Apocynin-loaded PLGA nanomedicine tailored with galactosylated chitosan intrigue asialoglycoprotein receptor in hepatic carcinoma: Prospective targeted therapy.

Nature serves as a priceless source for phytomedicines to treat different types of cancer, including hepatocellular carcinoma (HCC). Apocynin (APO), an anti-cancer phytomedicine, is a particular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH-oxidase) inhibitor, which has recently dawned for its multilateral pharmacological activities. As far as we are aware, no investigation has been carried out yet to develop a targeted-nanostructured delivery system of APO to HCC. Consequently, chitosan derivative with galactose groups namely; galactosylated chitosan (GC), particularly recognized by the asialoglycoprotein receptor (ASGR), was synthesized and its chemical structure was thoroughly characterized by substantial techniques. Afterwards, GC-coated nanoplatform for hepatocyte attachment "APO-loaded galactosylated chitosan-coated poly(d,l-lactide-co-glycolide) nanoparticles (APO-loaded GC-coated PLGA NPs)" was developed. The prosperous APO-loaded GC-coated PLGA NPs would be comprehensively appraised through extensive investigations. Their solid state characterization using Fourier transform-infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry proved APO's encapsulation in the polymeric matrix. Transmission electron microscopy imaging of the investigated NPs highlighted their spherical architecture with a nanosized range and a characteristic halo-like appearance traceable to the GC coating of the NPs' surface. Saliently, the results of in vitro cytotoxicity screening revealed the spectacular anti-cancer efficacy of APO-loaded GC-coated PLGA NPs formula against the HepG2 cell line. Moreover, the fluorescence microscope disclosed the distinguished cellular uptake of such formula via ASGPR mediated endocytosis. Inclusively, a multifunctional nano-phytomedicine delivery system with a promising active hepatocyte-targeting, effective uptake into HepG2 cells, and sustained drug release pattern was successfully developed.

Hollow Nanooxidase Enhanced Phototherapy Against Solid Tumors.

Although phototherapy has attracted extensive attention in antitumor field in recent years, its therapeutic effect is usually unsatisfactory because of the complexity and variability of the tumor microenvironment (TME). Herein, we report novel CoSn(OH)6@CoOOH hollow carriers with oxidase properties that can enhance phototherapy. Hollow CoSn(OH)6@CoOOH nanocubes (NCs) with a particle size of ∼160 nm were synthesized via a two-step process of coprecipitation and etching. These NCs can react with O2 to generate singlet oxygen without hydrogen peroxide and consume glutathione, and their hollow structure can be utilized to carry drug molecules. After loading indocyanine green (ICG) and 1,2-bis(2-(4,5-dihydro-1H-imidazol-2-yl)propan-2-yl) diazene dihydrochloride (AIPH), the resulting nanosystem (HCIA) exhibited enhanced phototherapy effects through the catalytic activity of oxidase, production of alkyl radicals, and consumption of glutathione. Cell and mouse experiments showed that HCIA combined with near-infrared laser irradiation significantly inhibited the growth of 4T1 tumors. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that PI3K-Akt and MAPK signaling pathways were highly relevant to this therapeutic system. Such hollow NCs with oxidase activity have considerable potential for the design of multifunctional drug delivery vehicles for tumor therapy.

Selenium and vitamin B6 cosupplementation improves dyslipidemia and fatty liver syndrome by SIRT1/SREBP-1c pathway in hyperlipidemic Sprague-Dawley rats induced by high-fat diet.

Previously, our group found that the dietary trace mineral element selenium and vitamin B6 (VitB6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1, increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element-binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation.

Phytotherapy for male luts: What happens then? 10-year research.

INTRODUCTION AND OBJECTIVES: Our objective is to assess the long-term results of phytotherapy, focusing on the interval between phytotherapy and pharmacological treatment and the predisposing risk factors to such switch on a 10-year follow-up. MATERIAL AND METHODS: The data of patients taking phytotherapy for mild to moderate male lower urinary tract symptoms (LUTS) from January to December 2010 were retrospectively reviewed from a prospectively maintained database. Patients were followed for 10 years through medical visits and telephone consultations. RESULTS: 102 patients underwent at least one cycle of phytotherapy for LUTS. Twenty (19.6%) patients resolved their symptoms after one phytotherapy cycle and stopped any treatment, 27 (26.4%) continued phytotherapy, and 52 (51%) switched to alpha-blockers and/or 5a-reductase inhibitors after a median interval of 24 months. The reasons for treatment switch were symptoms (n = 45) or clinical progression (increased residual volume n = 15; urinary retention, n = 5). Patients switching to synthetic drugs had median higher age (60 vs 49), prostate volume (40 vs 26 cc), prostate specific antigen (PSA) (1.9 vs 0.9 ng/ml), residual volume (40 vs 0 cc), and a lower maximum flow rate (Qmax) (12 vs 15 ml/s) at presentation. CONCLUSIONS: 46% patients with mild to moderate LUTS undergoing phytotherapy will be either free of treatment or still on phytotherapy at 10 years from disease presentation. Older patients with larger prostates, increased residual volume and PSA, should be informed regarding their higher risk of symptomatic or clinical progression: the risk of a treatment switch to alpha-blockers or 5a-reductase inhibitors becomes an actual fact after an average span of 2 years.

Enzyme/Nanocopper Hybrid Nanozymes: Modulating Enzyme-like Activity by the Protein Structure for Biosensing and Tumor Catalytic Therapy.

Artificial enzymes with modulated enzyme-mimicking activities of natural systems represent a challenge in catalytic applications. Here, we show the creation of artificial Cu metalloenzymes based on the generation of Cu nanoparticles in an enzyme matrix. Different enzymes were used, and the structural differences between the enzymes especially influenced the controlled the size of the nanoparticles and the environment that surrounds them. Herein, we demonstrated that the oxidase-like catalytic activity of these copper nanozymes was rationally modulated by enzyme used as a scaffold, with a special role in the nanoparticle size and their environment. In this sense, these nanocopper hybrids have confirmed the ability to mimic a unique enzymatic activity completely different from the natural activity of the enzyme used as a scaffold, such as tyrosinase-like activity or as Fenton catalyst, which has extremely higher stability than natural mushroom tyrosinase. More interestingly, the oxidoreductase-like activity of nanocopper hybrids was cooperatively modulated with the synergistic effect between the enzyme and the nanoparticles improving the catalase activity (no peroxidase activity). Additionally, a novel dual (metallic and enzymatic activity) of the nanozyme made the highly improved catechol-like activity interesting for the design of 3,4-dihydroxy-l-phenylalanine (l-DOPA) biosensor for detection of tyrosinase. These hybrids also showed cytotoxic activity against different tumor cells, interesting in biocatalytic tumor therapy.

Peroxisomal Acyl-CoA Oxidase Type 1: Anti-Inflammatory and Anti-Aging Properties with a Special Emphasis on Studies with LPS and Argan Oil as a Model Transposable to Aging.

To clarify appropriateness of current claims for health and wellness virtues of argan oil, studies were conducted in inflammatory states. LPS induces inflammation with reduction of PGC1-α signaling and energy metabolism. Argan oil protected the liver against LPS toxicity and interestingly enough preservation of peroxisomal acyl-CoA oxidase type 1 (ACOX1) activity against depression by LPS. This model of LPS-driven toxicity circumvented by argan oil along with a key anti-inflammatory role attributed to ACOX1 has been here transposed to model aging. This view is consistent with known physiological role of ACOX1 in yielding precursors of specialized proresolving mediators (SPM) and with characteristics of aging and related disorders including reduced PGC1-α function and improvement by strategies rising ACOX1 (via hormonal gut FGF19 and nordihydroguaiaretic acid in metabolic syndrome and diabetes conditions) and SPM (neurodegenerative disorders, atherosclerosis, and stroke). Delay of aging to resolve inflammation results from altered production of SPM, SPM improving most aging disorders. The strategic metabolic place of ACOX1, upstream of SPM biosynthesis, along with ability of ACOX1 preservation/induction and SPM to improve aging-related disorders and known association of aging with drop in ACOX1 and SPM, all converge to conclude that ACOX1 represents a previously unsuspected and currently emerging antiaging protein.

Pharmacological interventions for the treatment of neonatal jaundice.

In the neonate, hyperbilirubinaemia is usually due to a combination of an increased bilirubin load and decreased bilirubin elimination. Despite an understanding of the enzymatic pathways leading to bilirubin production and elimination, very few pharmacological interventions to prevent hyperbilirubinaemia are utilized and the mainstay of treatment remains phototherapy. Previously studied pharmacological agents such as D-penicillamine, phenobarbital and clofibrate may yet prove useful. Recent clinical trials using metalloporphyrins to inhibit heme catabolism and bilirubin production provides a novel pharmacological intervention for the treatment of neonatal jaundice. The safety and efficacy of these therapies will need to be confirmed prior to widespread use.

A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia.

BACKGROUND: Androgenetic alopecia (AGA) is characterized by the structural miniaturization of androgen-sensitive hair follicles in susceptible individuals and is anatomically defined within a given pattern of the scalp. Biochemically, one contributing factor of this disorder is the conversion of testosterone (T) to dihydrotestosterone (DHT) via the enzyme 5-alpha reductase (5AR). This metabolism is also key to the onset and progression of benign prostatic hyperplasia (BPH). Furthermore, AGA has also been shown to be responsive to drugs and agents used to treat BPH. Of note, certain botanical compounds have previously demonstrated efficacy against BPH. Here, we report the first example of a placebo-controlled, double-blind study undertaken in order to examine the benefit of these botanical substances in the treatment of AGA. OBJECTIVES: The goal of this study was to test botanically derived 5AR inhibitors, specifically the liposterolic extract of Serenoa repens (LSESr) and beta-sitosterol, in the treatment of AGA. SUBJECTS: Included in this study were males between the ages of 23 and 64 years of age, in good health, with mild to moderate AGA. RESULTS: The results of this pilot study showed a highly positive response to treatment. The blinded investigative staff assessment report showed that 60% of (6/10) study subjects dosed with the active study formulation were rated as improved at the final visit. CONCLUSIONS: This study establishes the effectiveness of naturally occurring 5AR inhibitors against AGA for the first time, and justifies the expansion to larger trials.

Polyethylene glycol-modified bilirubin oxidase improves hepatic energy charge and urinary prostaglandin levels in rats with obstructive jaundice.

BACKGROUNDS/AIMS: No study has so far been conducted to clarify whether the presence of hyperbilirubinemia is detrimental to liver and renal functions. In the present study, the effects of polyethylene glycol-modified bilirubin oxidase (PEG-BOX) therapy on liver and renal function tests, hepatic energy charge and urinary prostaglandin levels were evaluated in a rat model of obstructive jaundice. METHODS: Sprague-Dawley rats were used in the experimental model of obstructive jaundice. PEG-BOX or an equivalent amount of PEG alone was intravenously injected into the animals and sampling of blood and urine, and liver harvesting were done sequentially after bile duct ligation. RESULTS: Conventional liver function tests showed no difference between PEG-BOX and control groups. However, bilirubin concentrations in the peripheral blood and liver tissue specimens markedly decreased, and the hepatic energy charge significantly increased in the PEG-BOX group as compared to controls. The blood concentration of bile acid was lower, but its urinary excretion was higher in the PEG-BOX group than in the control group. In vitro incubation of PEG-BOX with serum from rats with obstructive jaundice decreased the concentration of bilirubin but not that of bile acid. The urinary levels of prostaglandin E2 and the thromboxane B2/6-keto-prostaglandin Fla ratio were significantly lower in the PEG-BOX group than in the control group. CONCLUSIONS: The systemic reduction of bilirubin concentration may contribute to normalization of the urinary levels of prostaglandins and thromboxane B2, to decrease in serum bile acid levels, and to improvement of the hepatic energy charge in obstructive jaundice. These findings suggest that preoperative improvement of jaundice may be beneficial to patients with obstructive jaundice.