Development of a Machine Learning Algorithm for Drug Screening Analysis on High-Resolution UPLC-MSE/QTOF Mass Spectrometry.

BACKGROUND: Ultra-performance liquid chromatography (UPLC)-MSE/quadrupole time-of-flight (QTOF) high-resolution mass spectrometry employs untargeted, data-independent acquisition in a dual mode that simultaneously collects precursor ions and product ions at low and ramped collision energies, respectively. However, algorithmic analysis of large-scale multivariate data of comprehensive drug screening as well as the positivity criteria of drug identification have not been systematically investigated. It is also unclear whether ion ratio (IR), the intensity ratio of a defined product ion divided by the precursor ion, is a stable parameter that can be incorporated into the MSE/QTOF data analysis algorithm. METHODS: IR of 91 drugs were experimentally determined and variation of IR was investigated across 5 concentrations measured on 3 different days. A data-driven machine learning approach was employed to develop multivariate linear regression (MLR) models incorporating mass error, retention time, number of detected fragment ions and IR, accuracy of isotope abundance, and peak response using drug-supplemented urine samples. Performance of the models was evaluated in an independent data set of unknown clinical urine samples in comparison with the results of manual analysis. RESULTS: IR of most compounds acquired by MSE/QTOF were low and concentration-dependent (i.e., IR increased at higher concentrations). We developed an MLR model with composite score outputs incorporating 7 parameters to predict positive drug identification. The model achieved a mean accuracy of 89.38% in the validation set and 87.92% agreement in the test set. CONCLUSIONS: The MLR model incorporating all contributing parameters can serve as a decision-support tool to facilitate objective drug identification using UPLC-MSE/QTOF.

[Progress in the study of antiviral activity of cepharanthine against SARS-CoV-2].

As a member of the dibenzyl isoquinoline alkaloid family, cepharathine is an alkaloid from the traditional Chinese medicine cepharathine, which is mainly used for treatment of leukopenia and other diseases. Recent studies of the inhibitory effect of cepharathine against SARS-CoV-2 have attracted widespread attention and aroused heated discussion. As the original discoverer of the anti-SARS-CoV-2 activity of cepharanthine, here we briefly summarize the discovery of cepharanthine and review important progress in relevant studies concerning the discovery and validation of anti-SARS-CoV-2 activity of cepharathine, its antiviral mechanisms and clinical trials of its applications in COVID-19 therapy.

Traditional Chinese medicine reverses cancer multidrug resistance and its mechanism.

Chemotherapy is one of the most commonly used clinical treatments among the currently available cancer therapies. However, the phenomenon of Multidrug resistance (MDR) has become a challenge in the treatment process, weakening the impact of chemotherapy. Extensive research on elucidating the development of cancer MDR has identified the following mechanisms that play a critical role in the development of several MDR reversal agents: abnormal expression of cell membrane transporters, adaptation of cancer cells to the microenvironment, regulation of hypoxia, repair of DNA damage and reduction of apoptosis, the enhancement of the EMT process, the existence of cancer stem cells (CSCs), and the abnormal activation of key signaling pathways. However, they failed to demonstrate significant efficacy due to severe side effects during their clinical trials. Traditional Chinese medicines (TCMs) are known to play an important anti-cancer role since they have low toxicity, high efficacy, and safety and can reverse MDR. TCMs reversal agents can be divided into Chinese medicine monomers, synthetic monomers, analogs, or derivatives. Several studies have shown that TCMs can effectively overcome cancer MDR and can be effectively used for treating cancer patients.

Intervention effect of Potentilla discolor-Euonymus alatus on intestinal flora of type 2 diabetes mellitus rats.

OBJECTIVE: With this study, we aimed at exploring the regulation mechanism of Potentilla discolor-Euonymus alatus on intestinal flora of T2DM (Type 2 Diabetes Mellitus) rats induced by high-fat diet combined with streptozotocin. MATERIALS AND METHODS: T2DM rats were induced by high-fat diet combined with streptozotocin. There were normal control group, model group, metformin group, high-dose Chinese medicine group and low-dose Chinese medicine group. Each group included 10 rats. Normal control group: normal feeding, no modeling, ordinary feed, and gavage of 0.9% normal saline. Model group: T2DM rats, high-fat diet, and gavage of 0.9% normal saline. Metformin group: T2DM rats, high-fat diet and fed with metformin solution. High-dose Chinese medicine group: T2DM rats, high-fat diet, and gavage of concentrated Chinese medicine at a dose of 6 times the clinical dose. Low-dose Chinese medicine group: T2DM rats, high-fat diet, and gavage of concentrated Chinese medicine at a dose twice the clinical dose. The general situation of T2DM rats was observed, and the changes of intestinal flora were observed with 16SrDNA sequencing. RESULTS: The T2DM rats induced by high-fat diet combined with streptozotocin were molded. After intervention, at the class level, the ratio of γ-proteobacteria was 22.30% in the model group, 11.97% in the metformin group, 3.24% in the high-dose Chinese herbs group and 1.72% in the low-dose Chinese herbs group; the ratio of Erysipelothrix insidiosa was 4.73% in the model group, 4.68% in the metformin group, 3.93% in the high-dose Chinese herbsgroup and 2.92% in the low dose group; the ratio of Lactinobacillus was 2.30% in the model group, 0.01% in the metformin group, 0.00% in the high-dose Chinese herbs group, and 0.00% low-dose Chinese herbs group; at the portal level, the Firmicutes/Bacteroides was 0.88 in the normal control group, 3.40 in the model group, 1.71 in the metformin group, 2.74 in high-dose Chinese medicine group, and 1.34 in low-dose Chinese medicine group; at the genus level, the relative abundance of Lactobacillus in the model group was 3.28%, that of Akkermansia was 1.99%, that of Shigella coli was 22.08%, and that of Vibrio phaseus was 7.67%. All of them were improved after the intervention of metformin and traditional Chinese medicine. CONCLUSIONS: Potentilla discolor-Euonymus Alatus could improve the composition and structure of intestinal flora in T2DM rats and regulate the diversity of intestinal flora. The ratio of Firmicutes/Bacteroidetes was adjusted, mainly to increase the number of Bacteroides; the flora related to intestinal barrier was adjusted, mainly to increase the number of Lactobacillus and Akkermansia bacteria.

[Research advances in the relationship of dietary factors and prostate cancer risk].

Prostate cancer is the second most common malignancy in men worldwide. An increasing trend for prostate cancer incidence was observed in China. Enormous studies have been conducted to investigate the association between dietary factors and prostate cancer, however conflicted results were obtained. Red meat, processed meat, and dairy products consumption were reported to be associated with the increased prostate cancer risk, while tomatoes, soybeans and green tea might reduce the risk of prostate cancer occurance. However, no consensus could be reached without strong evidence. Furthermore, further studies are needed to investigate the association between vitamin and mineral supplements and prostate cancer risk. Some studies reported that men with higher dietary inflammatory index scores increased prostate cancer risk. There may be a long susceptible period when dietary factors affect prostate cancer risk, which poses challenges for collecting exposure and the follow-up. Measure bias and detection bias are the main reasons which impair the authenticity of studies on the relationship of dietary factors and prostate cancer risk. Researchers should apply various methods to measure participants' dietary consumption levels and ascertain essential outcomes, such as prostate cancer death. This article reviews updated epidemiological evidences on the association of dietary factors and prostate cancer, aims to benefit future nutritional epidemiology studies focus on the prostate cancer prevention.

Effects of l-carnitine in the distillers dried grains with solubles diet of sows on reproductive performance and antioxidant status of sows and their offspring.

Distillers dried grains with solubles (DDGS) are highly susceptible to lipid oxidation because DDGS contain about 10% crude fat, which is largely composed of polyunsaturated fatty acids. l-carnitine serves an important function in fatty acids ß-oxidation, and also has antioxidant properties. The objective of this study was to examine the effects of l-carnitine in the DDGS diet of gestating and lactating sows on reproductive performance, milk composition and antioxidant status of sows and their offspring. One hundred and twenty sows (Landrace×Large white, mean parity 4.2, initial BW 230 kg) were randomly allotted to 1 of 4 dietary treatments (n=30 sows/treatment). Treatments were arranged as a 2×2 factorial with two levels of dietary DDGS (0 v. 250 g/kg in gestating diets and 400 g/kg in lactating diets) and two levels of dietary l-carnitine (0 v. 100 mg/kg in gestating diets and 0 v. 200 mg/kg in lactating diets). Distillers dried grains with solubles had no significant effect on litter size but significantly reduced the birth weights and weaning weights of piglets (P0.05). Supplementing the diets with l-carnitine had no significant effect of total litter size (P>0.05) but increased the number of piglets born alive and piglets weaned, birth weight and weaning weight of piglets and litter weight at birth and weaning (P<0.05). l-carnitine supplementation also increased the concentration of l-carnitine in milk and l-carnitine status of piglets (P<0.05). The antioxidant enzyme activities of new born and weaning piglets were increased (P<0.05) by maternal dietary l-carnitine but this did not extend to finishing pigs. In conclusion, including DDGS in the sows diet could induce oxidative stress, which may be associated with the reduced individual birth and weaning weight of piglets. Dietary l-carnitine supplementation improved the antioxidant and l-carnitine status of sows, which may be associated with the improved reproduction and piglet performance and the antioxidant status of piglets at birth and weaning. There were no interactions between DDGS and l-carnitine.

Danshen (Salvia miltiorrhiza) protects ovariectomized rats fed with high-saturated fat-sucrose diet from bone loss.

Dietary patterns may interfere with the efficacy of herbal intervention. Our results demonstrated the protective effects of Salvia miltiorrhiza aqueous extract (SMA) on bone metabolism were influenced by levels of dietary fat and sucrose in ovariectomized (OVX) rats through its actions on attenuating lipid deposition and oxidative stress in rats. INTRODUCTION: Salvia miltiorrhiza (SM), also known as Danshen, has been tested as an osteoporosis treatment in a series of small, short human trials that generally report improvements in bone property. However, dietary patterns may interfere with the effects of herbal intervention. We hypothesized that dietary fat and sucrose levels could influence the effects of SM supplementation on bone in estrogen-deficient animals. METHODS: Six-month-old Sprague-Dawley sham or OVX rats were fed either a low-saturated fat-sucrose (LFS, a diet that was similar in composition to normal rat chow) or a high-fat-sucrose (HFS) diet and OVX rats were treated (8 rats/group) with SM aqueous extract (SMA, 600 mg/kg/day), 17ß-estradiol (1 mg/kg/day), or vehicle for 12 weeks. RESULTS: SMA significantly improved bone properties as revealed by the increase in trabecular bone mineral density and decrease in trabecular separation at proximal metaphysis of the tibia (PT) in HFS-fed OVX rats, but not in LFS-fed OVX rats. SMA greatly reduced lipid deposition and malondialdehyde levels, improved the activities of superoxide dismutase, catalase, and glutathione peroxidase in the livers of HFS-fed OVX rats. SMA could directly improve the proliferation and differentiation in vitro in an H2O2-induced preosteoblast cell model by attenuating cellular reactive oxygen species levels. CONCLUSIONS: The protective effects of SMA on bone metabolism were influenced by dietary fat and sucrose levels in OVX rats. The ability of SMA to reduce bone loss in HFS-fed OVX rats was associated with the attenuation of lipid deposition and oxidative stress levels.

Research gaps in the management and prevention of cutaneous squamous cell carcinoma in organ transplant recipients.

Although tremendous progress has been made in recent years in skin cancer care for organ transplant recipients, significant gaps remain in data-driven clinical guidelines, particularly for the treatment and prevention of cutaneous squamous cell carcinoma (cSCC), the most common malignancy among this population. In this review, we aim to summarize current knowledge around the management of cSCC and highlight the most significant gaps in knowledge that continue to pose challenges in the delivery of skin cancer care for organ transplant recipients. We suggest future directions for research that will bridge existing gaps and establish evidence-driven guidelines for primary prevention, screening and treatment of cSCC in this high-risk patient population.

Sirt1 mediates improvement in cognitive defects induced by focal cerebral ischemia following hyperbaric oxygen preconditioning in rats.

Hyperbaric oxygen preconditioning (HBO-PC) has been proposed as a safe and practical approach for neuroprotection in ischemic stroke. However, it is not known whether HPO-PC can improve cognitive deficits induced by cerebral ischemia, and the mechanistic basis for any beneficial effects remains unclear. We addressed this in the present study using rats subjected to middle cerebral artery occlusion (MCAO) as an ischemic stroke model following HBO-PC. Cognitive function and expression of phosphorylated neurofilament heavy polypeptide (pNF-H) and doublecortin (DCX) in the hippocampus were evaluated 14 days after reperfusion and after short interfering RNA-mediated knockdown of sirtuin1 (Sirt1). HBO-PC increased pNF-H and DCX expression and mitigated cognitive deficits in MCAO rats. However, these effects were abolished by Sirt1 knockdown. Our results suggest that HBO-PC can protect the brain from injury caused by ischemia-reperfusion and that Sirt1 is a potential molecular target for therapeutic approaches designed to minimize cognitive deficits caused by cerebral ischemia.

DNMT3A-mediated down-regulation of microRNA-105 promotes gastric cancer cell proliferation.

OBJECTIVE: It has been well-established that microRNAs (miRNAs), a class of short non-coding RNA molecules, play an important role in the development of gastric cancer. In the present study, we focused on miR-105, a novel miRNA not previously linked to gastric cancer. PATIENTS AND METHODS: 36 paired surgically resected gastric cancer tissues and matched adjacent normal tissues were used to detect the expression of miR-105. AGS cells were used to overexpress or silence of miR-105 and to determine its effect on several tumorigenic properties. A cell proliferation enzyme-linked immunosorbent assay was used to analyze the incorporation of BrdU during DNA synthesis of AGS cells. Total cDNA from AGS cells was used to amplify the 3'-UTR of YY1 by PCR and luciferase activity was determined using the Dual-Luciferase Reporter Assay System RESULTS: We found that expression of miR-105 was reduced in gastric cancer tissues, compared with adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-105 suppressed, whereas its inhibition promoted cell viability and proliferation. We further identified Yin Yang 1 (YY1) as a direct target of miR-105, by which miR-105 exerted its anti-proliferative role. Moreover, we found that DNMT3A was responsible for the down-regulation of miR-105 in gastric cancer cells. CONCLUSIONS: Our data demonstrate that miR-105 inhibits gastric cancer cell proliferation and progression, which might provide a therapeutical target for cancer therapy.

Dietary supplementation with glutamine and γ-aminobutyric acid improves growth performance and serum parameters in 22- to 35-day-old broilers exposed to hot environment.

This study was designed using 360 21-day-old chicks to determine the influences of diet supplementation with glutamine (5 g/kg), γ-aminobutyric acid (GABA, 100 mg/kg) or their combinations on performance and serum parameters exposed to cycling high temperatures. From 22 to 35 days, the experimental groups (2 × 2) were subjected to circular heat stress by exposing them to 30-34 °C cycling, while the positive control group was exposed to 23 °C constant. The blood of broilers was collected to detect serum parameters on days 28 and 35. Compared with the positive control group, the cycling high temperature decreased (p < 0.05) the feed consumption, weight gain and serum total protein (TP), glucose, thyroxine (T4), insulin, alkaline phosphatase (ALP), glutamine, GABA and glutamate levels, while increased (p < 0.05) the serum triglyceride (TG), corticosterone (CS), glucagon (GN), creatine kinase (CK), glutamic oxaloacetic transaminase (GOT), nitric oxide synthase (NOS), glutamate pyruvate transaminase (GPT) and lactate dehydrogenase (LDH) levels during 22-35 days. However, dietary glutamine (5 g/kg) increased (p < 0.05) the feed consumption, weight gain and serum levels of glutamine, TP, insulin and ALP, but decreased (p < 0.05) the serum TG, CK, GOT, NOS and GPT levels. Diet supplemented with GABA also increased (p < 0.05) weight gain and the serum levels of TP, T4, ALP, GABA and glutamine. In addition, the significant interactions (p < 0.05) between glutamine and GABA were found in the feed consumption, weight gain and the serum ALP, CK, LDH, GABA, T3 and T4 levels of heat-stressed chickens. This research indicated that dietary glutamine and GABA improved the antistress ability in performance and serum parameters of broilers under hot environment.

Is acupuncture no more than a placebo? Extensive discussion required about possible bias.

Numerous randomized controlled trials (RCTs) of acupuncture have been conducted in recent years. The results of several studies implied that acupuncture was only a powerful placebo; however, certain studies demonstrated that verum acupuncture had a greater effect than placebo and the mechanisms between a verum acupuncture group and a placebo/sham group were different. Researchers attempted to investigate the inherent factors that may potentially influence the results of trials. Certain problems observed in acupuncture RCTs also occurred in RCTs in other fields, including insufficient sample size, high dropout rates, inadequate follow-up and randomization. The study of acupuncture is so complex that specific methodological challenges are raised, which are frequently overlooked, including sham interventions, blinding, powerful placebo effects (even stronger than an inert pill) and variations in acupuncture administration. The aforementioned problems may contribute to bias, and researchers systematically attempt to solve these problems. The present review aimed to suggest techniques to design high-quality studies, minimize the placebo effect and optimize acupuncture administration in acupuncture studies. If these problems are addressed, then the results of acupuncture studies may be different.

Effect of curcumin on p38MAPK expression in DSS-induced murine ulcerative colitis.

The aim of this study was to determine the therapeutic effect of curcumin on dextran sulfate sodium-induced ulcerative colitis (UC) and to explore the related mechanism. Sixty mice were randomly divided into 6 groups. A group was the normal control group; B group was the model group; C group was the 1.5 mg/kg dexamethasone group based on the B group; and D, E and F groups were 15, 30, and 60 mg/kg curcumin groups, respectively, based on the B group. The mice were killed 7 days after treatment; the expression of TNF-α and MPO in colon tissue was determined with ELISA, and colon p-p38MAPK and p38MAPK mRNA expression was evaluated by immunohistochemistry and RT-PCR, respectively. In the C, D, E, and F groups, TNF-α and MPO levels significantly decreased (P < 0.05), and the expression of p-p38MAPK also significantly decreased (P < 0.01). The expression of p38MAPK mRNA in the C, D, E, and F groups decreased (P < 0.01), and there was a statistically significant difference between the E and F groups (P < 0.01). Curcumin had a therapeutic effect, which probably played a role in UC treatment by inhibiting the p38MAPK signaling pathway, thereby reducing the release of TNF-α.

Comparison of intensity-dependent inhibition of spinal wide-dynamic range neurons by dorsal column and peripheral nerve stimulation in a rat model of neuropathic pain.

BACKGROUND: Spinal cord stimulation (SCS) and peripheral nerve stimulation (PNS) are thought to reduce pain by activating a sufficient number of large myelinated (Aß) fibres, which in turn initiate spinal segmental mechanisms of analgesia. However, the volume of neuronal activity and how this activity is associated with different treatment targets is unclear under neuropathic pain conditions. METHODS: We sought to delineate the intensity-dependent mechanisms of SCS and PNS analgesia by in vivo extracellular recordings from spinal wide-dynamic range neurons in nerve-injured rats. To mimic therapeutic SCS and PNS, we used bipolar needle electrodes and platinum hook electrodes to stimulate the dorsal column and the tibial nerve, respectively. Compound action potentials were recorded to calibrate the amplitude of conditioning stimulation required to activate A-fibres and thus titrate the volume of activation. RESULTS: Dorsal column stimulation (50 Hz, five intensities) inhibited the windup (a short form of neuronal sensitization) and the C-component response of wide-dynamic range neurons to graded intracutaneous electrical stimuli in an intensity-dependent manner. Tibial nerve stimulation (50 Hz, three intensities) also suppressed the windup in an intensity-dependent fashion but did not affect the acute C-component response. CONCLUSIONS: SCS and PNS may offer similar inhibition of short-term neuronal sensitization. However, only SCS attenuates spinal transmission of acute noxious inputs under neuropathic pain conditions. Our findings begin to differentiate peripheral from spinal-targeted neuromodulation therapies and may help to select the best stimulation target and optimum therapeutic intensity for pain treatment.

Identification of phosphorylase kinase as a novel therapeutic target through high-throughput screening for anti-angiogenesis compounds in zebrafish.

Angiogenesis is essential for development and tumor progression. With the aim of identifying new compound inhibitors of the angiogenesis process, we used an established enhanced green fluorescent protein-transgenic zebrafish line to develop an automated assay that enables high-throughput screening of compound libraries in a whole-organism setting. Using this system, we have identified novel kinase inhibitor compounds that show anti-angiogenic properties in both zebrafish in-vivo system and in human endothelial cell in-vitro angiogenesis models. Furthermore, we have determined the kinase target of these compounds and have identified and validated a previously uncharacterized involvement of phosphorylase kinase subunit G1 (PhKG1) in angiogenesis in vivo. In addition, we have found that PhKG1 is upregulated in human tumor samples and that aberrations in gene copy number of PhK subunits are a common feature of human tumors. Our results provide a novel insight into the angiogenesis process, as well as identify new potential targets for anti-angiogenic therapies.

Compound Astragalus and Salvia miltiorrhiza extract inhibits cell proliferation, invasion and collagen synthesis in keloid fibroblasts by mediating transforming growth factor-ß / Smad pathway.

BACKGROUND: The transforming growth factor (TGF)-ß/Smad pathway plays a key role in keloid development. We have previously demonstrated that compound Astragalus and Salvia miltiorrhiza extract (CASE) inhibits liver fibrosis and reduces invasion capacity of HepG2 cells by mediating the TGF-ß/Smad pathway. We therefore hypothesize that CASE may also exert antifibrotic effects in keloids by mediating the TGF-ß/Smad pathway. OBJECTIVES: To investigate the effects of CASE on cell proliferation, invasion and collagen synthesis in keloid fibroblasts, and to explore the effects of CASE on the TGF-ß/Smad signal pathway in order to elucidate its mechanisms of action. METHODS: The inhibitory effects of CASE on keloid fibroblasts were evaluated. Cell proliferation was studied by MTT assay; cell invasion was observed utilizing Transwell invasion chambers; and collagen synthesis in keloid fibroblasts was measured by (3) H-proline incorporation assay. Expression of proteins induced by TGF-ß1 and their intracellular localization in keloid fibroblasts were investigated by Western blot and immunofluorescence, respectively. Plasminogen activator inhibitor-1 (PAI-1) transcriptional activity was measured by real-time reverse transcription-polymerase chain reaction. RESULTS: CASE significantly inhibited cell proliferation induced by newborn bovine serum as well as collagen synthesis and cell invasion induced by TGF-ß1 in keloid fibroblasts, while it showed weak effects on normal fibroblasts. The phosphorylation of Smad2/3 was markedly reduced by CASE treatment, while CASE exhibited stronger inhibitory effects on linker region phosphorylation (pSmad2L and pSmad3L) compared with effects on C-terminal region phosphorylation (pSmad2C and pSmad3C). In addition, CASE blocked formation of Smad2/3/4 complexes and their nuclear translocation, but upregulated Smad7 expression in a dose-dependent manner. PAI-1 mRNA and protein levels were also suppressed by CASE treatment. CONCLUSIONS: These results suggest that CASE exhibits inhibitory effects on cell proliferation, invasion and collagen synthesis in keloid fibroblasts, and its mechanisms of action may involve the TGF-ß/Smad pathway.

Influence of angiotensin-converting enzyme insertion/deletion polymorphism on nitric oxide production in hypertensives and hypercholesterolaemics.

UNLABELLED: WHAT IS NEW AND OBJECTIVE: Some evidence suggests that angiotensin-converting enzyme insertion/deletion (I/D) polymorphism may play a role in endothelium-dependent vasodilatation. However, the impact of I/D polymorphism on endogenous nitric oxide production, which may be of great therapeutic significance, has scarcely been studied. This study aimed to investigate this in hypertensives and hypercholesterolaemics. METHODS: Adult Han subjects were recruited by cluster sampling from two communities in Shunde, Guangdong province, China. Plasma nitrite and nitrate (NO(x)) levels were determined by colorimetry assay and angiotensin II and 6-keto-prostaglandin F1-alpha by radioimmunoassay. Angiotensin-converting enzyme gene I/D polymorphism were genotyped by polymer chain reaction-amplified fragment length polymorphism. RESULTS AND DISCUSSION: Of the 779 subjects who met our inclusion criteria, 502 were with normotensive and normocholesterolaemic, 76 had hypertension only, 146 hypercholesterolaemia only, and 55 had both hypertension and hypercholesterolaemia. Among subjects with hypertension only, the plasma levels of NO(x) for genotype DD were significantly lower than those for genotype II (P = 0·034). And the plasma levels of NO(x) for genotype DD was significantly higher than those for genotype II (P = 0·040) in subjects with hypercholesterolaemia only. WHAT IS NEW AND CONCLUSION: Our results suggest that I/D polymorphism has an impact on in vivo NO production in hypertensives and hypercholesterolaemics at the population level. Hypertensives with allele D may be benefit from L-arginine supplementation and hypercholesterolaemics with allele D may respond better to statins or antioxidants.

Disposition pathways and pharmacokinetics of herbal medicines in humans.

Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their pharmacokinetic profiles. To optimize the use of herbal remedies, further clinical studies to explore their biological fate including the disposition pathways and kinetics in the human body are certainly needed.

Impact of Lotensin and Salviae on the changes of TGF-beta1 and its receptors in a rat model of chronic cyclosporine-induced nephropathy.

OBJECTIVES: Transforming growth factor-beta(1) (TGF-beta(1)) and its receptors, type 1 (TR-1) and type 2 (TR-2) play important roles in chronic cyclosporine (CsA)-induced nephropathy. Lotensin is known as an angiotensin-converting enzyme inhibitor and may reduce chronic CsA-induced nephropathy. Recently it is reported that Salviae (a Chinese medicine), which can improve microcirculation and decrease the expression of TGF-beta(1) has the same effect as that of lotensin. Therefore, in this study we assessed the effects of Lotensin or Salviae on the chronic CsA-induced upregulation of TGF-beta(1), TR-1, and TR-2 in a rat model. MATERIALS AND METHODS: Sodium-depleted rats were administered CsA by gastric gavage and a new rat model of chronic CsA-induced nephropathy was established. Rats with chronic CsA-induced nephropathy were treated by lotensin or Salviae. The proteins of TGF-beta(1), TR-1, and TR-2, and the mRNA of TR-1 and TR-2 in the kidneys of CsA-treated rats, were measured by immunohistochemistry (IHC) and in situ hybridization (ISH). The results were investigated semiquantitatively by image analysis. RESULTS: Lotensin or Salviae individually attenuated CsA-induced nephropathy in the rat models, and downregulated the protein expressions of TGF-beta(1), TR-1, and TR-2, and the mRNA transcripts of TR-1 and TR-2 in the rat model. CONCLUSION: Our studies show that treatment with lotensin or Salviae is useful in preventing chronic CsA-induced nephropothy.

Fine-scale differences between Accumulibacter-like bacteria in enhanced biological phosphorus removal activated sludge.

A lab-scale sequencing batch reactor (SBR) and six full-scale wastewater treatment plants (WWTPs) performing enhanced biological phosphorus removal (EBPR) were surveyed. The abundance of Accumulibacter-related organisms in the full-scale plants was investigated using fluorescent in situ hybridization. Accumulibacter-related organisms were present in all of the full-scale EBPR plants, at levels ranging from 9% to 24% of total cells. The high percentage of Accumulibacter-related organisms seemed to be associated with configurations which minimize the nitrate recycling to the anaerobic zone and low influent BOD:TP ratios. PCR-based clone libraries were constructed from the community 16S rRNA gene plus the internally transcribed spacer region amplified from the SBR and five of the full-scale WWTPs. Comparative sequence analysis was carried out using Accumulibacter-related clones, providing higher phylogenetic resolution and revealing finer-scale clustering of the sequences retrieved from the SBR and full-scale EBPR