Acupoint application therapy alleviates pain by regulating immune function through inhibiting TLR4/MyD88/NF-κB p65 signaling in a primary dysmenorrhea rat model. / 穴位贴敷通过TLR4/MyD88/NF-κBé€šè·¯è°ƒèŠ‚åŽŸå‘æ€§ç—›ç»å¤§é¼ çš„å ç–«åŠŸèƒ½.

OBJECTIVES: To investigate the effects of graphene-based warm uterus acupoint paste on uterine Toll-like receptor 4 (TLR4)/myeloid differentiation factor 88 (MyD88)/nuclear transcription factor-kappa B p65 (NF-κB p65) signaling pathway and Th1/Th2 immune balance in primary dysmenorrhea ( PD ) model rats, so as to reveal its immunological mechanisms of relieving dysmenorrhea. METHODS: Thirty SD female rats were randomly divided into 3 groups：normal group, model group and acupoint paste group, with 10 rats in each group. PD rat model was established by subcutaneous injection of estradiol benzoate for 10 consecutive days. At the same time of modeling, graphene-based warm uterus acupoint paste was applied to the acupoints of "Guanyuan" (CV4), bilateral "Zigong" (EX-CA1) and "Sanyinjiao" (SP6) of rats in the acupoint paste group. The application was continuously applied once daily for 10 d, 5 h each time. On the 11th day, oxytocin was injected intraperitoneally to observe the writhing latency, writhing times within 30 min and writhing score of rats in each group. The spleen and thymus indexes were calculated. The pathological changes of spleen and thymus tissue were observed after HE staining. The contents of serum immunoglobulin (Ig) A, IgG, tumor necrosis factor-α (TNF-α), interleukin (IL)-2, interferon-γ (IFN-γ), IL-4 and IL-10 were detected by ELISA . The protein and mRNA expression levels of TLR4, MyD88 and NF-κB p65 in rat uterine tissue were detected by Western blot and real-time quantitative PCR, respectively. RESULTS: Compared with the normal group, the writhing times and writhing scores within 30 min of rats in the model group were significantly increased(P<0.001), and the rats showed writhing reaction (P<0.01). The spleen index and thymus index were significantly decreased(P<0.01, P<0.05). The spleen and thymus had obvious pathological changes. The contents of IgA, IgG, TNF-α, IL-2 and IFN-γ in serum were significantly increased, while the contents of serum IL-4 and IL-10 were significantly decreased(P<0.001, P<0.01). The expression levels of TLR4, MyD88, NF-κB p65 protein and corresponding mRNA in uterine tissue were significantly increased(P<0.001). Following intervention, compared with the model group, the writhing latency time of rats in the acupoint paste group was prolonged, and the writhing times and writhing scores within 30 min were significantly decreased (P<0.001). The spleen index and thymus index were significantly increased(P<0.01, P<0.05). The pathological changes of spleen and thymus were improved. The contents of serum IgA, IgG, TNF-α, IL-2 and IFN-γ were significantly decreased, while the contents of IL-4 and IL-10 were significantly increased(P<0.001, P<0.05, P<0.01). The expression of TLR4, MyD88, NF-κB p65 protein and the corresponding mRNA levels in uterine tissue were decreased(P<0.001, P<0.01). CONCLUSIONS: Graphene-based warm uterus acupoint paste can regulate the immune balance of Th1/ Th2 by regulating TLR4/ MyD88/ NF-κB p65 signaling pathway, repair the pathological damage of immune tissue, improve immune function, and effectively relieve the pain symptoms of PD rats.

Acupoint compatibility effect: increasing "effect value" and expanding "effect domain". / è §ç©´é ä¼æ•ˆåº”.

By summarizing and exploring the theoretic connotation, key of functions and effect mechanism of acupoint compatibility, the effect of acupoint compatibility is concluded as the increase of "effect value" and the expansion of "effect domain". The increase of "effect value" is the concrete embodiment by the value of medical assessment scale, the value of objective index detection in clinical trial and the value of index detection in experiment research. The expansion of "effect domain" is the increase of effect target and the extension of effect scope. The paper interprets the scientific connotation of acupoint compatibility therapy from a new perspective, and emphasizes the innovative approaches to research while bringing forth new ideas on the research method. It is anticipated that a novel breakthrough can be achieved in the study of acupoint compatibility and the improvement of acupuncture-moxibustion efficacy.

Associations between Vitamin D, Omega 6:Omega 3 Ratio, and Biomarkers of Aging in Individuals Living with and without Chronic Pain.

Elevated inflammatory cytokines and chronic pain are associated with shorter leukocyte telomere length (LTL), a measure of cellular aging. Micronutrients, such as 25-hydroxyvitamin D (vitamin D) and omega 3, have anti-inflammatory properties. Little is known regarding the relationships between vitamin D, omega 6:3 ratio, LTL, inflammation, and chronic pain. We investigate associations between vitamin D, omega 6:3 ratio, LTL, and C-reactive protein (CRP) in people living with/without chronic pain overall and stratified by chronic pain status. A cross-sectional analysis of 402 individuals (63% women, 79.5% with chronic pain) was completed. Demographic and health information was collected. Chronic pain was assessed as pain experienced for at least three months. LTL was measured in genomic DNA isolated from blood leukocytes, and micronutrients and CRP were measured in serum samples. Data were analyzed with general linear regression. Although an association between the continuous micronutrients and LTL was not observed, a positive association between omega 6:3 ratio and CRP was detected. In individuals with chronic pain, based on clinical categories, significant associations between vitamin D, omega 6:3 ratio, and CRP were observed. Findings highlight the complex relationships between anti-inflammatory micronutrients, inflammation, cellular aging, and chronic pain.

The effectiveness of acupoint herbal patching for functional dyspepsia: A protocol for systematic review and meta-analysis.

BACKGROUND: Functional dyspepsia (FD) has gradually developed into a multiple disease of the digestive system that most patients may be accompanied by mental and emotional disorders, such as insomnia, anxiety, and depression. Acupoint herbal patching (AHP) is usually used as an alternative therapy for patients with FD. This study aimed to design a systematic review and meta-analysis to explore the effects of AHP on FD. METHODS: We will search the Cochrane Central Register of Controlled Trials, the Web of Science, PubMed, Embase, the Chinese Biomedical Literature Database, the Chinese Scientific Journal Database, the Wan-Fang Database, and the China National Knowledge Infrastructure for randomized controlled trials of FD treated by AHP from inception to June 30, 2021. The primary outcome measures contain clinical effective rate, the symptom score of FD, and secondary outcome measures consist of quality of life, incidence of adverse events, and recurrence rate. We will use RevMan V.5.3 software to analyze data. Two reviewers will evaluate the risk of bias and the quality of the studies by the Cochrane Collaboration risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation approach, separately. RESULTS: This systematic review protocol will analyze the effectiveness, quality of life, improvement of the symptom, and safety of AHP therapy for FD. CONCLUSION: The findings of this systematic review will provide evidence to evaluate the effectiveness and safety of AHP for FD.

Acupuncture therapy for gastric ulcer: A protocol for systematic review and meta-analysis.

BACKGROUND: Gastric ulcer (GU) is a clinically common disease of the digestive system that adversely affects patients' quality of life and work ability. Although some articles have reported that acupuncture can improve the clinical symptoms of GU, the efficacy of acupuncture has not been scientifically or methodically evaluated. This study aimed to evaluate the effectiveness and safety of acupuncture for the treatment of patients with gastric ulcers. METHODS: The following electronic databases will be searched from the respective dates of database inception to March 23, 2021: The Cochrane Library, Web of Science, EMBASE, MEDLINE, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wanfang database, the Chinese Scientific Journal Database, and other sources. Randomized controlled trials comparing acupuncture with other interventions or sham acupuncture were included. Two independent researchers will perform article retrieval, duplication removal, screening, quality evaluation, and data analyses by Review Manager (V.5.3.5). Meta-analyzes, subgroup analysis, and/or descriptive analyses will be performed based on the included data conditions. RESULTS: The protocol of this study systematically assessed the effectiveness and safety of acupuncture for gastric ulcer patients. The primary outcome was the effective rate, and the secondary outcomes included negative conversing rate of Helicobacter pylori infection, untoward effect, recurrence rate, quality of life, and symptom scores. CONCLUSION: This study provides evidence of whether acupuncture is an effective and safe intervention for gastric ulcers. PROSPERO REGISTRATION NUMBER: CRD42021251067.

An atlas of metallome and metabolome interactions and associations with incident diabetes in the Strong Heart Family Study.

BACKGROUND: Chronic exposure to certain metals plays a role in disease development. Integrating untargeted metabolomics with urinary metallome data may contribute to better understanding the pathophysiology of diseases and complex molecular interactions related to environmental metal exposures. To discover novel associations between urinary metal biomarkers and metabolism networks, we conducted an integrative metallome-metabolome analysis using a panel of urinary metals and untargeted blood metabolomic data from the Strong Heart Family Study (SHFS). METHODS: The SHFS is a prospective family-based cohort study comprised of American Indian men and women recruited in 2001-2003. This nested case-control analysis of 145 participants of which 50 developed incident diabetes at follow up in 2006-2009, included participants with urinary metal and untargeted metabolomic data. Concentrations of 8 creatinine-adjusted urine metals/metalloids [antimony (Sb), cadmium (Cd), lead (Pb), molybdenum (Mo), selenium (Se), tungsten (W), uranium (U) and zinc (Zn)], and 4 arsenic species [inorganic arsenic (iAs), monomethylarsonate (MMA), dimethylarsinate (DMA), and arsenobetaine (AsB)] were measured. Global metabolomics was performed on plasma samples using high-resolution Orbitrap mass spectrometry. We performed an integrative network analysis using xMWAS and a metabolic pathway analysis using Mummichog. RESULTS: 8,810 metabolic features and 12 metal species were included in the integrative network analysis. Most metal species were associated with distinct subsets of metabolites, forming single-metal-multiple-metabolite clusters (|r|>0.28, p-value < 0.001). DMA (clustering with W), iAs (clustering with U), together with Mo and Se showed modest interactions through associations with common metabolites. Pathway enrichment analysis of associated metabolites (|r|>0.17, p-value < 0.1) showed effects in amino acid metabolism (AsB, Sb, Se and U), fatty acid and lipid metabolism (iAs, Mo, W, Sb, Pb, Cd and Zn). In stratified analyses among participants who went on to develop diabetes, iAs and U clustered together through shared metabolites, and both were associated with the phosphatidylinositol phosphate metabolism pathway; metals were also associated with metabolites in energy metabolism (iAs, MMA, DMA, U, W) and xenobiotic degradation and metabolism (DMA, Pb) pathways. CONCLUSION: In this integrative analysis of multiple metals and untargeted metabolomics, results show common associations with fatty acid, energy and amino acid metabolism pathways. Results for individual metabolite associations differed for different metals, indicating that larger populations will be needed to confirm the metal-metal interactions detected here, such as the strong interaction of uranium and inorganic arsenic. Understanding the biochemical networks underlying metabolic homeostasis and their association with exposure to multiple metals may help identify novel biomarkers, pathways of disease, potential signatures of environmental metal exposure.

The effectiveness of acupoint application of traditional Chinese medicine in treating primary dysmenorrhea: A protocol for meta-analysis and data mining.

BACKGROUND: Primary dysmenorrhea (PD) is a functional disease of the female reproductive system, which has adverse effects on patients' physical and mental health and quality of life. At present, acupoint application of traditional Chinese medicine (TCM) as adjuvant therapy is undergoing clinical trials in different medical centers. However, there is no systematic review or meta-analysis to evaluate the efficacy of acupoint application of TCM in the treatment of PD. There is also a lack of systematic evaluation and analysis of acupoints and herbs. METHODS: All randomized controlled trials related to acupoint catgut embedding therapy on PD will be searched in the following electronic databases: Cochrane Central Registry of controlled trials, PubMed, Wed of Science, EMBASE, Science Net, China Biomedical Literature Database, China Science Journal Database, China National Knowledge Infrastructure and Wan-Fang Database, from inception to May, 2021 were searched without language restrictions. The primary outcomes contain visual analog score, The Cox Menstrual Symptom Scale, while the secondary outcomes consist of adverse events and the recurrence rate. Two reviewers will independently perform data selection, data synthesis, and quality assessment. Data meeting the inclusion criteria will be extracted and analyzed by Revman v.5.3 software. Two reviewers will evaluate the study using the Cochrane collaborative bias risk tool. We will use the scoring method to assess the overall quality of the evidence supporting the main results. We will also use Spass software (version 19.0) for complex network analysis to explore the potential core prescription of acupoint application of traditional Chinese medicine in the treatment of PD. RESULTS: This study will analyze the clinical effective rate, functional outcomes, quality of life, improvement of clinical symptoms of PD, and effective prescriptions of acupoint application for patients with PD. CONCLUSION: Our findings will provide evidence for the effectiveness and potential treatment prescriptions of acupoint application for patients with PD.PROSPERO registration number: CRD 42021244357.

The effect of acupoint herbal patching on the quality of life of patients recovering from COVID-19: A protocol for systematic review and meta analysis.

BACKGROUND: There is a worldwide outbreak of COVID-19, and as the number of patients increases, an increasing number of patients are recovering. However, no relevant systematic review or meta-analysis has been designed to evaluate the effects of acupoint herbal patching on the life of patients recovering from COVID-19. METHODS: The following electronic databases will be searched from the respective dates of database inception to April 20, 2021: The Cochrane Library, Web of Science, EMBASE, MEDLINE, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wanfang database, the Chinese Scientific Journal Database (VIP), and other sources. All published randomized controlled trials in English or Chinese related to acupoint herbal patching for COVID-19 will be included. The primary outcome was the timing of the influence of acupoint herbal patching on the quality of life of convalescent patients. Secondary outcomes were accompanying symptoms (such as myalgia, expectoration, stuffiness, runny nose, pharyngalgia, anhelation, chest distress, dyspnea, crackles, headache, nausea, vomiting, anorexia, diarrhea) disappearance rate, negative COVID-19 results rate on two consecutive occasions (not on the same day), average hospitalization time, clinical curative effect, and improved quality of life. RESULTS: The main purpose of this systematic review protocol was to assess the effectiveness and safety of acupoint herbal patching therapy for treating patients recovering from COVID-19. CONCLUSION: The conclusion of our study will provide evidence to judge whether acupoint herbal patching is an effective intervention for the quality of life in patients recovering. PROSPERO REGISTRATION NUMBER: CRD42021246550.

Effects of Stimulating Local and Distal Acupoints on Diabetic Gastroparesis: A New Insight in Revealing Acupuncture Therapeutics.

One of the most important aspects of clinical acupuncture practice, like diabetic gastroparesis, is the selection of suitable acupoints. Furthermore, it is critical to examine the therapeutic impact differences between distal and local acupoints, as well as the prescription of their combination. In this study, diabetic gastroparesis rats were treated by needling Zhongwan (CV12) and Zusanli (ST36), and then used Single Photon Emission Computed Tomography-CT (SPECT-CT) technology to assess the effects of promoting gastric motility. In addition, morphological observation, immunohistochemical examination, and biomarker assays, such as determination of growth factor 1, motilin, and ghrelin contents in serum samples, were performed to better understand the impact of certain various acupuncture treatments. All of the therapies improved the symptoms of diabetic gastroparesis rats, according to the findings. Stimulating these acupoints, on the other hand, can have a different therapeutic effect. In addition, needling local and distal acupoints together can have an antagonistic or synergistic impact on specific physiological and biochemical indexes such as gastric motility, ghrelin, gastrin, and growth factor 1, among others. Our findings demonstrated the benefits of acupoints and acupuncture in the management of diabetic gastroparesis, as well as a new insight into acupuncture therapeutics.

[Professor WANG Fu-chun's experience of four elements of acupuncture manipulation practice].

Through collecting the 30-year medical experience of professor WANG Fu-chun, the methods of acupuncture manipulation practice were summarized so as to provide the reference for the medical staffs in acupuncture teaching and clinical work. Professor WANG proposes four key elements of acupuncture manipulation practice, i.e. the style of needling practice, the consciousness of needling practice, the strength of needling practice and qi of needling practice. Acupuncture manipulation is a highly operational clinical skill. The knowledge learning from the experience of the instructors is the important way to improve acupuncture techniques. Besides, beginners need to improve their techniques through learning the theories, a large amount of exercises as well as the self-perception.

Therapeutic Potential of Baicalein in Alzheimer's Disease and Parkinson's Disease.

Alzheimer's disease and Parkinson's disease are the two most common, progressive central neurodegenerative diseases affecting the population over the age of 60 years. Apart from treatments that temporarily improve symptoms, there is no medicine currently available to inhibit or reverse the progression of Alzheimer's disease and Parkinson's disease. In traditional Chinese medicine, the root of Scutellaria baicalensis Georgi is a classic compatible component in the decoction of herbal medicine used for treating central nervous system diseases. Modern pharmacokinetic studies have confirmed that baicalein (5,6,7-trihydroxyflavone) is a major bioactive flavone constituent root of S. baicalensis Georgi. Studies showed that baicalein possesses a range of key pharmacological properties, such as reducing oxidative stress, anti-inflammatory properties, inhibiting aggregation of disease-specific amyloid proteins, inhibiting excitotoxicity, stimulating neurogenesis and differentiation action, and anti-apoptosis effects. Based on these properties, baicalein shows therapeutic potential for Alzheimer's disease and Parkinson's disease. In this review, we summarize the pharmacological protective actions of baicalein that make it suitable for the treatment of Alzheimer's disease and Parkinson's disease, and discuss the potential mechanisms underlying the effects.

[Analysis of analogical function acupoints for mental diseases based on Indications of Acupoints, National Standard].

OBJECTIVE: To summarize the acupoints for mental diseases in Indications of Acupoints,National Standard(GB/T30233-2013) so as to provide theoretical evidence for acupoint compatibility and acupuncture-moxibustion prescription. METHODS: The acupoints for mental diseases in Indications of Acupoints,National Standard were artificially retrieved,and then their frequencies,meridians and locations were analyzed. RESULTS: Eighty acupoints were collected totally. Shenmen (HT 7) was with the highest frequency,and Baihui (GV 20) was followed. The frequently-used meridians in turn were governor vessel (GV),bladder meridian of foot-taiyang,small intestine meridian of hand-taiyang and stomach meridian of foot-yangming,etc.,among which GV showed the highest number with 17 (21.25%) acupoints. As for the positions of analogical function acupoints,they in turn were head and face,upper limbs,lower lumbs,back and waist,chest and abdomen,with 30 percent acupoints locating at head and face. CONCLUSIONS: Analogical acupoints for mental diseases are focused at head and face,and they are mainly along GV. The treatment is based on syndrome differentiation.

[Inhibitory effect of flavonoids from Glycyrrhiza uralensis on expressions of TGF-ß1 and Caspase-3 in thioacetamide-induced hepatic fibrosis in rats].

OBJECTIVE: To study the inhibitory effect of flavonoids from Glycyrrhiza uralensis on thioacetamide-induced chonic hepatic fibrosis in rats and the effect on the protein expressions of transforming growth factor-ß1 (TGF-ß1) and Caspase-3 in livers. METHOD: Male Sprague-Dawley rats were randomly divided into totally seven groups: the normal control group, the model group, LF groups s (400, 200, 100, 50 mg · kg(-1) · d(-1)) and the silymarin positive control group (30 mg · kg(-1) · d(-1)). The hepatic fibrosis model was induced in the rats through intraperitoneal injection with 3% thioacetamide (TAA) at a dose of 150 mg · kg(-1) body weight twice a week for 12 weeks. During the course, the control group and the model group were orally administered with saline (1 mL · kg(-1) · d(-1)). After the modeling and drug intervention, the pathologic changes and fibrosis in liver tissues were observed by HE staining and Masson's Trichrome staining. The serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and liver hydroxyproline (HYP) contents were assayed by biochemical process. The serum hyaluronic acid (HA) was assessed by radioimmunoassay. In addition, the protein expressions of liver TGF-ß1 and Caspase-3 were examined by immunohistochemical method. The mRNA expression of TGF-ß1 in hepatic tissues was examined by quantitative Real-time PCR analysis. RESULT: Compared with the model group, flavonoids can protect the integrity of the structure of liver tissues, significantly reduce the hepatic cell degeneration and necrosis and the proliferation of fibrous tissues, notably reduce the serum AST, ALT, ALP and HA and HYP in hepatic tissues and down-regulate the protein expressions of liver TGF-ß1 and Caspase-3 and the mRNA expression of TGF-ß1 in hepatic tissues. CONCLUSION: The licorice flavonoids can resist the thioacetamide-induced hepatic fibrosis in rats. Its mechanism may be related to the down-regulation of the protein expressions of TGF-ß1 and Caspase-3.

Leukotriene haplotype × diet interaction on carotid artery hypertrophy and atherosclerosis in American Indians: the Strong Heart Family Study.

OBJECTIVE: Gene × diet interaction plays an important role in atherosclerosis, an inflammatory disorder. Leukotrienes are the most potent inflammatory mediators, and genetic variants encoding leukotriene genes have been implicated in atherosclerosis. This study tests nutrigenetic interaction of a previously defined leukotriene haplotype on carotid artery hypertrophy and atherosclerosis in American Indians. METHODS: This study included 3402 American Indians participating in the Strong Heart Family Study (SHFS). Carotid artery measurements, including intima-media thickness (IMT), vascular mass, and plaque, were assessed using ultrasound. Eleven tagSNPs in the leukotriene A4 hydrolase (LTA4H) gene were genotyped in all subjects. Main haplotype effect and haplotype × diet interaction were examined by generalized estimating equation, adjusting for known risk factors. RESULTS: There was no significant main effect of haplotype or diet on any of the carotid artery measures. However, a previously defined LTA4H haplotype, called HapE, significantly interacted with dietary intake of n-3 and n-6 fatty acids on both IMT (P(HapE × n3) = 0.018, P(HapE × n6) = 0.040) and vascular mass (P(HapE × n3) = 0.012, P(HapE × n6) = 0.018), but not plaque. The direction of this nutrigenetic interaction on IMT was consistent with that reported in a recent study of Caucasian twins. CONCLUSION: Dietary intake of polyunsaturated fatty acids significantly modifies the effect of a leukotriene haplotype on carotid artery hypertrophy but not atherosclerosis in American Indians, independent of established cardiovascular risk factors. Replication of nutrigenetic interaction in two distinct ethnic groups suggests the robustness and generalizability of our findings to diverse populations.

[Antidepressant activities of flavonoids from Glycyrrhiza uralensis and its neurogenesis protective effect in rats].

Adult rats chronic unpredictable stress model of depression (CUS) was adopted to elucidate the antidepressant pharmacological activity and related neurogenesis protective effect of the total flavonoids extract (licorice flavonoids, LF) from the Glycyrrhiza uralensis Fisch. cultivated locally in Ningxia. The rats were exposed to 9 kinds of unpredictable sequence of stressors and were given flavonoids (300 mg x kg(-1), 100 mg x kg(-1) and 30 mg x kg(-1)) for 28 days. The antidepressant effect was elucidated by open field test, forced swimming test and tail suspension test. The level of serum corticosterone was detected by radioimmunoassay. 5'-Bromo-2'-deoxyuridine (BrdU) labeling experiments was employed to study the neurogenesis protective activities. The flavonoids can increase the sum of line crosses and number of rears, and decrease the number of fecal boli produced in the open field test of the CUS rats. Also the flavonoids can decrease the immobility time in forced swim test as well as in the tail suspension test. In addition, the flavonoids (300 mg x kg(-1)) can decrease the serum corticosterone level of the CUS rats, and increase the number of the new born BrdU positive progenitor cells at the subgranular zone (SGZ) of dentate gyrus (DG) region in hippocampus. The results demonstrated that the total flavonoids extract from the cultivated Glycyrrhiza uralensis Fisch. could produce the anti-depressive effect on chronic unpredictable stress of depression model rats and its mechanism may be associated with its neurogenesis protective effect.

Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model.

BACKGROUND: The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). METHODS: BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. RESULTS: The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. CONCLUSIONS: Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.

In vitro cytotoxicity of two novel oral formulations of Amphotericin B (iCo-009 and iCo-010) against Candida albicans, human monocytic and kidney cell lines.

BACKGROUND: Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation. The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells. METHODS: Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation. RESULTS: None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 µg/L (n = 4-10, p < 0.05).The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 ± 2.9 for iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (µg of AmpB/L, n = 6-12, p < 0.05). CONCLUSIONS: The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizone™ and Ambisome™, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.

[The role of iron and hepcidin in hepatic fibrosis].

Liver iron overload can be found in a number of different chronic liver diseases. Iron is proposed to play a role in promoting hepatic fibrosis by various mechanisms, including iron-catalyzed production of free radical and lipid peroxidation, alteration of essential biomolecules, triggering cell apoptosis and necrosis, and activation and transformation of the hepatic stellate cell into a myofibroblastic cell. Recent evidences demonstrate that the decrease of hepcidin, a 25-amino acid peptide produced by the hepatocytes, may play a significant role in promoting hepatic iron overload in various chronic liver diseases. Therefore, the supplemental hepcidin therapy may reduce liver iron concentration. Hepcidin or hepcidin-related therapeutics could find a place in the treatment of various iron overload diseases and hepatic fibrosis.