Transition Metal-Catalyzed Transformations of Chalcones.

Chalcones are a class of naturally occurring flavonoid compounds associated to a variety of biological and pharmacological properties. Several reviews have been published describing the synthesis and biological properties of a vast array of analogues. However, overviews on the reactivity of chalcones has only been explored in a few accounts. To fill this gap, a systematic survey on the most recent developments in the transition metal-catalyzed transformation of chalcones was performed. The chemistry of copper, palladium, zinc, iron, manganese, nickel, ruthenium, cobalt, rhodium, iridium, silver, indium, gold, titanium, platinum, among others, as versatile catalysts will be highlighted, covering the literature from year 2000 to 2023, in more than 380 publications.

Comparative metabolomics of leaves and stems of three Italian olive cultivars under drought stress.

The Mediterranean will be one of the focal points of climate change. The predicted dry and hot summers will lead to water scarcity in agriculture, which may limit crop production and growth. The olive tree serves as a model woody plant for studying drought stress and improving water resource management; thus, it is critical to identify genotypes that are more drought tolerant and perform better under low irrigation or even rainfed conditions. In this study, the metabolomic approach was used to highlight variations in metabolites in stems and leaves of three Italian olive cultivars (previously characterized physiologically) under two and four weeks of drought stress. Phenolic and lipophilic profiles were obtained by gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry, respectively. The findings identified the leaf as the primary organ in which phenolic variations occurred. The Maurino cultivar exhibited a strong stress response in the form of phenolic compound accumulation, most likely to counteract oxidative stress. The phenolic compound content of 'Giarraffa' and 'Leccino' plants remained relatively stable whether they were exposed to drought or not. Variations in the lipid profile occurred in leaves and stems of all the cultivars. A high accumulation of compounds related to epicuticular wax components was observed in the leaf of 'Giarraffa', while a strong reduction of lipids and long-chain alkanes occurred in 'Maurino' when exposed to drought stress conditions.

An in-depth exploration of six decades of the Kröhnke pyridine synthesis - a review.

The Kröhnke Pyridine Synthesis has been discovered about six decades ago (1961), by Fritz Kröhnke and Wilfried Zecher at the University of Giessen. The original method involved the reaction of α-pyridinium methyl ketone salts with α,ß-unsaturated carbonyl compounds in the presence of a nitrogen source, frequently ammonium acetate. Since its discovery, the Kröhnke methodology has been demonstrated to be suitable for the preparation of mono-, di-, tri- and tetra-pyridines, with important applications in several research fields. Over the years, a number of modifications to the original approach have been developed and reported, enabling for the broad applicability of these methods even in modern days, also for the synthesis of non-pyridine compounds. In this critical and tutorial review, we will thoroughly explore and discuss the potential of the original method, the refinements that have been made over the years, as well as some applications arising from each type of pyridine and/or non-pyridine compounds produced by Kröhnke's approach.

Pyrazoles have a multifaceted anti-inflammatory effect targeting prostaglandin E2, cyclooxygenases and leukocytes' oxidative burst.

Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

Recent Advances in Fluorescent Theranostics for Alzheimer's Disease: A Comprehensive Survey on Design, Synthesis, and Properties.

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia that is rapidly becoming a major health problem, especially in developed countries because of their increasing life expectancy. Two main problems are often associated with the disease: (i) the absence of a widely accessible "gold-standard" for early diagnosis and (ii) lack of effective therapies with disease-modifying effects. The recent success of the monoclonal antibody lecanemab played an important role not only in clarifying a possible druggable pathway but also in spelling the revival of small molecule drug discovery. Unlike bulky biologics, small molecules are structurally less complex, generally cheaper, and compatible with at-home oral consumption, making it feasible for people to start their drug regimen early and stay on it longer. In this sense, small-molecule near-infrared fluorescent theranostics have been gaining more and more attention from the scientific community, as they have the potential to simultaneously provide diagnostic outputs and deliver therapeutic action, paving the way toward personalized medicine in AD patients. They also have the potential to shift the diagnostic "status-quo" from expensive and limited-access PET radiotracers toward inexpensive and handy imaging tools widely available for primary patient screening and preclinical animal studies. Herein, we review the most recent advances in the field of fluorescent theranostics for Alzheimer's disease, detailing their design strategies, synthetic approaches and imaging and therapeutic properties in vitro and in vivo. With this Review, we intend to provide a milestone in the acquired knowledge in the field of AD theranostics, encouraging the future development of properly designed theranostic compounds with improved chances to reach clinical applications.

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective.

Since the beginning of the XXI century, Leishmaniasis has been integrated into the World Health Organization's list of the 20 neglected tropical diseases, being considered a public health issue in more than 88 countries, especially in the tropics, subtropics, and the Mediterranean area. Statistically, this disease presents a world prevalence of 12 million cases worldwide, with this number being expected to increase shortly due to the 350 million people considered at risk and the 2-2.5 million new cases appearing every year. The lack of an appropriate and effective treatment against this disease has intensified the interest of many research groups to pursue the discovery and development of novel treatments in close collaboration with the WHO, which hopes to eradicate it shortly. This paper intends to highlight the quinoline scaffold's potential for developing novel antileishmanial agents and provide a set of structural guidelines to help the research groups in the medicinal chemistry field perform more direct drug discovery and development programs. Thus, this review paper presents a thorough compilation of the most recent advances in the development of new quinoline-based antileishmanial agents, with a particular focus on structure-activity relationship studies that should be considerably useful for the future of the field.

Fucus vesiculosus-Rich Extracts as Potential Functional Food Ingredients: A Holistic Extraction Approach.

Brown macroalgae are rich sources of nutrients and health-promoting compounds. Nevertheless, their consumption is still limited by their strong organoleptic characteristics, thus requiring the development of extraction strategies to profit from their nutritional value. To fulfil this, two sequential extraction approaches were developed, differing in the solvent used in the first extraction step, water in approach 1 or food-grade ethanol in approach 2, to obtain economic and affordable extracts rich in specific compounds from Fucus vesiculosus. The use of water in the first step of extraction allowed us to recover water-soluble phlorotannins, laminarans and mannuronic-rich alginates, making the subsequent 70% ethanol extract richest in fucoxanthin (0.07% algae DW), and the hot water fractions purest in fucoidans and alginates with a lower mannuronic-to-guluronic (M/G) ratio (2.91). Conversely, when beginning extraction procedures with 96% ethanol, the recovered yields of phlorotannins increased (0.43 g PGE/100 g algae DW), but there was a concomitant seven-fold decrease in the recovery of fucoxanthin in the subsequent 70% ethanol extract. This approach also led to less pure hot water fractions containing fucoidans, laminarans and alginates with a higher M/G ratio (5.50). Overall, this work unveiled the potential of the first extraction steps in sustainable and holistic cascade strategies to modulate the composition of food-grade extracts, creating prospects of their application as tailored functional ingredients in food products.

Melanoxetin: A Hydroxylated Flavonoid Attenuates Oxidative Stress and Modulates Insulin Resistance and Glycation Pathways in an Animal Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E2 levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.

Influenza A virus propagation requires the activation of the unfolded protein response and the accumulation of insoluble protein aggregates.

Influenza A virus (IAV) employs multiple strategies to manipulate cellular mechanisms and support proper virion formation and propagation. In this study, we performed a detailed analysis of the interplay between IAV and the host cells' proteostasis throughout the entire infectious cycle. We reveal that IAV infection activates the inositol requiring enzyme 1 (IRE1) branch of the unfolded protein response, and that this activation is important for an efficient infection. We further observed the accumulation of virus-induced insoluble protein aggregates, containing both viral and host proteins, associated with a dysregulation of the host cell RNA metabolism. Our data indicate that this accumulation is important for IAV propagation and favors the final steps of the infection cycle, more specifically the virion assembly. These findings reveal additional mechanisms by which IAV disrupts host proteostasis and uncovers new cellular targets that can be explored for the development of host-directed antiviral strategies.

Drug Discovery Based on Oxygen and Nitrogen (Non-)Heterocyclic Compounds Developed @LAQV-REQUIMTE/Aveiro.

Artur Silva's research group has a long history in the field of medicinal chemistry. The development of new synthetic methods for oxygen (mostly polyphenols, e.g., 2- and 3-styrylchromones, xanthones, flavones) and nitrogen (e.g., pyrazoles, triazoles, acridones, 4-quinolones) heterocyclic compounds in order to be assessed as antioxidant, anti-inflammatory, antidiabetic, and anticancer agents has been the main core work of our research interests. Additionally, the synthesis of steroid-type compounds as anti-Alzheimer drugs as well as of several chromophores as important dyes for cellular imaging broadened our research scope. In this review article, we intend to provide an enlightened appraisal of all the bioactive compounds and their biological properties that were synthesized and studied by our research group in the last two decades.

Gossypetin Is a Novel Modulator of Inflammatory Cytokine Production and a Suppressor of Osteosarcoma Cell Growth.

Osteosarcoma (OS) is a common childhood sarcoma, and its treatment is hindered by adverse effects, chemoresistance, and recurrence. Interleukin (IL)-6 production by tumors plays a significant role in inflammation, carcinogenesis, and metastasis. This study aimed to investigate the antiproliferative potential of luteolin derivatives in OS and to evaluate interleukin production. MG-63, Saos-2, HOS, and 143B human OS cell lines were incubated with luteolin and eight derivatives containing hydroxy, chlorine, or alkyl substitutions. The cell viability and growth were evaluated in the presence of these compounds. Apoptosis was also examined through the analysis of the Bax expression and caspase-3 activity. Finally, the gossypetin effects were measured regarding the production of proinflammatory cytokines interleukin (IL)-6, IL-1ß, and IL-12p70. Our findings show that gossypetin was the most potent compound, with proliferation-suppressing activities that induced a series of critical events, including the inhibition of the cell viability and growth. Apoptosis was associated with enhanced caspase-3 activity and increased Bax expression, indicating the involvement of the intrinsic pathway of apoptosis. Moreover, pre-/co-treatment with gossypetin significantly reduced the autocrine production of proinflammatory cytokines. Further investigation is required; nevertheless, considering the link between inflammation, carcinogenesis, and metastasis in OS, our findings suggest that gossypetin exhibits anti-proliferative and anti-inflammatory properties that are potentially relevant in the clinical context.

Special Issue "Recent Advances in the Synthesis, Functionalization and Applications of Pyrazole-Type Compounds II".

Pyrazole and its derivatives are considered privileged N-heterocycles with immense therapeutic potential [...].

In Vitro Antiprotozoal Activity of Hibiscus sabdariffa Extract against a Ciliate Causing High Mortalities in Turbot Aquaculture.

Philasterides dicentrarchi is an histophagous parasite that infects flatfish, namely turbot (Scophthalmus maximus), and cause significant losses in aquaculture units. The available measures for P. dicentrarchi control have limited efficiency, and some cause harm to fish. Hence, sustainable and natural control strategies are urgently needed. This study evaluated the in vitro bioactivity of the ethanol extract of Hibiscus sabdariffa calyces on P. dicentrarchi population growth rate (PGR), oxidative stress biomarkers (glutathione-S-transferases (GST), glutathione reductase (GR), glutathione peroxidase (GPx), total glutathione (TG) and catalase (CAT), neurotoxicity (acetylcholinesterase, AChE), activity and gene expression of proteases as major virulence factors. H. sabdariffa extract inhibited parasite PGR (IC50 = 1.57 mg mL-1), and caused significant changes in the activity of antioxidant enzymes (LOEC = 0.22 mg mL-1), especially GPx, TG, and CAT. The activity of proteases was also severely inhibited (IC50 = 0.76 mg mL-1), and gene expression of catepsin 90 and leishmanolysin proteases was downregulated. Organic acids and phenolic phytochemicals in hibiscus extract are potentially responsible for the antiprotozoal bioactivity herein determined. Therefore, H. sabdariffa extract can be a promising disease-control alternative against the ciliate proliferation, cellular defense mechanisms and pathogenicity. Still, its applicability in aquaculture settings, and potential effects on farmed fish, should be further elucidated.

Excited-State Proton Transfer in Luminescent Dyes: From Theoretical Insight to Experimental Evidence.

The effective utilization of luminescent dyes often relies on a comprehensive understanding of their excitation and relaxation pathways. One such pathway, Excited-State Proton Transfer (ESPT), involves the tautomerization of the dye in its excited state, resulting in a new structure that exhibits distinct emission properties, such as a very large Stokes' shift or dual-emission. Although the ESPT phenomenon is well-explained theoretically, its experimental demonstration can be challenging due to the presence of numerous other phenomena that can yield similar experimental observations. In this review, we propose that an all-encompassing methodology, integrating experimental findings, computational analyses, and a thorough evaluation of diverse mechanisms, is essential for verifying the occurrence of ESPT in luminescent dyes. Investigations have offered significant understanding of the elements impacting the ESPT process and the array of approaches that can be used to validate the existence of ESPT. These discoveries hold crucial ramifications for the advancement of molecular probes, sensors, and other applications that depend on ESPT as a detection mechanism.

Facile Access to Structurally Diverse Antimalarial Indoles Using a One-Pot A3 Coupling and Domino Cyclization Approach.

A multistep and diversity-oriented synthetic route aiming at the A3 coupling/domino cyclization of o-ethynyl anilines, aldehydes and s-amines is described. The preparation of the corresponding precursors included a series of transformations, such as haloperoxidation and Sonogashira cross-coupling reactions, amine protection, desilylation and amine reduction. Some products of the multicomponent reaction underwent further detosylation and Suzuki coupling. The resulting library of structurally diverse compounds was evaluated against blood and liver stage malaria parasites, which revealed a promising lead with sub-micromolar activity against intra-erythrocytic forms of Plasmodium falciparum. The results from this hit-to-lead optimization are hereby reported for the first time.

Selective Induction of DNA Damage and Cell Cycle Arrest Mediated by Chromone-Triazole Dyads Derivatives: Effects on Breast and Prostate Cancer Cells.

Chromones and triazoles are groups of heterocyclic compounds widely known to exhibit a broad spectrum of biological activities. The combination of these two pharmacophores could result in multiple mechanisms of action to increase the potency of anticancer drugs and reduce their side effects. The in vitro antitumor effect of eight chromone-based compounds was evaluated in breast (T-47D and MDA-MB-231) and prostate (PC3) cancer cell lines, and in non-cancerous human mammary epithelial cells (HuMEC) using a resazurin-based method. Flow cytometry was used to evaluate the cell cycle and cell death, and É£-H2AX detection to identify DNA damage. The compounds showed selective cytotoxicity against cancer cell lines, with (E)-2-(2-(5-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl)vinyl)-4H-chromen-4-one (compound 2 a) being more potent in non-metastatic T-47D cells (IC50 0.65 µM). Replacing the hydrogen by a methyl group on the triazole ring in compound 2 b enhanced the cytotoxic activity up to IC50 0.24 µM in PC3, 0.32 µM in MDA-MB-231 and 0.52 µM in T-47D. Compound 2 b was 3-fold more potent than doxorubicin in PC3 (IC50 0.73 µM) and 4-fold in MDA-MB-231 (IC50 1.51 µM). The addition of tetrahydroisoindole-1,3-dione moiety in compound 5 did not improve its effectiveness in any of the cell lines but it exerted the lowest cytotoxic effect in HuMEC (IC50 221.35 µM). The compounds revealed different cytotoxic mechanisms: 2 a and 2 b induced G2/M arrest, and compound 5 did not affect the cell cycle.

Methodologies for Assessing Pancreatic Lipase Catalytic Activity: A Review.

Obesity is a disease of epidemic proportions with a concerning increasing trend. Regarded as one of the main sources of energy, lipids can also represent a big part of an unnecessary intake of calories and be, therefore, directly related to the problem of obesity. Pancreatic lipase is an enzyme that is essential in the absorption and digestion of dietary fats and has been explored as an alternative for the reduction of fat absorption and consequent weigh loss.Literature describes a great variability of methodologies and experimental conditions used in research to evaluate the in vitro inhibitory activity of compounds against pancreatic lipase. However, in an attempt to choose the best approach, it is necessary to know all the reaction conditions and understand how these can affect the enzymatic assay.The objective of this review is to understand and summarize the methodologies and respective experimental conditions that are mainly used to evaluate pancreatic lipase catalytic activity.156 studies were included in this work and a detailed description of the most commonly used UV/Vis spectrophotometric and fluorimetric instrumental techniques are presented, including a discussion regarding the differences found in the parameters used in both techniques, namely enzyme, substrate, buffer solutions, kinetics conditions, temperature and pH.This works shows that both UV/Vis spectrophotometry and fluorimetry are useful instrumental techniques for the evaluation of pancreatic lipase catalytic activity, presenting several advantages and limitations, which make the choice of parameters and experimental conditions a crucial decision to obtain the most reliable results.

Impact of Fermentation and Pasteurization on the Physico-Chemical and Phytochemical Composition of Opuntia ficus-indica Juices.

Opuntia ficus-indica fruits are a source of valuable compounds, presenting a high nutritional value and several health benefits. However, due to its low shelf life and increased production, there are considerable post-harvest losses of this cactus fruit. So, ways need to be found to drain the increased production of this fruit that is being wasted. The chemical composition of prickly pear makes it an appealing substrate for fermentation. This study investigates the production of fermented beverages produced from Opuntia ficus-indica cv 'Rossa' and evaluates the effects of different fermentation times (18 and 42 h) and post-fermentation pasteurization by high-pressure (500 MPa for 10 min) and temperature (71.1 °C for 30 s) on the physico-chemical and biological characteristics of the produced beverages. According to the results, the beverage produced from 48 h of fermentation has an alcohol content value of 4.90 ± 0.08% (v/v) and a pH of 3.91 ± 0.03. These values contribute to an extended shelf life and improved organoleptic characteristics compared to the sample fermented for 18 h. Additionally, the longer fermentation resulted in 50% fewer total soluble solids, 90% less turbidity, and lower pH when compared to the sample fermented for 18 h. Moreover, overall, high-pressure processing demonstrates better retention of "fresh-like" characteristics, along with higher levels of phytochemical compounds and antioxidant capacity, similar to those observed in the juice for SO•- and NO•-scavenging abilities.

Pentaketides and 5-p-Hydroxyphenyl-2-pyridone Derivative from the Culture Extract of a Marine Sponge-Associated Fungus Hamigera avellanea KUFA0732.

Five undescribed pentaketide derivatives, (R)-6,8-dihydroxy-4,5-dimethyl-3-methylidene-3,4-dihydro-1H-2-benzopyran-1-one (1), [(3S,4R)-3,8-dihydroxy-6-methoxy-4,5-dimethyl-1-oxo-3,4-dihydro-1H-isochromen-3-yl]methyl acetate (2), (R)-5, 7-dimethoxy-3-((S)-(1-hydroxyethyl)-3,4-dimethylisobenzofuran-1(3H)-one (4b), (S)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran 1(3H)-one (5), and a p-hydroxyphenyl-2-pyridone derivative, avellaneanone (6), were isolated together with the previously reported (R)-3-acetyl-7-hydroxy-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (3), (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3H)-one (4a) and isosclerone (7), from the ethyl acetate extract of a culture of a marine sponge-derived fungus, Hamigera avellanea KUFA0732. The structures of the undescribed compounds were elucidated using 1D and 2D NMR, as well as high-resolution mass spectral analyses. The absolute configurations of the stereogenic carbons in 1, 4b, 5, and 6 were established by X-ray crystallographic analysis. The absolute configurations of C-3 and C-4 in 2 were determined by ROESY correlations and on the basis of their common biosynthetic origin with 1. The crude fungal extract and the isolated compounds 1, 3, 4b, 5, 6, and 7 were assayed for their growth inhibitory activity against various plant pathogenic fungi viz. Alternaria brassicicola, Bipolaris oryzae, Colletotrichum capsici, C. gloeosporiodes, Curvularia oryzae, Fusarium semitectum, Lasiodiplodia theobromae, Phytophthora palmivora, Pyricularia oryzae, Rhizoctonia oryzae and Sclerotium rolfsii.

The Impact of Resveratrol-Enriched Bread on Cardiac Remodeling in a Preclinical Model of Diabetes.

The World Health Organization aims to stop the rise of diabetes by 2025, and diet is one of the most efficient non-pharmacological strategies used to prevent it. Resveratrol (RSV) is a natural compound with anti-diabetic properties, and incorporating it into bread is a suitable way to make it more accessible to consumers as it can be included as part of their daily diet. This study aimed to evaluate the effect of RSV-enriched bread in preventing early type 2 diabetes cardiomyopathy in vivo. Male Sprague Dawley rats (3 weeks old) were divided into four groups: controls with plain bread (CB) and RSV bread (CBR), and diabetics with plain bread (DB) and RSV bread (DBR). Type 2 diabetes was induced by adding fructose to the drinking water for two weeks followed by an injection of streptozotocin (STZ) (40 mg/kg). Then, plain bread and RSV bread (10 mg RSV/kg body weight) were included in the rats' diet for four weeks. Cardiac function, anthropometric, and systemic biochemical parameters were monitored, as well as the histology of the heart and molecular markers of regeneration, metabolism, and oxidative stress. Data showed that an RSV bread diet decreased the polydipsia and body weight loss observed in the early stages of the disease. At the cardiac level, an RSV bread diet diminished fibrosis but did not counteract the dysfunction and metabolic changes seen in fructose-fed STZ-injected rats.