Wiley: Journal of Pharmacy and Pharmacology: Table of Contents

Expression of Concern

Mon, 04 Jan 2021 00:00:00 -0800

Journal of Pharmacy and Pharmacology, EarlyView.

Recombinant ling zhi‐8 enhances Tregs function to restore glycemic control in streptozocin‐induced diabetic rats

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

To explore the effect of recombinant LZ-8 (rLZ-8) on streptozocin (STZ)-induced diabetic rats and further illustrate its underlying mechanism.

Methods

Rats were intraperitoneally injected with single-dose STZ 50 mg/kg for induction of type 1 diabetes (T1D), and then, the diabetic rats were treated with rLZ-8 for 3 months. The clinical symptoms, fasting blood glucose, insulin, cytokines, histopathology, flow cytometry and immunofluorescence were used to evaluate the therapeutic effect and underlying mechanism of rLZ-8 on alleviating diabetes mellitus (DM).

Key findings

Treatment with rLZ-8 obviously alleviated the clinical symptoms of T1D and dose-dependently reduced the levels of blood glucose, blood lipid and haemoglobin A1c (HbA1c) in diabetic rat model. Meanwhile, rLZ-8 markedly increased insulin secretion and protected against STZ-induced pancreatic tissue injury. Additionally, rLZ-8 dramatically inhibited the levels of TNF-α and IL-1β, and obviously increased the level of IL-10 in serum and pancreas. Further investigation indicated that rLZ-8 treatment significantly increased the number of regulatory T cells (Tregs) and up-regulated the expression of Foxp3 to restore balance between anti-inflammatory and inflammatory cytokines.

Conclusions

These data suggest that rLZ-8 can antagonize STZ-induced T1D, and its mechanism may be related to inhibit inflammation and enhance Tregs generation.

Geniposide in Gardenia jasminoides var. radicans Makino modulates blood pressure via inhibiting WNK pathway mediated by the estrogen receptors

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

To investigate the effects of geniposide in an iridoid found in Gardenia jasminoides var. radicans Makino (GJRM) in spontaneous hypertensive rat (SHR) and explore the possible mechanisms.

Methods

In this study, we detected the content of geniposide in GJRM by high-performance liquid chromatography (HPLC). Then, we used acute diuretic experiments to determine whether geniposide has diuretic effect. Moreover, we carried out experiments on SHR to further study the mechanism of hypertension, while real-time PCR, Western blot and immunohistochemistry were used for the experiments in vivo test. Hypotonic model was used for in vitro test.

Key findings

Our data showed that the content of geniposide in the extract of GJRM is 27.54%. Meanwhile, 50 mg/kg geniposide showed the strongest effect on promoting urine volume. Further study indicated that the extract of GJRM and geniposide could significantly reduce blood pressure and promote the excretion of urine and Na⁺ in SHR. In addition, geniposide significantly inhibited the activation of the with-no-lysine kinase (WNK) signalling pathway and significantly increases the protein expressions of estrogen receptor α (ERα), estrogen receptor β (ERβ) and G protein-coupled receptor 30 (GPR30) in SHR. In hypotonic model, geniposide significantly inhibits the phosphorylation of NKCC and NCC and could be antagonistic to estrogen receptor antagonists.

Conclusions

Collectively, we would suggest that geniposide may potentially be utilized as an adjunct to existing thiazide and thiazide-like diuretics to control hypertension, mainly through inhibiting the activation of the WNK signalling pathway mediated by the estrogen receptor.

Losartan and azelastine either alone or in combination as modulators for endothelial dysfunction and platelets activation in diabetic hyperlipidemic rats

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Aim

The present study aimed mainly to demonstrate the effect of the antihistamine azelastine (AZ) and Angiotensin receptor blocker ( ARB), represented by losartan (LOS) either alone or in combined form on certain metabolic aspects, endothelial dysfunction and platelets activation markers in diabetic hyperlipidemic rat model.

Methods

Rats were randomly classified to five groups: One group fed normal chow diet (NC). Four groups received alloxan and CCT-diet. One group received no treatment (DHC while the other three groups received AZ, LOS and their combination form, respectively for 8 weeks. Serum and tissue samples were collected for biochemical and histological evaluations.

Results

DHC rats demonstrated significant hyperglycaemia, dyslipidemia, disturbances in endothelial and platelet activation markers. AZ or LOS administration demonstrated hypoglycaemic and hypolipidemic effects. VCAM-1 and sE-selectin (Endothelial function markers) along with CD63 (Platelet activation marker) showed significant decrease as compared to control group. AZ administration exerted little prominent effects than that of LOS, while their combination demonstrated remarkable changes compared to monotherapy. Histopathological findings were in agreement to certain extent with the biomarkers results.

Conclusions

Both drug categories may be expressed as suitable therapeutic tools for atherosclerotic complications either alone or along with other hypolipidemic drugs.

Shikonin ameliorates experimental autoimmune encephalomyelitis (EAE) via immunomodulatory, anti‐apoptotic and antioxidative activity

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Multiple sclerosis is a common autoimmune inflammatory disease of the central nervous system. There are several underlying mechanisms for the pathogenesis of the disease, including inflammation, oligodendrocyte apoptosis and oxidative stress.

Methods

The mechanism of action of shikonin was investigated in the C57BL/6 experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.

Key findings

The results revealed that EAE induction significantly increased the extent of demyelination in the corpus callosum tissues of the animals, while treatment of the mice with shikonin significantly decreased the extent of demyelination. Real-time polymerase chain reaction-based analysis of the brain samples from the EAE mice revealed significant enhancement in the expression levels of tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and Bax genes as well as a reduction in the expression levels of transforming growth factor-ß (TGF-β) and Bcl2. But, shikonin treatment significantly reduced the expression levels of TNF-α, IFN-γ and Bax. On the other hand, the expression levels of TGF-β and Bcl2 as well as the activity of glutathione peroxidase-1 (GPX-1) enzyme were significantly increased following the shikonin treatment.

Conclusions

This study emphasized the immune-modulatory and antioxidative effects of shikonin, which may have an important healing effect on the severity of EAE.

Umbelliprenin relieves paclitaxel‐induced neuropathy

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Umbelliprenin (UMB) is a prenylated coumarin that acts as an in vitro antioxidant and inhibits lipoxygenase managing the inflammation pathways, while in vivo it exerts anti-inflammatory activities.

Methods

In this study, neuropathic pain was induced by four intraperitoneal doses of 2 mg/kg per day of paclitaxel (PTX) on days 1, 3, 5 and 7. Here, 49 male mice were randomly divided in the following groups: sham (not treated animals), negative control (PTX-treated receiving normal saline), single-dose UMB 6.25, 12.5 and 25 mg/kg groups (PTX-treated receiving UMB 6.25, 12.5 and 25 mg/kg, respectively), prevention (PTX-treated receiving PTX along with UMB 12.5 mg/kg on days 1, 3, 5 and 7) and positive control group (PTX-treated receiving imipramine 10 mg/kg as acute treatment). Hot-plate test was done to assess response to heat. Finally, interleukin (IL)-6 levels in the sciatic nerve and lipid peroxidation in sera were assessed.

Key findings

Umbelliprenin was found equally effective for acute treatment with imipramine, when comparing the prevention group and the positive control group. Single, 25 mg/kg UMB effectively attenuated hyperalgesia, lipid peroxidation and IL-6 levels.

Conclusions

Umbelliprenin alleviated neuropathic pain, and decreased serum IL-6 levels and oxidative stress. UMB deserves further investigations, especially in clinical settings.

Glucuronidation and its effect on the bioactivity of amentoflavone, a biflavonoid from Ginkgo biloba leaves

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Ginkgo biloba leaves contain amentoflavone (AMF), a dietary flavonoid that possesses antioxidant and anticancer activity. Flavonoids are extensively subjected to glucuronidation. This study aimed to determine the metabolic profile of AMF and the effect of glucuronidation on AMF bioactivity.

Methods

A pharmacokinetic study was conducted to determine the plasma concentrations of AMF and its metabolites. The metabolic profile of AMF was elucidated using different species of microsomes. The antioxidant activity of AMF metabolites was determined using DPPH/ABTS radical and nitric oxide assays. The anticancer activity of AMF metabolites was evaluated in U87MG/U251 cells.

Key findings

Pharmacokinetic studies indicated that the oral bioavailability of AMF was 0.06 ± 0.04%, and the area under the curve of the glucuronidated AMF metabolites (410.938 ± 62.219 ng/ml h) was significantly higher than that of AMF (194.509 ± 16.915 ng/ml h). UGT1A1 and UGT1A3 greatly metabolized AMF. No significant difference was observed in the antioxidant activity between AMF and its metabolites. The anticancer activity of AMF metabolites significantly decreased.

Conclusions

A low AMF bioavailability was due to extensive glucuronidation, which was mediated by UGT1A1 and UGT1A3. Glucuronidated AMF metabolites had the same antioxidant but had a lower anticancer activity than that of AMF.

Therapeutic effects of açaí seed extract on hepatic steatosis in high‐fat diet‐induced obesity in male mice: a comparative effect with rosuvastatin

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Obesity is considered a risk factor for the development of non-alcoholic fatty liver disease (NAFLD). The hydroalcoholic extract obtained from the açai seed (ASE), rich in proanthocyanidins, has been shown a potential body weight regulator with antioxidant properties. This study aimed to investigate the therapeutic effect of ASE in obesity-associated NAFLD and compare it with Rosuvastatin.

Methods

Male C57BL/6 mice received a high-fat diet or standard diet for 12 weeks. The treatments with ASE (300 mg/kg per day) or rosuvastatin (20 mg/kg per day) began in the eighth week until the 12th week.

Key findings

Our data show that the treatments with ASE and rosuvastatin reduced body weight and hyperglycaemia, improved lipid profile and attenuated hepatic steatosis in HFD mice. ASE and Rosuvastatin reduced HMGCoA-Reductase and SREBP-1C and increased ABGC8 and pAMPK expressions in the liver. Additionally, ASE, but not Rosuvastatin, reduced NPC1L1 and increased ABCG5 and PPAR-α expressions. ASE and rosuvastatin increased SIRT-1 expression and antioxidant defence, although only ASE was able to decrease the oxidative damage in hepatic tissue.

Conclusions

The therapeutic effect of ASE was similar to that of rosuvastatin in reducing dyslipidemia and hepatic steatosis but was better in reducing oxidative damage and hyperglycaemia.

Preclinical studies indicate that INFLATIV, an herbal medicine cream containing Pereskia aculeata, presents potential to be marketed as a topical anti‐inflammatory agent and as adjuvant in psoriasis therapy

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

A previous study reported that the hexane fraction (HF) obtained from Pereskia aculeata leaves showed promising topical anti-inflammatory activity. Intending its future use in clinical practice, a herbal medicine cream named INFLATIV was developed. Its anti-inflammatory and antipsoriatic potential were investigated. INFLATIV was subjected to preliminary accelerated stability tests and to a degradation profile assessment.

Methods

INFLATIV was prepared at 6% and 12%. The anti-inflammatory activity was assessed by croton oil single and multiple application challenge in mice. Mouse tail test was used for antipsoriatic potential investigation. Cutaneous atrophy test was performed. Preliminary accelerated stability tests were performed together with a degradation profile by GC-MS analysis.

Key findings

The anti-inflammatory activity shown by INFLATIV was comparable to dexamethasone. However, the skin atrophy caused by that drug was not observed. INFLATIV modified skin parakeratotic differentiation into orthokeratosis, which revealed its antipsoriatic potential. The ingredients used were suitable to carry the bioactives as they were well permeated by the skin. The preliminary accelerated stability tests indicated that INFLATIV 6% is more stable than 12%.

Conclusions

The results demonstrated the relevant therapeutic and marketing potentials of INFLATIV, which is likely to be further evaluated in clinical trials for drug registration process with regulatory agencies.

Characterization of metabolic activity, isozyme contribution and species differences of bavachin, and identification of efflux transporters for bavachin‐O‐glucuronide in HeLa1A1 cells

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters.

Methods

Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs.

Key findings

Five phase I metabolites (M1–M5) and three glucuronides (G1–G3) were identified. The CL _int values for M4 and G1 by HLM were 127.99 and 1159.07 μl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 μl/min per mg) and CYP2C9 (107.51 μl/min per mg), and UGT1A1 (697.19 μl/min per mg), UGT1A7 (535.78 μl/min per mg), UGT1A8 (247.72 μl/min per mg) and UGT1A9 (783.68 μl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches.

Conclusions

CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.

Characterization of lignans in Forsythiae Fructus and their metabolites in rats by ultra‐performance liquid chromatography coupled time‐of‐flight mass spectrometry

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

This study was designed to profile the chemical information of Forsythiae Fructus (FF) and investigate the in-vivo FF-related xenobiotics, especially for lignans.

Methods

Rats were oral administrated of FF and pinoresinol-4-O-glucoside, respectively. Blood and urine samples were collected after ingestion, and xenobiotics was profiled by an UPLC/Qtof MS method.

Key findings

A total of 19 lignans were identified or tentatively characterized in FF, and 63 lignan-related xenobiotics were found in rat plasma and urine after ingestion of FF. It was found that lignans could be transformed into metabolites by furan ring opening, hydrogenation, demethylation, dehydration and phase II reactions (sulfation and glucuronidation). The whole metabolic behaviour of bisepoxylignan was revealed by evaluating the metabolism of pinoresinol-4-O-glucoside in vivo. It was found that the configuration of C-8/C-8ʹ was retained after furan ring opening and metabolic reactions always occurred at position of C-3/C-4/C-5 or C-3ʹ/C-4ʹ/C-5ʹ. Additionally, other types components in FF and in vivo were also characterized.

Conclusions

This work revealed the in-vivo metabolism of FF, and reported the characteristic metabolic reactions of lignans for the first time. It was also provided the foundation for the further investigation on pharmacodynamic components of FF or TCMs containing FF.

Circadian clock regulates hepatotoxicity of Tripterygium wilfordii through modulation of metabolism

Huan Zhao, Yongbin Tong, Danyi Lu, Baojian Wu — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

We aimed to determine the diurnal rhythm of Tripterygium wilfordii (TW) hepatotoxicity and to investigate a potential role of metabolism and pharmacokinetics in generating chronotoxicity.

Methods

Hepatotoxicity was determined based on assessment of liver injury after dosing mice with TW at different circadian time points. Circadian clock control of metabolism, pharmacokinetics and hepatotoxicity was investigated using Clock-deficient (Clock ^−/−) mice.

Key findings

Hepatotoxicity of TW displayed a significant circadian rhythm (the highest level of toxicity was observed at ZT2 and the lowest level at ZT14). Pharmacokinetic experiments showed that oral gavage of TW at ZT2 generated higher plasma concentrations (and systemic exposure) of triptolide (a toxic constituent) compared with ZT14 dosing. This was accompanied by reduced formation of triptolide metabolites at ZT2. Loss of Clock gene sensitized mice to TW-induced hepatotoxicity and abolished the time-dependency of toxicity that was well correlated with altered metabolism and pharmacokinetics of triptolide. Loss of Clock gene also decreased Cyp3a11 expression in mouse liver and blunted its diurnal rhythm.

Conclusions

Tripterygium wilfordii chronotoxicity was associated with diurnal variations in triptolide pharmacokinetics and circadian expression of hepatic Cyp3a11 regulated by circadian clock. Our findings may have implications for improving TW treatment outcome with a chronotherapeutic approach.

Metabolome modulatory effects of Kigelia africana (Lam.) Benth. fruit extracts on oxidative stress, hyperlipidaemic biomarkers in STZ‐induced diabetic rats and antidiabetic effects in 3T3 L1 adipocytes

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

The management of diabetes is considered a global problem, and a cure is yet to be discovered. This study investigated the modulatory effect of Kigelia africana fruit on oxidative stress and hyperlipidaemic biomarkers in STZ-induced diabetic rats, profiled phytoconstituents using GC-TOF-MS and evaluated antidiabetic effects on 3T3 L1 adipocytes.

Methods

Thirty male Wistar rats (120–150 g) were divided into six groups (n = 5). Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) and treated with 100, 200 and 400 of hexane fraction of KA for 28 days. Immunohistochemical evaluation was carried out using avidin-biotin immunoperoxidase (ABI) method. Catalase and SOD activities as well as the levels of total protein, albumin, bilirubin, triglyceride, cholesterol, and high-density lipoprotein were measured.

Key findings

The expressions of oxidative stress and hyperlipidaemic biomarkers alongside fasting blood glucose concentrations were remarkedly decreased in KA-treated diabetic rats. Moreover, there was a significant increase in endocrine cell distribution, area covered with increase in β-cell mass, composition and morphology of KA-treated animals. Additionally, there was constant up-regulation in 3T3 L1 adipocytes due to the presence of phytoconstituents.

Conclusion

Kigelia africana fruit can act as a modulatory agent due to its ameliorative effects against oxidative stress.

Investigation on the metabolic characteristics of isobavachin in Psoralea corylifolia L. (Bu‐gu‐zhi) and its potential inhibition against human cytochrome P450s and UDP‐glucuronosyltransferases

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Isobavachin is a phenolic with anti-osteoporosis activity. This study aimed to explore its metabolic fates in vivo and in vitro, and to investigate the potential drug–drug interactions involving CYPs and UGTs.

Methods

Metabolites of isobavachin in mice were first identified and characterized. Oxidation and glucuronidation study were performed using liver and intestine microsomes. Reaction phenotyping, activity correlation analysis and relative activity factor approaches were employed to identify the main CYPs and UGTs involved in isobavachin metabolism. Through kinetic modelling, inhibition mechanisms towards CYPs and UGTs were also explored.

Key findings

Two glucuronides (G1 - G2) and three oxidated metabolites (M1 - M3) were identified in mice. Additionally, isobavachin underwent efficient oxidation and glucuronidation by human liver microsomes and HIM with CL_int values from 5.53 to 148.79 μl/min per mg. CYP1A2, 2C19 contributed 11.3% and 17.1% to hepatic metabolism of isobavachin, respectively, with CL_int values from 8.75 to 77.33 μl/min per mg. UGT1As displayed CL_int values from 10.73 to 202.62 μl/min per mg for glucuronidation. Besides, significant correlation analysis also proved that CYP1A2, 2C19 and UGT1A1, 1A9 were main contributors for the metabolism of isobavachin. Furthermore, mice may be the appropriate animal model for predicting its metabolism in human. Moreover, isobavachin exhibited broad inhibition against CYP2B6, 2C9, 2C19, UGT1A1, 1A9, 2B7 with K_i values from 0.05 to 3.05 μm.

Conclusions

CYP1A2, 2C19 and UGT1As play an important role in isobavachin metabolism. Isobavachin demonstrated broad-spectrum inhibition of CYPs and UGTs.

A comparative study on pharmacokinetics and tissue distribution of 5‐hydroxy‐4‐methoxycanthin‐6‐one and its metabolite in normal and dextran sodium sulfate‐induced colitis rats by HPLC‐MS/MS

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

This study aimed to investigate the existing form of 5-hydroxy-4-methoxycanthin-6-one (PQ-A) in vivo after oral administration and the effects on its pharmacokinetics and tissue distribution by colitis.

Methods

A rapid HPLC-MS/MS method was established to simultaneously determine PQ-A and its main metabolite, 1-methoxicabony-β-carboline (PQ-B), in biological samples acquired from normal and dextran sodium sulfate (DSS)-induced colitic rats administered orally with PQ-A. Then, the pharmacokinetics of both PQ-A and PQ-B, and tissue distribution of PQ-A in the above two states were analysed.

Key findings

The pharmacokinetic results showed that the prototype of PQ-A was the main existing form in both physiological and pathological conditions. And significant difference between the above two status in pharmacokinetics of PQ-A was observed, such as higher exposure and longer elimination in colitis than that in normal rats. It suggested that the pharmacokinetics of medications for colitis was affected by enteritis. The tissue distribution studies displayed that PQ-A mainly accumulated in intestinal tract. Especially, the distribution of PQ-A in intestinal tract was increased obviously in colitic rats.

Conclusions

These results contributed to further illuminate the ADME process of PQ-A in different status and were prospected to be the reference to the clinical application of similar medicines in pathological states.

Catechol protects against iron‐mediated oxidative brain injury by restoring antioxidative metabolic pathways; and modulation of purinergic and cholinergic enzymes activities

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

This study was aimed at investigating neuroprotective effect of catechol on redox imbalance, cholinergic dysfunctions, nucleotide hydrolysing enzymes activities, and dysregulated metabolic pathways in iron-mediated oxidative brain injury.

Methods

Oxidative injury was induced in brain tissues by incubating with 0.1 mm FeSO₄ and treated with different concentrations of catechol.

Key findings

Catechol significantly elevated glutathione level, superoxide dismutase and catalase activities, while depleting malondialdehyde and nitric oxide levels. It also inhibited the activities of acetylcholinesterase, butyrylcholinesterase, and ATPase, with concomitant elevation of ENTPDase activity. GC-MS analysis revealed that treatment with catechol completely depleted oxidative-generated lipid metabolites. While LC-MS analysis revealed depletion of oxidative-generated metabolites in brain tissues treated with catechol, with concomitant restoration of oxidative-depleted metabolites. Catechol also led to reactivation of oxidative-inactivated taurine and hypotaurine, purine, glutathione, glycerophospholipid, nicotinate and nicotinamide, fructose and mannose, pyrimidine metabolisms and pentose phosphate pathways. Catechol was predicted in silico to be permeable across the blood–brain barrier with a predicted oral LD₅₀ value of 100 mg/kg and a toxicity class of 3.

Conclusion

These results suggest the neuroprotective effects of catechol in iron-mediated oxidative brain injury.

Population pharmacokinetics of micafungin over repeated doses in critically ill patients: a need for a loading dose?

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

To study the population pharmacokinetics of micafungin in critically ill patients, evaluate and optimize dosage regimens.

Methods

An HPLC–fluorescence bioassay for micafungin was developed, fully validated and applied to a pharmacokinetic study conducted in 14 ICU patients. Dense blood sampling was performed from days 1 to 7. A population pharmacokinetic model accounting for interindividual (IIV) and interoccasion variability (IOV) of the PK parameters was developed. Simulations were performed to estimate the probability of target attainment (PTA) for several dosing regimens.

Key findings

A two-compartment pharmacokinetic model best described the data, with population clearance CL = 1.31 L/h and central volume V1 = 14.2 L. The relatively high IOV observed (45% for CL, 27% for V1) sets limits for the dose individualization in this population. The low PTA on the first day of treatment suggests the need of a loading dose. PTA and CFR estimates show that the current micafungin dosage may be insufficient for the treatment of borderline susceptible Candida strains.

Conclusions

A loading dose of up to 300 mg of micafungin is needed for the treatment of invasive candidiasis in ICU patients while a maintenance dose of up to 200 mg can be considered in empirical antifungal treatment.

Berberine, a natural alkaloid sensitizes human hepatocarcinoma to ionizing radiation by blocking autophagy and cell cycle arrest resulting in senescence

Gautham Ramesh, Shubhankar Das, Satish Rao Bola Sadashiva — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objective

To study the radiosensitizing potential of Berberine and the underlying mechanism in human hepatocarcinoma (HepG2) cells.

Methods

HepG2 cells were challenged with X-rays in combination with Berberine treatment and several in vitro assays were performed. Alteration in cell viability was determined by MTT assay. Changes in intracellular ROS levels, mitochondrial membrane potential/mass, intracellular acidic vesicular organelles as well as cell cycle arrest and apoptotic cell death were analysed by flow cytometry. Induction of autophagy was assessed by staining the cells with Monodansylcadaverine/Lysotracker red dyes and immunoblotting for LC3I/II and p62 proteins. Phase-contrast/fluorescence microscopy was employed to study mitotic catastrophe and senescence. Cellular senescence was confirmed by immunoblotting for p21 levels and ELISA for Interleukin-6.

Key findings

X-rays + Berberine had a synergistic effect in reducing cell proliferation accompanied by a robust G2/M arrest. Berberine-mediated radiosensitization was associated with elevated levels of LC3II and p62 suggesting blocked autophagy that was followed by mitotic catastrophe and senescence. Treatment of cells with X-rays + Berberine resulted in increased oxidative stress, hyperpolarized mitochondria with increased mitochondrial mass and reduced ATP levels.

Conclusions

The study expands the understanding of the pharmacological properties of Berberine and its applicability as a radiosensitizer towards treating liver cancer.

The hepatoprotective effect and mechanism of lotus leaf on liver injury induced by Genkwa Flos

Zhipeng Wang, Panpan Zhao, Yuanyuan Zhang, Shan Shi, Xiaohui Chen — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

As a traditional Chinese medicine, lotus leaf was reported to have significant hepatoprotective effect. To explore the hepatoprotective mechanism of lotus leaf, a rapid and reliable UPLC-MS/MS method was conducted to simultaneously determine six specific endogenous substances including 5-oxoproline, phenylalanine, tryptophan, C₁₈-phytosphingosine, lysophosphatidylcholine (16 : 0) and lysophosphatidylcholine (18 : 1).

Methods

With the help of HPLC–FT-ICR-MS, the chemical constituents of louts leaf extract were elucidated. By observing histopathological changes and determining hepatotoxicity-related biochemical indicators, rat model of liver injury was developed and the hepatoprotective effect of lotus leaf was verified. With the developed UPLC-MS/MS method, six endogenous metabolites related to hepatotoxicity were monitored to investigate the hepatoprotective mechanism of lotus leaf.

Key findings

In the qualitative analysis, a total of twenty compounds including ten flavonoids, nine alkaloids and one proanthocyanidin were identified. Based on the results of determining six endogenous metabolites related to hepatotoxicity, it was predicted that the hepatoprotective mechanism of lotus leaf might be related to glutathione metabolism, phenylalanine metabolism, tryptophan metabolism, sphingolipid metabolism and phospholipid metabolism.

Conclusions

This study could be a meaningful investigation to provide mechanistic insights into the hepatoprotective effect of lotus leaf and further lay a theoretical basis for the clinical application of lotus leaf.

Pinoresinol‐4‐O‐β‐D‐glucopyranoside: a lignan from prunes (Prunus domestica) attenuates oxidative stress, hyperglycaemia and hepatic toxicity in vitro and in vivo

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

This study aimed to explore the pharmacological properties of pinoresinol-4-O-β-D-glucopyranoside (PG), isolated from prunes.

Methods

In-vitro antioxidant activity was assessed using ferric reducing antioxidant power (FRAP) and 2,2'-azino-bis [3-ethylbenzothiazoline-6-sulfonic acid]-diammonium salt (ABTS) assays. In-vivo hepatoprotective activity was evaluated using CCl₄-induced hepatotoxicity mouse model. The antihyperglycaemic activity was determined in vitro using α-glucosidase and α-amylase inhibiting activity and in vivo using streptozotocin-treated model. Molecular modelling was done on α-amylase, α-glucosidase, aldose reductase and peroxisome proliferator-activated receptor gamma.

Key findings

Pinoresinol-4-O-β-D-glucopyranoside showed promising antioxidant activity in FRAP and ABTS assays with total antioxidant capacity equal 418.47 and 1091.3 µmol/g in terms of ascorbic acid, respectively. PG (50 mg/kg b.w.) exhibited a hepatoprotective activity in vivo as it lowered AST and ALT levels. PG showed a potent in-vitro antihyperglycaemic activity as it inhibited α-glucosidase with an IC₅₀ value of 48.13 μg/ml. PG caused a prominent decline in serum glucose level by 37.83% in streptozotocin-treated mice with promising elevation in insulin level of 25.37%. Oxidative stress markers were reduced by PG, and it showed a high fitting on α-amylase and α-glucosidase active sites.

Conclusions

Pinoresinol-4-O-β-D-glucopyranoside is a natural entity combating oxidative stress, hepatic damage and diabetes.

Issue Information

Tue, 03 Nov 2020 08:05:53 -0800

Journal of Pharmacy and Pharmacology, Volume 72, Issue 12, Page i-iv, December 2020.

Carissa carandas L. – phyto‐pharmacological review

Sonia Singh, Meenakshi Bajpai, Pradeep Mishra — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

Carissa carandas is an evergreen thorny shrub (Apocynaceae family), commonly, known as karonda. It has small berry-shaped fruits, used as additive in many pickles or as a spice in northern India.

Methods

The present review covers the literature survey from 1968 to 2020. The data have been collected from various journals, books, thesis and some of the electronic search via Internet-based information such as PubMed, Google Scholar, ScienceDirect, EBSCO, online electronic journals, SpringerLink, Wiley and Ayush.

Key findings

From literature survey, it has been found that the herbal drug contains wide variety of flavonoids, phenolic acids, steroids, volatile oils, lignans, alkaloids, polysaccharides and so on. These phytochemicals exhibit a range of pharmacological activities including antioxidant, anti-inflammatory, antidiabetic, antimicrobial and antifungal properties.

Conclusions

This current review offers primary data for further research work. The in-vitro evaluations as well as in-vivo models/experiments have provided a biosynthetic observation for its various ethno-pharmacological uses and even pharmacological properties. This review would provide all valuable information which will be beneficiary to conduct some important pharmacokinetic and toxicological research works on human models with respect to ensure the effects of active ingredients in the body and even to validate its safety issues in clinical aspects.

A comprehensive review of therapeutic approaches available for the treatment of cholera

Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

The oral rehydration solution is the most efficient method to treat cholera; however, it does not interfere in the action mechanism of the main virulence factor produced by Vibrio cholerae, the cholera toxin (CT), and this disease still stands out as a problem for human health worldwide. This review aimed to describe therapeutic alternatives available in the literature, especially those related to the search for molecules acting upon the physiopathology of cholera.

Key findings

New molecules have offered a protection effect against diarrhoea induced by CT or even by infection from V. cholerae. The receptor regulator cystic fibrosis channel transmembrane (CFTR), monosialoganglioside (GM1), enkephalinase, AMP-activated protein kinase (AMPK), inhibitors of expression of virulence factors and activators of ADP-ribosylarginine hydrolase are the main therapeutic targets studied. Many of these molecules or extracts still present unclear action mechanisms.

Conclusions

Knowing therapeutic alternatives and their molecular mechanisms for the treatment of cholera could guide us to develop a new drug that could be used in combination with the rehydration solution.

Recent trends in targeting miRNAs for cancer therapy

Vandit Shah, Jigna Shah — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

MicroRNAs (miRNAs) are a type of small noncoding RNA employed by the cells for gene regulation. A single miRNA, typically 22 nucleotides in length, can regulate the expression of numerous genes. Over the past decade, the study of miRNA biology in the context of cancer has led to the development of new diagnostic and therapeutic opportunities.

Key findings

MicroRNA dysregulation is commonly associated with cancer, in part because miRNAs are actively involved in the mechanisms like genomic instabilities, aberrant transcriptional control, altered epigenetic regulation and biogenesis machinery defects. MicroRNAs can regulate oncogenes or tumour suppressor genes and thus when altered can lead to tumorigenesis. Expression profiling of miRNAs has boosted the possibilities of application of miRNAs as potential cancer biomarkers and therapeutic targets, although the feasibility of these approaches will require further validation.

Summary

In this review, we will focus on how miRNAs regulate tumour development and the potential applications of targeting miRNAs for cancer therapy.

C2C12 cell model: its role in understanding of insulin resistance at the molecular level and pharmaceutical development at the preclinical stage

Chun Y. Wong, Hani Al‐Salami, Crispin R. Dass — Tue, 03 Nov 2020 08:05:53 -0800

Abstract

Objectives

The myoblast cell line, C2C12, has been utilised extensively in vitro as an examination model in understanding metabolic disease progression. Although it is indispensable in both preclinical and pharmaceutical research, a comprehensive review of its use in the investigation of insulin resistance progression and pharmaceutical development is not available.

Key findings

C2C12 is a well-documented model, which can facilitate our understanding in glucose metabolism, insulin signalling mechanism, insulin resistance, oxidative stress, reactive oxygen species and glucose transporters at cellular and molecular levels. With the aid of the C2C12 model, recent studies revealed that insulin resistance has close relationship with various metabolic diseases in terms of disease progression, pathogenesis and therapeutic management. A holistic, safe and effective disease management is highly of interest. Therefore, significant efforts have been paid to explore novel drug compounds and natural herbs that can elicit therapeutic effects in the targeted sites at both cellular (e.g. mitochondria, glucose transporter) and molecular level (e.g. genes, signalling pathway).

Summary

The use of C2C12 myoblast cell line is meaningful in pharmaceutical and biomedical research due to their expression of GLUT-4 and other features that are representative to human skeletal muscle cells. With the use of the C2C12 cell model, the impact of drug delivery systems (nanoparticles and quantum dots) on skeletal muscle, as well as the relationship between exercise, pancreatic β-cells and endothelial cells, was discovered.