Effect of Pulicaria mauritanica on Glucose Metabolism and Glycogen Content in Streptozotocin-Induced Diabetic Rats.

AIMS: The study aimed to assess the antihyperglycemic activity of Pulicaria mauritanica. BACKGROUND: Pulicaria mauritanica is a medicinal and aromatic plant used for the treatment of many diseases such as inflammation, diabetes, and intestinal disorders. OBJECTIVE: The main goals of this present paper were to confirm the antihyperglycemic capacity of aqueous extract from Pulicaria mauritanica in normoglycemic and diabetic rats over a period of time (7 days of treatment). METHODS: The effect of the aqueous extract of Pulicaria mauritanica from aerial parts (AEPM) on glucose and lipid metabolism was tested using an acute test (single dose during 6 hours) and subchronic assay (repeated oral administration for seven days) at a dose of 60 mg/kg and the serum glucose levels were measured in normoglycemic and streptozotocin(STZ)-induced diabetic rats. In addition, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus was evaluated. The antioxidant activity, phytochemical screening, and quantification of some secondary metabolites of this extract were also performed. RESULTS: AEPM at a dose of 60 mg/kg reduced the plasma glucose concentrations significantly in STZ-induced diabetic rats after a single oral administration (p<0.05). This lowering effect became more significant during the repeated oral administration in hyperglycemic rats (p<0.0001). Also, the findings showed that this plant exhibited a significant increase in liver and skeletal soleus muscle glycogen content in diabetic rats. AEPM revealed a remarkable antioxidant activity in addition to the presence of polyphenol compounds such as flavonoids, tannins, saponins, sterols, glucides, terpenoids, quinones, anthraquinones, and mucilage. CONCLUSION: The study shows that AEPM exhibits antihyperglycemic activity in diabetic rats, and it increases liver and muscle glycogen content.

Diacerein ameliorates letrozole-induced polycystic ovarian syndrome in rats.

Polycystic ovary syndrome (PCOS) is the most common gynaecological endocrine disease that causes anovulatory infertility. The current study aimed to explore the possible role of diacerein (DIA), an IL-1ß inhibitor, in treating letrozole-induced PCOS in rats that exhibit the metabolic and endocrinal criteria of PCOS patients. PCOS was induced in female Wistar rats by the oral administration of letrozole (1 mg/kg, per orally, p.o.) for 21 days. Rats were then treated with DIA (25 mg/kg/day, p.o.), DIA (50 mg/kg/day, p.o.), or metformin (2 mg/100 g/day, p.o.) for 14 days after the PCOS induction. PCOS resulted in a significantly higher body weight, ovarian weight, ovarian size, and cysts, as well as an elevation in serum testosterone, LH, insulin, glycemia, and lipid profile levels. All of these effects were significantly reduced by the DIA administration. Additionally, DIA remarkably inhibited the letrozole-induced oxidative stress in the ovaries, muscles, and liver by reducing the upraised levels of malondialdehyde and total nitrite and increasing the suppressed levels of superoxide dismutase and catalase. DIA enhanced the protective proteins Keap-1, Nrf2, and OH-1 levels. Finally, DIA inhibited the elevated mRNA levels of NLRP3 and caspase-1, the up-regulated inflammatory cytokines IL-6, TNF-α, and the IL-1ß/NFκB signaling pathway. Our results proved that DIA ameliorates letrozole-induced PCOS through its antioxidant and anti-inflammatory properties.

A research update on the therapeutic potential of rhein and its derivatives.

Rhein is one of the anthraquinones components of Rheum. It shows excellent clinical efficacy and is widely used in the management of several disease conditions including tumors, inflammation, diabetic nephropathy, and viral infections. In this review, we summarize the recent studies on the pharmacological activities of rhein and its derivatives, as well as their association with different diseases and possible mechanisms based on our previous review. This review serves as an updated and a supplement to our previous report highlighting the use of rhein in nanotechnology. It also serves as a reference study and offers an overall picture of the use of rhein and its derivatives in nanotechnology.

A comparative pilot study of oral diacerein and locally treated diacerein-loaded nanoparticles in a model of osteoarthritis.

Diacerein (DIA) is a slow-acting drug for osteoarthritis (OA). Oral DIA administration, however, exerts side effects including diarrhea and urine discoloration. We fabricated DIA-loaded poly(d,l-lactide-co-glycolide) nanoparticles (DIA/PLGA NPs) that allow sustained release of DIA. In vitro, rat synoviocytes were used to investigate the cytotoxicity and anti-inflammatory effects of DIA-loaded NPs. In vivo, monosodium iodoacetate (MIA)-induced OA rats were divided into seven groups that included non-treated healthy control rats and rats injected with MIA alone or in combination with NPs, DIA(5%) solution, DIA(1%)/NPs, DIA(5%)/NPs, or oral DIA. The in vitro studies revealed that DIA/PLGA NPs dose-dependently suppressed mRNA levels of pro-inflammatory cytokines and enzymes, including interleukin-1 (IL-1), IL-6, tumor necrosis factor-α, matrix metalloproteinase-3 (MMP-3), MMP-13, cyclo-oxygenase-2, and a disintegrin and metalloproteinase with thrombospondin motifs-5 in synoviocytes. The in vivo studies demonstrated that intra-articular treatment of OA rat models with DIA-loaded PLGA NPs markedly decreased mRNA levels of these pro-inflammatory factors and increased those of anti-inflammatory cytokines (IL-4 and IL-10). Micro-computed tomography and histological evaluations indicated that intra-articular injection of DIA-loaded NPs was effective in protecting against cartilage degradation. Administration of DIA/PLGA NPs via intra-articular injection is promising for inhibiting inflammation and protecting against cartilage degradation in OA.

Melanosis coli: A comprehensive review.

Melanosis coli (MC) is a common condition characterized by a black or brown pigment deposited in the colorectal mucosa. It is a reversible condition that is influenced by many factors, such as living habits and bowel function. However, the epidemiology and etiology of MC are still unclear. Most studies show that there is a significant correlation between the use of anthraquinone laxatives and the occurrence of MC. At present, the mechanism of the apoptosis theory is widely recognized as regards the pathogenesis of MC. There is no specific clinical manifestation of MC, and its diagnosis is mainly based on a complimentary examination, such as endoscopic and histopathological tests. General treatment, such as changing living habits, is preferred, and medical or surgical treatment should not be considered in the absence of serious malignancy. The aim of this review is to systematically present and outline the concepts of the epidemiology, etiology, histopathology, pathogenesis, clinical manifestations, diagnosis and treatment of MC, in order to improve the understanding of this condition.

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics.

OBJECTIVE: Chrysophanol is a natural anthraquinone, also known as chrysophanic acid and 1,8-dihydroxy-3-methyl-anthraquinone. It has been widely used in the food and pharmaceutical fields. This review is intended to provide a comprehensive overview of the pharmacology, toxicity and pharmacokinetic researches of chrysophanol. KEY FINDING: Information on chrysophanol was collected from the Internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PM using a combination of keywords including 'pharmacology', 'toxicology' and 'pharmacokinetics'. The literature we collected included from January 2010 to June 2019. Chrysophanol has a wide spectrum of pharmacological effects, including anticancer, antioxidation, neuroprotection, antibacterial and antiviral, and regulating blood lipids. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity, and pharmacokinetics indicate that the use of chrysophanol in combination with other drugs can reduce toxicity and enhance efficacy. SUMMARY: Chrysophanol can be used in many diseases. Future research directions include how the concentration of chrysophanol affects pharmacological effects and toxicity; the mechanism of synergy between chrysophanol and other drugs.

In vitro study of the nephrotoxicity of total Dahuang (Radix Et Rhizoma Rhei Palmati) anthraquinones and emodin in monolayer human proximal tubular epithelial cells cultured in a transwell chamber.

OBJECTIVE: To examine changes in the morphology and physiological functions of human proximal tubular epithelial cells (HK-2 cells) caused by total Dahuang (Radix Et Rhizoma Rhei Palmati) anthraquinones (TDA) and emodin. METHODS: HK-2 cells were cultured on polycarbonate (PCF) membranes to form a complete monolayer of cells. A fluorescein isothiocyanate-dextran (FITC) permeability assay was conducted and secretion of γ-glutamyltranspeptidase (GGT), lactate dehydrogenase (LDH), N-acetyl-ß-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) was examined. The reabsorption of glucose and the excretion of para-aminohippuric acid (PAH) by HK-2 cells were also examined. The morphology of HK-2 cells was observed using optical microscopy and scanning electron microscopy. The cytoskeleton of HK-2 cells was observed under a fluorescence microscope. RESULTS: Compared with the results for the dimethyl sulfoxide group, treatment of cells with TDA and emodin showed statistically significant differences in the FITC leakage rate, the apical / basolateral ratio of LDH and GGT, and the secretion of GGT, LDH, NAG and KIM-1. At 64 µg/mL, TDA markedly inhibited blood glucose reabsorption and remarkably suppressed PAH excretion by HK-2 cells. Both TDA and emodin caused various degrees of damage to the morphology and cytoskeleton of HK-2 cells with the degree of damage correlating positively with the dosage of the tested substances. CONCLUSION: Both TDA and emodin caused damage to human renal proximal tubular epithelial cells at certain dosages. At the same dosage, TDA caused more severe damage than emodin to the HK-2 cells.

Design and evaluation of rhubarb total free anthraquinones oral colon-specific drug delivery granules to improve the purgative effect

Rhubarb is commonly used as a cathartic in Asian countries. However, researchers have devotedextensive concerns to the quality control and safety of rhubarb and traditional Chinese preparations composed of rhubarb due to the instable purgative effect and potential nephrotoxicity of anthraquinones. In this study, we aimed to prepare rhubarb total free anthraquinones (RTFA) oral colon-specific drug delivery granules (RTFA-OCDD-GN) to delivery anthraquinones to colon to produce purgative effect. RTFA-OCDD-GN were prepared using chitosan and Eudragit S100 through a double-layer coating process and the formulation was optimized. Continuous release studies were performed in a simulated gastric fluid (pH 1.2), followed by a small-intestinal fluid (pH 6.8) and a colonic fluid (pH 7.4, containing rat cecal contents). The purgative effect test was performed in rats. The dissolution profile of RTFA-OCDD-GN showed that the accumulative dissolution rate of RTFA was about 83.0% in the simulated colonic fluid containing rat cecal contents and only about 9.0% in the simulated gastrointestinal fluids. And the RTFA-OCDD-GN could produce the comparative purgative activity as rhubarb, suggesting it could deliver the free AQs to the colon. The RTFA-OCDD-GN was a useful media to enhance the purgative activity of free anthraquinones after administered orally.

Cytotoxicity of Structurally Diverse Anthranoids and Correlation with Mechanism of Action and Side Effects.

The purpose of this contribution is to evaluate the cytotoxicity and apoptosis inducing ability of structurally diverse anthraquinones to establish a relationship between structure and toxicity. Besides the wide spread use of anthraquinones in pharmacological drugs for constipation and non-prescription dietary supplements for weight loss, extracts are still commercialized as crude extracts and long-term side effects are still relevant. In this work we developed a method to quantify the cascarosides isolated from Rhamnus purshiana (Cascara Sagrada) using LC-MS/MS and evaluated the effects of this extract and isolated compounds on cellular viability using NOK-SI, HeLa, and T98G cell lineages. Apoptosis inducing ability was also analyzed via evaluating key-proteins involved in apoptosis pathways. Using cascarosides isolated from bark extracts, we found that the presence of glucose moieties in the chemical structure reduced the toxicity. This communication reviewed the mechanisms of action, toxicity of anthraquinones and correlated the toxicity with chemical structures of cascarosides. Results indicate that cascarosides-enriched cascara extract, as well as glycosylated anthraquinones, may have some beneficial effects for laxative action of herbal medicines. Considering our results, a cascarosides-enrichment in cascara extract is recommended.

Inhibitory effect of aloe emodin mediated photodynamic therapy on human oral mucosa carcinoma in vitro and in vivo.

We report a study on inhibition of human oral squamous cell carcinoma in vitro and in vivo, using novel photosensitizer (PS) aloe emodin (AE) mediated photodynamic therapy (PDT). Distinct morphology changes of oral mucosa carcinoma KB cells were observed under an optical microscope and cell migrations were inhibited owing to AE-PDT. The cell proliferation was blocked in G1 phase and the apoptosis increase were both caused by massive reactive oxygen species (ROS) generated from photoactivated AE. The upregulation of Caspase-3 and Bax protein levels and downregulation of Bcl-2 protein levels were observed after AE-PDT. The survival time of tumor mouse was prolonged without side effects ascribed to AE-PDT and its inhibitory effect on mice transplantation tumors was significant. It is indicated that AE mediated PDT is an innovative way to oral cancer treatment with the dominances of effectivity, minimal invasion, tissue integrity retention and none side effects on main organs.

Chitosan-coated diacerein nanosuspensions as a platform for enhancing bioavailability and lowering side effects: preparation, characterization, and ex vivo/in vivo evaluation.

Nanodrug delivery systems have been widely reviewed for their use in several drug formulations to improve bioavailability, sustain effect, and decrease side effects of many candidate drugs. The objective of this study was to evaluate the potential of chitosan (CS)-coated nanosuspensions to enhance bioavailability and reduce the diarrheal side effect of diacerein (DCN) after oral administration. DCN nanosuspensions (DNS) were prepared by sonoprecipitation technique using different stabilizers at three different concentrations. The selected DNS with optimum particle size (PS), polydispersity index (PDI), and Zeta potential (ZP) was coated with three different concentrations of CS-coated DNS (CS-DNS) and screened. In vitro dissolution was performed for the selected lyophilized formulae and compared with DCN powder in addition to the assessment of drug crystallinity via scanning electron microscopy, X-ray powder diffraction, and differential scanning calorimetry. Ex vivo drug permeability using noneverted rat intestine, intraluminal content, and mucoadhesion evaluation was studied for nominated formulae in comparison to DCN suspension. Moreover, in vivo study, pharmacokinetic parameters, and evaluation of diarrheal potential were conducted after oral administration of selected formulae. Polyvinyl pyrrolidone (PVP)-stabilized DNS showed a significant increase (P≤0.05) in PS and PDI as the stabilizer concentration increased. PVP-stabilized DNS with the lowest CS concentration was protected from aggregation by lyophilization with mannitol. A remarked enhancement in dissolution parameters was observed in the nanocrystals' formulae. Morphological examination and X-ray diffraction confirmed drug crystallinity. The intermediate permeation parameters of CS-DNS-F10, lowest rhein-to-DCN ratio in intraluminal content along with the highest percentage of mucoadhesive, could serve as a sustaining profile of coated formula. CS-DNS-F10 showed a significantly higher Cmax of 0.74±0.15 µg/mL at a delayed Tmax of 3.60±0.55 hours with a relative bioavailability of 172.1% compared to DCN suspension. CS-coated nanosuspensions could serve as promising revenue to enhance bioavailability and reduce the diarrheal side effect of DCN after oral administration.

[Correlation between chronic constipation and colorectal neoplasms].

The correlation between chronic constipation and colorectal neoplasms has been arousing wide interest. There have been a number of domestic and international epidemiological and clinical researches focusing on this issue. Based on these researches, the correlation between constipation and colorectal neoplasms was studied from three aspects: constipation and colorectal polyps; constipation and colorectal cancer; melanosis coli (MC), laxatives and colorectal neoplasms. We find that constipation can significantly increase the incidence of colorectal polyps and constipation does not significantly increase the incidence of colorectal cancer but is one of the risk factors for colorectal cancer. In addition, MC, laxatives and the incidence of colorectal polyps are also closely correlated. Given the fact that colorectal polyps are precancerous lesions, patients with long-term constipation should take less anthraquinone laxatives, and those with colorectal polyps should be followed up periodically.

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.

Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of aspergiolide A in early drug development.

Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A), from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD) of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary.

A novel compound NSC745885 exerts an anti-tumor effect on tongue cancer SAS cells in vitro and in vivo.

OBJECTIVE: Oral squamous cell carcinoma (OSCC) is a prevalent cancer, especially in developing countries. Anthracyclines and their anthraquinone derivatives, such as doxorubicin, exhibit a cell growth inhibitory effect and have been used as anti-cancer drugs for many years. However, the cardiotoxicity of anthracycline antibiotics is a major concern in their clinical application. NSC745885 is a novel compound synthesized from 1,2-diaminoanthraquinone, which subsequently reacts with thionyl chloride and triethylamine. The present study aimed to investigate the anti-oral cancer potential and the safety of NSC745885. METHODS: We investigated the anti-cancer potential of NSC745885 in oral squamous carcinoma cell lines and in an in vivo oral cancer xenograft mouse model. The expression of apoptotic related genes were evaluated by real-time RT-PCR and western bloting, and the in vivo assessment of apoptotic marker were measured by immunohistochemical staining. The anti-tumor efficiency and safety between doxorubicin and NSC745885 were also compared. RESULTS: Our results demonstrated that NSC745885 exhibits anti-oral cancer activity through the induction of apoptosis in cancer cells and in tumor-bearing mice, and this treatment did not induce marked toxicity in experimental mice. This compound also exhibits a comparable anti-tumor efficiency and a higher safety in experimental mice when compared to doxorubicin. CONCLUSIONS: The data of this study provide evidence for NSC745885 as a potential novel therapeutic drug for the treatment of human OSCC.