehyde levels were determined using high-performance liquid chromatography to assess the potential bioenergetic mechanisms. A total of 283 adults participated in this study. Leukocytes from subjects with a balanced constitution had higher OCRs than those with unbalanced constitutions. Yang deficiency and cold syndrome also demonstrated lower energy metabolism, as indicated by reduced basal metabolic rate and cellular levels of ATP and malondialdehyde. Decreased mitochondrial enzyme activity has been observed in individuals with the cold syndrome. Unbalanced body constitutions in TCM impair mitochondrial function in leukocytes, which may contribute to the high disease susceptibility. Cold syndrome is characterized by reduced mitochondrial mass, which may explain its symptoms of low-energy metabolism and cold intolerance.

Xuanfei Baidu Decoction suppresses complement overactivation and ameliorates IgG immune complex-induced acute lung injury by inhibiting JAK2/STAT3/SOCS3 and NF-κB signaling pathway.

BACKGROUND: The significant clinical efficacy of Xuanfei Baidu Decoction (XFBD) is proven in the treatment of patients with coronavirus disease 2019 (COVID-19) in China. However, the mechanisms of XFBD against acute lung injury (ALI) are still poorly understood. METHODS: In vivo, the mouse model of ALI was induced by IgG immune complexes (IgG-IC), and then XFBD (4g/kg, 8g/kg) were administered by gavage respectively. 24 h after inducing ALI, the lungs were collected for histological and molecular analysis. In vitro, alveolar macrophages inflammation models induced by IgG-IC were performed and treated with different dosage of XFBD-containing serum to investigate the protective role and molecular mechanisms of XFBD. RESULTS: The results revealed that XFBD mitigated lung injury and significantly downregulated the production of pro-inflammatory mediators in lung tissues and macrophages upon IgG-IC stimulation. Notably, XFBD attenuated C3a and C5a generation, inhibited the expression of C3aR and C5aR and suppressed the activation of JAK2/STAT3/SOCS3 and NF-κB signaling pathway in lung tissues and macrophages induced by IgG-IC. Moreover, in vitro experiments, we verified that Colivelin TFA (CAF, STAT3 activator) and C5a treatment markedly elevated the IgG-IC-triggered inflammatory responses in macrophages and XFBD weakened the effects of CAF or C5a. CONCLUSION: XFBD suppressed complement overactivation and ameliorated IgG immune complex-induced acute lung injury by inhibiting JAK2/STAT3/SOCS3 and NF-κB signaling pathway. These data contribute to understanding the mechanisms of XFBD in COVID-19 treatment.

Transperineal Botulinum Toxin Injection for Chronic Pelvic Pain Syndrome after Transurethral Resection of the Prostate.

PURPOSE: To evaluate the efficacy of botulinum toxin type A (BTX-A) injection in patients with chronic pelvic pain syndrome (CPPS) after transurethral resection of the prostate (TURP). MATERIALS AND METHODS: Six patients after TURP received the injection of BTX-A around the prostate capsule or pelvic floor under ultrasound guidance. The clinical outcomes including overall pain intensity (assessed by visual analog scale, VAS), the Functional Pelvic Pain scale (FPPS), and mental state by anxiety and depression questionnaires, the generalized anxiety disorder (GAD-7) and Hamilton depression rating scale (HAM-D)) were assessed at pre-treatment, and 1, 4, 12 weeks after treatment. RESULTS: Six male patients, aged 65 to 76 years were enrolled. The improvement of VAS pain score, the Functional Pelvic Pain scale, and mental assessment were observed at 1, 4, and 12 weeks after treatment for all six patients. All 6 patients had no safety concerns through 12 weeks visit, except 3 patients complained transient pain at injection site. CONCLUSION: Injection of BTX-A around the prostate under ultrasound guidance may be effective and safe for patients with CPPS after TURP.

The metabolic profile elucidation of Lonicera japonica flos water extract and the metabolic characteristics evaluation of bioactive compounds in human gastrointestinal tract in vitro.

Lonicera japonica Flos (LJF) is taken orally as a health food and medicinal plant in China for a long time. The gastrointestinal metabolism of LJF was investigated in vitro by three independent models (gastric juice, intestinal juice, and human intestinal bacteria), qualitative analyzed by UPLC-LTQ-Orbitrap-MSn and quantified by HPLC-DAD. 72 prototype compounds were detected in LJF water extraction (LJF-WE), including 14 organic acids, 43 iridoids, 14 flavonoids and one other compound. The prototype and metabolic components of LJF-WE bio-transformed by simulated gastric fluid (70 and 12), intestinal fluid (69 and 12) and human fecal bacteria (29 and 70) were characterized, respectively. The metabolites were formed through desaccharization, isomerization, hydrogenation, methylation, dehydration, and then cyclization, glucuronization and dimethylation followed. 8 bioactive compounds including neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, sweroside, secoxyloganin, isochlorogenic acid B, isochlorogenic acid A and isochlorogenic acid C were much stable in simulated gastric fluid and intestinal fluid, compared with human fecal bacteria. Especially, sweroside and secoxyloganin with glucoside bonds degradated extraordinarily fast, because of the abundant ß-glucosidases in human fecal bacteria.

Characterization of Various Subunit Combinations of ADP-Glucose Pyrophosphorylase in Duckweed (Landoltia punctata).

Background: Landoltia punctata can be used as renewable and sustainable biofuel feedstock because it can quickly accumulate high starch levels. ADP-glucose pyrophosphorylase (AGPase) catalyzes the first committed step during starch biosynthesis in higher plants. The heterotetrameric structure of plant AGPases comprises pairs of large subunits (LSs) and small subunits (SSs). Although several studies have reported on the high starch accumulation capacity of duckweed, no study has explored the underlying molecular accumulation mechanisms and their linkage with AGPase. Therefore, this study focused on characterizing the roles of different L. punctate AGPases. Methodology. Expression patterns of LpAGPs were determined through comparative transcriptome analyses, followed by coexpressing their coding sequences in Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana, and Nicotiana tabacum. Results: Comparative transcriptome analyses showed that there are five AGPase subunits encoding cDNAs in L. punctata (LpAGPS1, LpAGPS2, LpAGPL1, LpAGPL2, and LpAGPL3). Nutrient starvation (distilled water treatment) significantly upregulated the expression of LpAGPS1, LpAGPL2, and LpAGPL3. Coexpression of LpAGPSs and LpAGPLs in Escherichia coli generated six heterotetramers, but only four (LpAGPS1/LpAGPL3, LpAGPS2/LpAGPL1, LpAGPS2/LpAGPL2, and LpAGPS2/LpAGPL3) exhibited AGPase activities and displayed a brownish coloration upon exposure to iodine staining. Yeast two-hybrid and bimolecular fluorescence complementation (BiFC) assays validated the interactions between LpAGPS1/LpAGPL2, LpAGPS1/LpAGPL3, LpAGPS2/LpAGPL1, LpAGPS2/LpAGPL2, and LpAGPS2/LpAGPL3. All the five LpAGPs were fusion-expressed with hGFP in Arabidopsis protoplasts, and their green fluorescence signals were uniformly localized in the chloroplast, indicating that they are plastid proteins. Conclusions: This study uncovered the cDNA sequences, structures, subunit interactions, expression patterns, and subcellular localization of AGPase. Collectively, these findings provide new insights into the molecular mechanism of fast starch accumulation in L. punctata.

A triple combination strategy of UHPLC-MSn, hypolipidemic activity and transcriptome sequencing to unveil the hypolipidemic mechanism of Nelumbo nucifera alkaloids.

ETHNOPHARMACOLOGICAL RELEVANCE: Nelumbo nucifera (N. nucifera), a kind of edible Chinese herbal, has been studied in treating hyperlipidemia. However, the hypolipidemic mechanism of N. nucifera remains unknown. Aims of this review: We aimed to screen the effective constituent of N. nucifera alkaloids and elucidated the potential mechanism for treating hyperlipidemia. A triple combination strategy of UHPLC-MSn, hypolipidemic activity and transcriptome sequencing was built to unveil the hypolipidemic mechanism of Nelumbo nucifera alkaloid. MATERIALS AND METHODS: We comprehensively investigated the characterization of N. nucifera alkaloids by using UHPLC-LTQ-Orbitrap MSn. And the hypolipidemic activity of candidate active ingredients were evaluated on sodium oleate-induced HepG2 cell. Finally, O-nornuciferine and N. nucifera alkaloid extraction were analyzed by RNA sequence (RNA-seq) to decipher the underlying hypolipidemic mechanism and were verified by qRT-PCR. RESULTS: 35 compounds were identified from N. nucifera alkaloid extraction by UHPLC-LTQ-Orbitrap MSn. Among them, O-nornuciferine and N. nucifera alkaloid extraction which showed significant hypolipidemic activity were analyzed by transcriptome sequencing. After the intervention of O-nornuciferine and N. nucifera alkaloid extraction, 1 and 158 differentially expressed genes (DEGs) were identified, severally. The enrichment analysis indicated that the hypolipidemic effect was adjusted by the expression of numerous key DEGs involved in bile secretion, glycerolipid and sphingolipid metabolism, PPAR signaling pathway. CONCLUSIONS: O-nornuciferine and N. nucifera alkaloids had exibited significant effects in hyperlipidemia. The candidate genes were LDLR, LPL and ANGPTL4, etc. It was most likely that they adjusted lipid metabolism by modulating expression levels of various key factors which were involved in bile secretion, glycerolipid metabolism, sphingolipid metabolism and PPAR signaling pathway, and so on. This study clarified the hypolipidemic mechanism of the alkaloids in N. nucifera, and laid a foundation for the subsequent development of clinical application and better quality of N. nucifera.

Saikosaponin D Attenuates Pancreatic Injury Through Suppressing the Apoptosis of Acinar Cell via Modulation of the MAPK Signaling Pathway.

Chronic pancreatitis (CP) is a progressive fibro-inflammatory syndrome. The damage of acinar cells is the main cause of inflammation and the activation of pancreatic stellate cells (PSCs), which can thereby possibly further aggravate the apoptosis of more acinar cells. Saikosaponind (SSd), a major active ingredient derived from Chinese medicinal herb bupleurum falcatum, which exerted multiple pharmacological effects. However, it is not clear whether SSd protects pancreatic injury of CP via regulating the apoptosis of pancreatic acinar cells. This study systematically investigated the effect of SSd on pancreatic injury of CP in vivo and in vitro. The results revealed that SSd attenuate pancreatic damage, decrease the apoptosis and suppress the phosphorylation level of MAPK family proteins (JNK1/2, ERK1/2, and p38 MAPK) significantly in the pancreas of CP rats. In addition, SSd markedly reduced the apoptosis and inflammation of pancreatic acinar AR42J cells induced by cerulein, a drug induced CP, or Conditioned Medium from PSCs (PSCs-CM) or the combination of PSCs-CM and cerulein. Moreover, SSd significantly inhibited the activated phosphorylation of JNK1/2, ERK1/2, and p38 MAPK induced by cerulein or the combination of PSCs-CM and cerulein in AR42J cells. Furthermore, SSd treatment markedly decreased the protein levels of p-JNK and p-p38 MAPK caused by PSCs-CM alone. In conclusion, SSd ameliorated pancreatic injury, suppressed AR42J inflammation and apoptosis induced by cerulein, interrupted the effect of PSCs-CM on AR42J cells inflammation and apoptosis, possibly through MAPK pathway.

Chaihu Guizhi Ganjiang Decoction Ameliorates Pancreatic Fibrosis via JNK/mTOR Signaling Pathway.

Pancreatic fibrosis is a pathological characteristic of chronic pancreatitis (CP) and pancreatic cancer. Chaihu Guizhi Ganjiang Decoction (CGGD) is a traditional Chinese medicine, which is widely used in the clinical treatment of digestive diseases. However, the potential anti-fibrosis mechanism of CGGD in treating CP remains unclear. Here, we conducted a series of experiments to examine the effect of CGGD on the CP rat model and primary isolated pancreatic stellate cells (PSCs). The results revealed that CGGD attenuated pancreatic damage, decreased collagen deposition, and inhibited PSC activation in the pancreas of CP rats. However, compared with the CP group, CGGD had no effect on body weight and serum amylase and lipase. In addition, CGGD suppressed autophagy by downregulating Atg5, Beclin-1, and LC3B and facilitated phosphorylation of mTOR and JNK in pancreatic tissues and PSCs. Moreover, the CGGD-containing serum also decreased LC3B or collagen I expression after rapamycin (mTOR inhibitor) or SP600125 (JNK inhibitor) treatment in PSCs. In conclusion, CGGD attenuated pancreatic fibrosis and PSC activation, possibly by suppressing autophagy of PSCs through the JNK/mTOR signaling pathway.

Protective effect of plastrum testudinis extract on dopaminergic neurons in a Parkinson's disease model through DNMT1 nuclear translocation and SNCA's methylation.

The pathological characteristics of Parkinson's disease (PD) include dopaminergic neuron damage, specifically disorders caused by dopamine synthesis, in vivo. Plastrum testudinis extract (PTE) and its bioactive ingredient ethyl stearate (PubChem CID: 8122) were reported to be correlated with tyrosine hydroxylase (TH), which is a biomarker of dopaminergic neurons. This suggests that PTE and its small-molecule active ingredient ethyl stearate have potential for development as a therapeutic drug for PD. In this study, we treated 6-hydroxydopamine (6-OHDA)-induced model rats and PC12 cells with PTE. The mechanism of action of PTE and ethyl stearate was investigated by western blotting, bisulfite sequencing PCR (BSP), real-time PCR, immunofluorescence and siRNA transfection. PTE effectively upregulated the TH expression and downregulated the alpha-synuclein expression in both the substantia nigra and the striatum of the midbrain in a PD model rat. The PC12 cell model showed that both PTE and its active monomer ethyl stearate significantly promoted TH expression and blocked alpha-synuclein, agreeing with the in vivo results. BSP showed that PTE and ethyl stearate increased the methylation level of the Snca intron 1 region. These findings suggest that some of the protective effects of PTE on dopaminergic neurons are mediated by ethyl stearate. The mechanism of ethyl stearate may involve disrupting the abnormal aggregation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) with alpha-synuclein by releasing DNMT1, upregulating Snca intron 1 CpG island methylation, and ultimately, reducing the expression of alpha-synuclein.

Combined pulsed-dye laser and medical therapy for treatment of cutaneous sarcoidosis lesions: a case report.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that most frequently occurs in the lungs. However, cutaneous lesions are often the primary sign. Cutaneous sarcoidosis is difficult to treat, although different therapies have been applied. We herein report a case in which cutaneous sarcoidosis was treated with pulsed-dye laser (PDL) therapy along with oral administration of acitretin and hydroxychloroquine; no topical medications were applied. All patient details are de-identified. The treatment areas gradually improved after several courses of PDL therapy. This case illustrates that PDL therapy can serve as an auxiliary treatment for cutaneous sarcoidosis.

Effects of total flavonoids from Eucommia ulmoides Oliv. leaves on polycystic ovary syndrome with insulin resistance model rats induced by letrozole combined with a high-fat diet.

ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv. leaves are the dry leaves of Eucommia ulmoides Oliv. Modern studies have shown that Eucommia ulmoides Oliv. leaves and its extracts have many pharmacological effects, such as regulating hypothalamus pituitary ovary (HPO) axis function, estrogen like effects, correcting insulin resistance (IR), regulating lipids, and reducing weight, which are consistent with the clinical manifestations in polycystic ovary syndrome (PCOS) patients. PCOS patients often have HPO axis disorder, low estrogen, high androgen, high IR complication rate, and obesity. Previous preclinical studies have shown that total flavonoids from Eucommia ulmoides Oliv. leaves (TFEL) can improve the imbalance in sex hormone secretion in perimenopausal animal models by regulating the function of the HPO axis. Thus, it is important to understand if flavonoids are the active parts of Eucommia ulmoides Oliv. leaves that interfere with polycystic ovary syndrome with insulin resistance (PCOS-IR), and determine the regulatory role they play in sex hormones and IR? AIM OF THE STUDY: Investigate the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway in the ovary and kisspeptin/insulin like growth factor/leptin receptor1/androgen receptor (Kiss1/IGF-1/LEPR/AR) in the HPO axis to determine the mechanism of TFEL intervention in a rat model of PCOS-IR model rats. MATERIALS AND METHODS: A rat model of PCOS-IR was established using a high-fat diet (49 d) combined with letrozole (1 mg/kg·d, for 28 d). Then, metformin (300 mg/kg·d) and TFEL (220 mg/kg·d, 110 mg/kg·d, and 55 mg/kg·d) were administered continuously for 21 days. At the end of the experiment, samples were taken and the related indexes were measured. RESULTS: TFEL reduced the body weight, Lee's index, ovarian index, ovarian area and ovarian volume, increased serum E2, SHBG levels and ISI, decreased serum levels of T, LEP, INS, and FBG (whole blood), and reduced the HOMA-IR in rats with PCOS-IR. TFEL downregulate Kiss1, IGF-1, and AR in the arcuate nucleus of hypothalamus, and upregulate Kiss1, downregulate IGF-1 and AR in the pituitary gland, and upregulate Kiss1, downregulate IGF-1, LEPR, and AR in the ovary of rats with PCOS-IR. TFEL could downregulate p-IRS-1Ser307, upregulate IRS-1, p-IRS-1Tyr895, PI3Kp85α, p-PI3Kp85α, AKT, p-AKT, and GLUT4 in the ovary, and ameliorated histopathological changes in the ovary and pancreas of rats with PCOS-IR. CONCLUSION: TFEL can inhibit ovarian hyperplasia, regulate disorders of glucose and lipid metabolism and improve the secretion of sex hormones, by regulating the expression of PI3K/AKT signaling pathway-related proteins in the ovary and Kiss1/IGF-1/LEPR/AR in the HPO axis.

Exploring the Biochemical Basis of the Meridian Tropism Theory for the Qi-Invigorating Traditional Chinese Medicine Herb Panax ginseng.

We examined the effect of the Qi-invigorating Traditional Chinese Medicines (TCM) herb Panax ginseng (P.G.) on mitochondrial functions and cellular antioxidant capacity in different organs of mice. We found that the P.G. extracts had a significant effect on tissues of mice, with the generation of total adenylate pool (TAP) enhanced in all visceral tissues, but not for the brain. The mitochondrial membrane potential (MMP) and antioxidant capacity reflected by superoxide dismutase (SOD) and glutathione (GSH) increased only for the meridian tissues that P.G. belongs to including Heart, Spleen and Lung. Reactive oxygen species (ROS), as a combined result of the increased energy metabolism and antioxidant capacity, varied in different organs. We concluded that: 1) the Qi-invigorating TCM herb P.G. had a significant effect on mice by enhancing TAP production in all of the visceral tissues examined, except for the brain; 2) for the meridional tissues of P.G. (Heart, Spleen and Lung), the P.G. extracts not only promoted the TAP production, but also boosted the antioxidant capacity demonstrated by the simultaneous increase in TAP, and SOD and GSH.

Phenotypic and genetic variation in phosphorus-deficiency-tolerance traits in Chinese wheat landraces.

BACKGROUND: Phosphorus deficiency is a major limiting factors for affecting crop production globally. To understand the genetic variation of phosphorus-deficiency-tolerance, a total of 15 seedling traits were evaluated among 707 Chinese wheat landraces under application of phosphorus (AP) and non-application of phosphorus (NP). A total of 18,594 single-nucleotide polymorphisms and 38,678 diversity arrays technology sequencing markers were used to detect marker-trait associations under AP and NP. RESULTS: Top ten genotypes with extremely tolerance and bottommost ten genotypes with extremely sensitivity were selected from 707 Chinese wheat landraces for future breeding and genetic analysis. A total of 55 significant markers (81 marker-trait associations) for 13 traits by both CMLM and SUPER method. These were distributed on chromosomes 1A, 1B, 2A, 2B, 2D, 3A, 4B, 5A, 5B, 6A, 6B, 6D, 7A and 7B. Considering the linkage disequilibrium decay distance, 25 and 12 quantitative trait loci (QTL) were detected under AP and NP, respectively (9 QTL were specific to NP). CONCLUSIONS: The extremely tolerant landraces could be used for breeding phosphorus-deficiency-tolerant cultivars. The QTL could be useful in wheat breeding through marker-assisted selection. Our findings provide new insight into the genetic analysis of P-deficiency-tolerance, and will be helpful for breeding P-deficiency-tolerant cultivars.

The response-time relationship and covariate effects of acupuncture for chronic pain: A systematic review and model-based longitudinal meta-analysis.

BACKGROUND AND OBJECTIVE: Critical clinical questions regarding how soon and how long the analgesic effect will be achieved by acupuncture, as well as who will be responsive to acupuncture, need further address. The aim of the study was to investigate the response-time relationship and covariate effects of acupuncture. DATABASES AND DATA TREATMENT: PubMed and EMBASE were searched up to December 2018 for randomized controlled trials that involved sham acupuncture, true acupuncture and conventional therapy. We used a model-based longitudinal meta-analysis to characterize the response-time profile of these treatments. RESULTS: Seventy-seven randomized clinical trials involved chronic shoulder, neck, knee and low back pain were included. The response-time analysis suggested that the treatment duration of acupuncture will be 5 weeks or more to achieve 80% of maximum analgesic effect. Moreover a lower baseline pain intensity and the location of low back pain resulted in a lower pain relief of acupuncture intervention. The absolute maximum analgesic effects of sham acupuncture and conventional therapy were 22.6 and 15.8 points at a 0-100 NRS scale. The absolute effect of true acupuncture was 26.1 points for low back pain (relative effect of 3.5 and 9.4 points to sham and conventional therapy), 34.9 points for other pain body locations (relative effect of 12.3 and 19.1 points to sham and conventional therapy), in patients with a baseline pain intensity of 60 points. CONCLUSION: The treatment duration of acupuncture will not be less than 5 weeks to achieve 80% maximum analgesic effect. Higher analgesic effect was related to higher baseline pain intensity and pain location of neck, shoulder and knee. SIGNIFICANCE: Our systematic review and meta-analysis provides the clear evidence for the treatment duration and significant related covariates of acupuncture intervention for chronic pain. These results provide useful suggestion for acupuncture intervention in clinical pain management.

Plastrum Testudinis Extracts Promote NSC Differentiation into Dopaminergic Neuron by Regulating the Interaction of TET1 and FoxA2.

In recent years, stem cells have gained much attention for the treatment of neurodegenerative diseases. However, inducing neural stem cell directionally differentiation is a difficult problem in the treatment of Parkinson's disease (PD) by stem cell therapy. Plastrum Testudinis (PT) can enhance the number of TH-positive neurons in the PD rat brain substantia nigra, but the underlying mechanism has not been clarified. Here, we aimed at further investigating the mechanism by which PT can promote NSC differentiation into dopaminergic neurons. A rat model of PD was used for detecting the effect of PT on the rat brain substantia nigra in vivo. The results showed the expressions of tyrosine hydroxylase (TH) and TET1 enzyme were increased after treatment with PT. Consequently, Plastrum Testudinis extracts (PTEs) were used for inducing NSC differentiation into dopaminergic neurons ex vivo. During differentiation of NSCs induced by PTE, TH expression was increased, with a concomitant increase in both TET1 and FoxA2. Next, we performed coimmunoprecipitation analysis to examine the interaction between TET1 protein and FoxA2 protein. Our results show that PTE can increase the binding rate of TET1 and FoxA2. Thus, our findings show that PTE can increase the efficiency of NSCs to directionally differentiate into dopaminergic neurons and provide experimental evidence for PT in the treatment of Parkinson's disease.

Analysis of Centranthera grandiflora Benth Transcriptome Explores Genes of Catalpol, Acteoside and Azafrin Biosynthesis.

Cardiovascular diseases (CVDs) are a major cause of health loss in the world. Prevention and treatment of this disease by traditional Chinese medicine is a promising method. Centranthera grandiflora Benth is a high-value medicinal herb in the prevention and treatment of CVDs; its main medicinal components include iridoid glycosides, phenylethanoid glycosides, and azafrin in roots. However, biosynthetic pathways of these components and their regulatory mechanisms are unknown. Furthermore, there are no genomic resources of this herb. In this article, we provide sequence and transcript abundance data for the root, stem, and leaf transcriptome of C. grandiflora Benth obtained by the Illumina Hiseq2000. More than 438 million clean reads were obtained from root, stem, and leaf libraries, which produced 153,198 unigenes. Based on databases annotation, a total of 557, 213, and 161 unigenes were annotated to catalpol, acteoside, and azafrin biosynthetic pathways, respectively. Differentially expressed gene analysis identified 14,875 unigenes differentially enriched between leaf and root with 8,054 upregulated genes and 6,821 downregulated genes. Candidate MYB transcription factors involved in catalpol, acteoside, and azafrin biosynthesis were also predicated. This work is the first transcriptome analysis in C. grandiflora Benth which will aid the deciphering of biosynthesis pathways and regulatory mechanisms of active components.