Phytochemicals as Antimicrobials: Prospecting Himalayan Medicinal Plants as Source of Alternate Medicine to Combat Antimicrobial Resistance.

Among all available antimicrobials, antibiotics hold a prime position in the treatment of infectious diseases. However, the emergence of antimicrobial resistance (AMR) has posed a serious threat to the effectiveness of antibiotics, resulting in increased morbidity, mortality, and escalation in healthcare costs causing a global health crisis. The overuse and misuse of antibiotics in global healthcare setups have accelerated the development and spread of AMR, leading to the emergence of multidrug-resistant (MDR) pathogens, which further limits treatment options. This creates a critical need to explore alternative approaches to combat bacterial infections. Phytochemicals have gained attention as a potential source of alternative medicine to address the challenge of AMR. Phytochemicals are structurally and functionally diverse and have multitarget antimicrobial effects, disrupting essential cellular activities. Given the promising results of plant-based antimicrobials, coupled with the slow discovery of novel antibiotics, it has become highly imperative to explore the vast repository of phytocompounds to overcome the looming catastrophe of AMR. This review summarizes the emergence of AMR towards existing antibiotics and potent phytochemicals having antimicrobial activities, along with a comprehensive overview of 123 Himalayan medicinal plants reported to possess antimicrobial phytocompounds, thus compiling the existing information that will help researchers in the exploration of phytochemicals to combat AMR.

Clinical efficacy of Azithromycin for COVID-19 management: A systematic meta-analysis of meta-analyses.

BACKGROUND: Azithromycin has been adopted as a component of the COVID-19 management protocol throughout the global healthcare settings but with a questionable if not downright unsubstantiated evidence base. OBJECTIVES: In order to amalgamate and critically appraise the conflicting evidence around the clinical efficacy of Azithromycin (AZO) vis a vis COVID-19 management outcomes, a meta-analysis of meta-analyses was carried out to establish an evidence-based holistic status of AZO vis a vis its efficacy as a component-in-use of the COVID-19 management protocol. METHODS: A comprehensive systematic search was carried out through PubMed/Medline, Cochrane and Epistemonikos with a subsequent appraisal of abstracts and full-texts, as required. The Quality of Reporting of Meta-analyses (QUOROM) checklist and the Assessment of Multiple Systematic Reviews (AMSTAR) methodology were adopted to assess the methodological quality of the included meta-analyses. Random-effects models were developed to calculate summarized pool Odds Ratios (with 95% confidence interval) for the afore determined primary and secondary outcomes. RESULTS: AZO, when compared with best available therapy (BAT) including or excluding Hydroxychloroquine, exhibited statistically insignificant reduction in mortality [(n= 27,204 patients) OR= 0.77 (95% CI: 0.51-1.16) (I2= 97%)], requirement of mechanical ventilation [(n= 14,908 patients) OR= 1.4 (95% CI: 0.58-3.35) (I2= 98%)], induction of arrhythmia [(n= 9,723 patients) OR= 1.21 (95% CI: 0.63-2.32) (I2= 92%)] and QTc prolongation (a surrogate for torsadogenic effect) [(n= 6,534 patients) OR= 0.62 (95% CI: 0.23-1.73) (I2= 96%)]. CONCLUSION: The meta-analysis of meta-analyses portrays AZO as a pharmacological agent that does not appear to have a comparatively superior clinical efficacy than BAT when it comes to COVID-19 management. Secondary to a very real threat of anti-bacterial resistance, it is suggested that AZO be discontinued and removed from COVID-19 management protocols.

Integrating network pharmacology approaches for the investigation of multi-target pharmacological mechanism of 6-shogaol against cervical cancer.

Traditional treatment of cancer has been plagued by a number of obstacles, such as multiple drug resistance, toxicity and financial constraints. In contrast, phytochemicals that modulate a variety of molecular mechanisms are garnering increasing interest in complementary and alternative medicine. Therefore, an approach based on network pharmacology was used in the present study to explore possible regulatory mechanisms of 6-shogaol as a potential treatment for cervical cancer (CC). A number of public databases were screened to collect information on the target genes of 6-shogaol (SuperPred, Targetnet, Swiss target prediction and PharmMapper), while targets pertaining to CC were taken from disease databases (DisGeNet and Genecards) and gene expression omnibus (GEO) provided expression datasets. With STRING and Cytoscape, protein-protein interactions (PPI) were generated and topology analysis along with CytoNCA were used to identify the Hub genes. The Gene Ontology (GO) database Enrichr was used to annotate the target proteins, while, using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, signaling pathway enrichment analysis was conducted. Molecular docking and survival analysis for the Hub genes revealed four genes (HSP90AA1, HRAS, ESR1 and EGFR) with lowest binding energy and majority of the Hub genes (EGFR, SRC, CASP-3, HSP90AA1, MTOR, MAPK-1, MDM2 and ESR1) were linked with the overall survival of CC patients. In conclusion, the present study provides the scientific evidence which strongly supports the use of 6-shogoal as an inhibitor of cellular proliferation, growth, migration as well as inducer of apoptosis via targeting the hub genes involved in the growth of CC.Communicated by Ramaswamy H. Sarma.

The Role of Natural Products and Their Multitargeted Approach to Treat Solid Cancer.

Natural products play a critical role in the discovery and development of numerous drugs for the treatment of various types of cancer. These phytochemicals have demonstrated anti-carcinogenic properties by interfering with the initiation, development, and progression of cancer through altering various mechanisms such as cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. Treating multifactorial diseases, such as cancer with agents targeting a single target, might lead to limited success and, in many cases, unsatisfactory outcomes. Various epidemiological studies have shown that the steady consumption of fruits and vegetables is intensely associated with a reduced risk of cancer. Since ancient period, plants, herbs, and other natural products have been used as healing agents. Likewise, most of the medicinal ingredients accessible today are originated from the natural resources. Regardless of achievements, developing bioactive compounds and drugs from natural products has remained challenging, in part because of the problem associated with large-scale sequestration and mechanistic understanding. With significant progress in the landscape of cancer therapy and the rising use of cutting-edge technologies, we may have come to a crossroads to review approaches to identify the potential natural products and investigate their therapeutic efficacy. In the present review, we summarize the recent developments in natural products-based cancer research and its application in generating novel systemic strategies with a focus on underlying molecular mechanisms in solid cancer.

Optical coherence tomography findings in patients with transfusion-dependent ß-thalassemia.

BACKGROUND: Structural ophthalmologic findings have been reported in patients with ß-thalassemia due to chronic anemia, iron overload, and iron chelation therapy toxicity in few previous studies. We aimed to investigate structural ocular findings and their relationship with hematological parameters in patients with transfusion-dependent ß-thalassemia (TDT). METHODS: In this cross-sectional study, from January 2018 to January 2019, 39 patients with TDT over the age of 18 participated. Multicolor fundus imaging, optical coherence tomography (OCT), and blue light fundus autofluorescence imaging were performed for all patients and 27 age- and sex-matched controls. RESULTS: The mean age of patients was 28.6 ± 6.2 years. The central macular thickness and macular thicknesses in all quadrants were significantly thinner in patients than controls (P<0.05). None of the retinal nerve fiber layer (RNFL) measurements were significantly different between TDT patients and controls. There was a significantly negative correlation between hemoglobin with central macula thickness (r=-0.439, P=0.005). All measurements of macular subfield thickness were insignificantly thinner in patients with diabetes mellitus (DM) compared to the non-DM subgroup. CONCLUSIONS: Macular thickness was significantly thinner in central macula and entire quadrants in TDT patients compared to healthy individuals; however, all RNFL measurement thicknesses were comparable between the two groups. Close monitoring of TDT patients by periodic ophthalmologic examinations with more focus on diabetic patients, patients with severe anemia and iron overload should be warranted.

Cordycepin for Health and Wellbeing: A Potent Bioactive Metabolite of an Entomopathogenic Cordyceps Medicinal Fungus and Its Nutraceutical and Therapeutic Potential.

Cordyceps is a rare naturally occurring entomopathogenic fungus usually found at high altitudes on the Himalayan plateau and a well-known medicinal mushroom in traditional Chinese medicine. Cordyceps contains various bioactive components, out of which, cordycepin is considered most vital, due to its utmost therapeutic as well as nutraceutical potential. Moreover, the structure similarity of cordycepin with adenosine makes it an important bioactive component, with difference of only hydroxyl group, lacking in the 3' position of its ribose moiety. Cordycepin is known for various nutraceutical and therapeutic potential, such as anti-diabetic, anti-hyperlipidemia, anti-fungal, anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anticancer, antiviral, hepato-protective, hypo-sexuality, cardiovascular diseases, antimalarial, anti-osteoporotic, anti-arthritic, cosmeceutical etc. which makes it a most valuable medicinal mushroom for helping in maintaining good health. In this review, effort has been made to bring altogether the possible wide range of cordycepin's nutraceutical potential along with its pharmacological actions and possible mechanism. Additionally, it also summarizes the details of cordycepin based nutraceuticals predominantly available in the market with expected global value. Moreover, this review will attract the attention of food scientists, nutritionists, pharmaceutical and food industries to improve the use of bioactive molecule cordycepin for nutraceutical purposes with commercialization to aid and promote healthy lifestyle, wellness and wellbeing.

Phytochemicals as Potential Anticancer Drugs: Time to Ponder Nature's Bounty.

Medicinal plants have been used from the beginning of human civilization, which is mostly evident from the ancient script and traditional herbal medicine recipe. Despite the historically enriched demonstration about the use of plant as therapeutics, the pharmaceutical industries lack interest on phytochemical research compared with synthetic drug. Mostly, the absence of information about plant-based medicinal therapeutics is responsible to draw the attention of researchers to think about natural products as potential drug for detrimental diseases, such as cancer. This review will cover about clinically successful plant-based anticancer drugs and underappreciated, but potential, drugs to bridge the information gap between plant biologists and clinical researchers. Additionally, unprecedented advancement of synthetic chemistry, omics study to pin point the target genes/proteins, and efficient drug delivery system have made it easier for researchers to develop a phytochemical as an efficient anticancer drug.

Study of Metal-Metal Interactions and Their Biomarkers Using an Intestinal Human Cell Line.

From the time of dietary intake to their utilization, the number of important interactions occurs among mineral elements, which can affect their bioavailability because of similarity in physicochemical properties and common absorptive pathways. However, the studies that have analyzed the interactions among copper, iron, and zinc have conflicting results and need further exploration. HT-29 cells grown to confluence in 6-well plates were incubated with increasing concentrations (0 to 200 µM) of Cu, Fe, and Zn for 3 and 6 h for uptake studies. Interaction studies involved measuring the uptake of metal in the presence of 0:1-4:1 ratio of the other metal for 3 h using atomic absorption spectrophotometer. The concentration of metal biomarkers and cytokines was also measured in the cell lysate following extracellular supplementation. The presence of 50 µM Zn significantly decreased (P < 0.05) cellular Cu uptake in HT-29 cells at 0.5:1 Cu:Zn ratio and also the cellular Fe uptake at the ratios 0.5:1, 2:1, and 4:1 Fe:Zn. The presence of 50 µM Fe significantly (P < 0.05) decreased cellular Cu uptake at the ratios 1:1, 2:1, and 4:1 Cu:Fe. The concentration of metallothionein responded significantly (P < 0.05) to changes in extracellular Zn concentration (supplementation and depletion). There was a decrease in concentration of IL-1ß and TNF-α (P < 0.05) with an increasing extracellular concentration of Cu and Fe. The results of the study indicated that the presence of one mineral in the diet and multi mineral supplement may influence the bioavailability of the other mineral. Copper and iron may find application in promoting gut health.

Phenolic contents, elemental analysis, antioxidant and lipoxygenase inhibitory activities of Zanthoxylum armatum DC fruit, leaves and bark extracts.

Zanthoxylum armatum (DC) is a traditional spice and important herb used in Asia as a part of food and household medicine for the treatment of various conditions. The present study was designed to investigate in vitro for phenolic/flavonoid contents, antioxidant activities, lipoxygenase inhibitory activity, minerals and heavy-metal contents. The leaves, bark and fruit of Zanthoxylum armatum were extracted with organic solvent and evaluated for phenolic contents (Folin-Chiocalteu method), for flavonoids contents (colorimetric method), for in vitro antioxidant assays (DPPH and FRAP), lipoxygenase inhibitory activity (5-LOX assay), mineral contents (atomic absorption), and for heavy-metal contaminants (atomic absorption). The fruit contained the highest phenolic (25.6±1.2mg GAE/g) and flavonoid (26.3±1.4mg QE/g) contents and therefore, exhibited the most effective antioxidant properties in DPPH (88.5±0.9% inhibition) and FRAP (94.21±3.2% inhibition) assays. The extracts also inhibited the LOX enzyme, and the fruit showed more inhibition (63.8±1.2 %) as compared with the leaves and bark. Z. armatum contain valuable minerals and fortified with magnesium (4.948±0.2, 3.07±0.03 and 3.53±0.12) and potassium (0.19±0.011, 1.91±0.003, and 1.90±0.05) for leaves, fruit, and bark, respectively. The chemical profiling for heavy metals showed that their concentrations were within permissible limits. The data suggest that Z. armatum is a safe and valuable natural agent with functional properties for food and pharmaceutical industries.

Zanthoxylum armatum DC extracts from fruit, bark and leaf induce hypolipidemic and hypoglycemic effects in mice- in vivo and in vitro study.

BACKGROUND: Zanthoxylum armatum DC is an important medicinal plant of south East Asia, and has been used to treat various ailments in traditional medicine including diabetes. This study investigated the in vitro and in vivo antidiabetic and biochemical effects of extracts of Z. armatum in mice. METHOD: The extracts of fruit, bark and leaf from Z. armatum were tested for α-glucosidase inhibition activity. Albino mice of either sex weighing (26-30 g) assigned into groups. Diabetes was induced by IP injection of alloxan monohydrate (150 mg/kg). The extracts (500 mg/kg) and standard (Glibenclamide 10 mg/kg) were administered to mice for 15 days. Serum biochemical parameters were monitored for the period of study. RESULTS: The leaves and bark extracts showed maximum α-glucosidase inhibition (96.61 ± 2.13 and 93.58 ± 2.31% respectively). The extracts treated and the standard treated groups showed significant decrease in the fasting blood glucose levels compared to diabetic control. The effect was more pronounced in mice treated with leaves extract. In the in vivo studies body weights of diabetic mice treated with Z. armatum extracts and the standard did not reduced to extent as observed in diabetic control and this difference was significant (p < 0.05). There was a significance (p < 0.001) improvement in blood hemoglobin, urea, creatinine, cholesterol, and triglycerides of the extracts treated diabetic mice. The extracts showed hypolipidemic effect by reducing the LDL level. The extracts produced no prominent changes in proteins levels. CONCLUSION: It can be concluded that Z. armatum extracts showed excellent antidiabetic potential in vivo and in vitro and could be considered for further appraisal in clinical assessment and drug development.

Gaultheria trichophylla (Royle): a source of minerals and biologically active molecules, its antioxidant and anti-lipoxygenase activities.

BACKGROUND: Gaultheria trichophylla (Royle) is used as food and for treating many ailments in folk medicine especially against inflammation. The purpose of this in vitro study was to evaluate the ability of extracts of G. trichophylla as anti-oxidant and anti-inflammatory agent and for its mineral contents. METHODS: Powdered plant material (100 g) was extracted with 100 ml each of methanol, chloroform, and n-hexane using soxhlet extractor. Antioxidant activity of methanol extract was assessed by DPPH radical scavenging and FRAP assays. Determination of enzyme inhibition activity was determined using 5-LOX inhibitory activity. Total phenolic and flavonoids contents were measured by Folin-Chicalteu and colorimeteric methods respectively. Minerals and heavy metals contents were determined using Atomic absorption spectrophotometer. Qualitative HPLC analysis were performed using some standard phenolic compounds. RESULTS: The highest phenolic (17.5 ± 2.5 mg GA equivalent/g) and flavonoids (41.3 ± 0.1 mg QE equivalent/g) concentrations were found in methanol extract, which also showed more scavenging activity of 1, 1-diphenyl-2-picrylhydrazyl and ferrous reducing power with IC50 = 81.2 ± 0.2 and IC50 = 11.2 ± 0.1 µg/ml, respectively. The methanol and chloroform extracts showed best inhibition of 5-lipoxygenase enzyme with 90.5 ± 0.7% and 66.9 ± 0.1% at 0.5 mg/ml, respectively. G. trichophylla extract was also evaluated for mineral contents (K, Na, Ca, Mg, Fe, and Cu), and for chemical profiling of heavy metals (Cr, Pb, Cd, Co, Zn, Ni and Hg). CONCLUSION: Our current findings suggest that this plant is good source of minerals and concentration of all heavy metals were within permissible limits. The results revealed that this ignored plant has great pharmaceutical and nutraceutical potential.

Salvia officinalis L. induces alveolar bud growing in adult female rat mammary glands.

OBJECTIVES: In traditional medicine Salvia officinalis (sage) has been used as menstrual cycle regulator. In the present study the effects of sage extract on breast tissue were examined. MATERIALS AND METHODS: Fourteen female rats were divided into two groups: 1) Distilled water-treated rats (Con) that were gavaged with 1ml distilled water and 2) Saliva officinalis hydroalcoholic extract (SHE)-treated rats that were gavaged with 30mg/kg/body weight of sage extract for 30 days. The estrus cycle changes were monitored by daily examination of vaginal smear. Whole mounts of right pelvic breast were spread on the slide and stained by carmine. The number of alveolar buds (ABs) type 1 and 2 and lobules of mammary gland were scored. Tissue sections of left pelvic mammary gland were prepared and its histomorphometrical changes were measured. Blood samples were taken from dorsal aorta and estradiol and progesterone concentrations were measured using radioimmunoassay. RESULTS: Estrous cycles decreased significantly in SHE-treated animals. The number of alveolar buds and lobules in mammary gland whole mount of SHE-treated group were higher than the Con group. The number and diameter of ducts in histological section of mammary gland in SHE-treated group increased as compared to the Con group. CONCLUSION: Sage promotes alveologenesis of mammary glands and it can be used as a lactiferous herb.

MPDB 1.0: a medicinal plant database of Bangladesh.

UNLABELLED: The term of medicinal plants include a various types of plants used in herbalism with medicinal activities. These plants are considered as rich resources of ingredients which can be used as complementary and alternative medicines and, also in drug developments and synthesis. In addition, some plants regarded as valuable origin of nutrition. Thus, all these plants are recommended as therapeutic agents. Information related to medicinal plants and herbal drugs accumulated over the ages are scattered and unstructured which make it prudent to develop a curated database for medicinal plants. MPDB 1.0 database is dedicated to provide the first window to find the plants around Bangladesh claimed to have medicinal and/or nutritive values by accumulating data from the published literatures. This database contains 406 medicinal plants with their corresponding scientific, family and local names as well as utilized parts for treatment from different districts of Bangladesh. Information regarding ailments is available for 353 plants. In addition, we have found active compounds for 78 plants with their corresponding PubMed ID. AVAILABILITY: www.medicinalplantbd.net.

Effects of onion juice on the normal flora of eyelids and conjunctiva in an animal model.

BACKGROUND: Traditional medicine/complementary alternative medicine may suggest new ideas to modern medicine in order to face new challenges however these concepts should be acknowledged based on experimental studies. OBJECTIVES: We aimed to study the effects of onion (Allium cepa) juice on the normal flora of conjunctiva and eye lids, and to follow the histopathology changes of conjunctiva in an animal study. MATERIALS AND METHODS: Twenty-four rabbits were randomly classified into three equal groups. Groups 1, 2 and 3 received fresh red onion juice, as an eye drop, into the right eye twice daily for; one week, one month, and two months, respectively. Microbiological sampling by sterile swabs was performed before and after the intervention. Cultural characteristics, including the growth rate and the kind of organisms, are reported. At the end of the study, pathological samples were collected from the inferior fornix. RESULTS: After the intervention, the number of positive cultures in the samples, collected from both the conjunctiva and eyelid, had decreased. Group 3 demonstrated the lowest amount of growth after the administration of the onion juice and the bacterial isolation rates from each organism had decreased. All pathological samples revealed some degree of inflammation. There was no evidence of metaplasia or dysplasia. There was no significant difference between the growth rates of organisms in the experimental groups using statistical analysis. CONCLUSIONS: According to our experiment, onion has an inhibitory effect on the growth of normal eye flora; although the duration of onion juice instillation did not show any significant effect on the group results. Hence, this finding is an initiating point for further investigations into the antimicrobial properties of this herb to treat common eye infections, including conjunctivitis and blepharitis.

The Healing Effect of Teucrium polium in Acetic Acid-Induced Ulcerative Colitis in the Dog as an Animal Model.

BACKGROUND Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn's disease (CD), are debilitating and chronic disorders with unpredictable courses and complicated treatment measures. Therefore, an efficient treatment protocol seems necessary as therapeutic prophylaxis for these disorders.This study aims to determine the healing effect of Teucrium polium (T. polium) in acetic acid-induced UC in an experimental dog model. METHODS From September to December 2010, eight male (20-25 kg) crossbred dogs were used for induction of UC by 6% acetic acid, transrectally. After one week, three biopsies (10, 20 and 30 cm proximal to the anal verge) were taken from the colon of each animal for histological studies. In the presence of UC, 400 mg/kg/day of T. polium extract was administered orally and transrectally (via enema) for 30 days in six of the dogs. The remaining two dogs were used as controls and did not receive T. polium. Multiple biopsies were taken 7, 14, and 30 days after discontinuation of T. polium in the same manner as before treatment. RESULTS After administration of acetic acid, we noted the presence of multiple ulcers, diffuse inflammation, PMN infiltration in the lamina propria, glandular destruction and goblet cell depletion. Treatment with T. polium restored the colonic architecture with an increased number of healthy cells and a reduction in inflammatory cells. Damage of the surface epithelial cells and mucosal layer of the lumen were reversed, which lead to faster ulcer healing. CONCLUSION T. polium may be a treatment choice for UC and can broaden the current therapy options for UC.

Chemical composition of hepatic lipids mediates reperfusion injury of the macrosteatotic mouse liver through thromboxane A(2).

BACKGROUND & AIMS: Chemical composition of hepatic lipids is an evolving player in steatotic liver ischemia/reperfusion (I/R) injury. Thromboxane A(2) (TXA(2)) is a vasoactive pro-inflammatory lipid mediator derived from arachidonic acid (AA), an omega-6 fatty acid (Ω-6 FA). Reduced tolerance of the macrosteatotic liver to I/R may be related to increased TXA(2) synthesis due to the predominance of Ω-6 FAs. METHODS: TXA(2) levels elicited by I/R in ob/ob and wild type mice were assessed by ELISA. Ob/ob mice were fed Ω-3 FAs enriched diet to reduce hepatic synthesis of AA and TXA(2) or treated with selective TXA(2) receptor blocker before I/R. RESULTS: I/R triggered significantly higher hepatic TXA(2) production in ob/ob than wild type animals. Compared with ob/ob mice on regular diet, Ω-3 FAs supplementation markedly reduced hepatic AA levels before ischemia and consistently blunted hepatic TXA(2) synthesis after reperfusion. Sinusoidal perfusion and hepatocellular damage were significantly ameliorated despite downregulation of heme oxygenase-1. Hepatic transcript and protein levels of IL-1ß and neutrophil recruitment were significantly diminished after reperfusion. Moreover, TXA(2) receptor blockage conferred similar protection without modification of the histological pattern of steatosis. A stronger protection was achieved in the steatotic compared with lean animals. CONCLUSIONS: Enhanced I/R injury in the macrosteatotic liver is explained, at least partially, by TXA(2) mediated microcirculatory failure rather than size-related mechanical compression of the sinusoids by lipid droplets. TXA(2) blockage may be a simple strategy to include steatotic organs and overcome the shortage of donor organs for liver transplantation.

Antioxidant flavonoids from Alhagi maurorum.

A new flavonoid, isorhamnetin-3-O-[-alpha-l-rhamnopyranosyl-(1 --> 3)]-beta-D-glucopyranoside (1), along with two known flavonoids 3'-O-methylorobol (2) and quercetin 3-O-beta-d-glucopyranoside (3), was isolated from Alhagi maurorum. Their structures were established with the help of mass spectrometry, 1D and 2D NMR spectroscopy, and in comparison with the literature data. Compounds 1 and 2 exhibited moderate antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay.

Omega 3 - Omega 6: What is right for the liver?

Linoleic and alpha-linolenic acids are the fatty acids designated as "essential" since they are not synthesized by mammalian cells and must be provided in the diet. The recent dietary shift towards the consumption of n-6 (omega-6) at the expense of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) is thought to be a primary cause of many diseases related to the Western diet. The body converts linoleic acid to arachidonic acid and derives eicosapentaenoic acid from alpha-linolenic acid. Ideally the effects of these fatty acids and their eicosanoid derivatives are tailored to the specific biological needs of the body. The balance between n-3 and n-6 PUFAs is essential for metabolism and maintenance of the functions of both classes. The availability of n-3 long chain PUFAs plays a major role in regulating both fat accumulation and its elimination by the liver. Derangement of hepatic n-6:n-3 PUFA ratio impacts on the histological pattern of fatty liver through modulation of the amount of intrahepatic lipids. Moreover, the influence of PUFAs and their eicosanoid products on hepatic microcirculation and ischemia/reperfusion injury has been demonstrated in many studies. This concise review article will focus on the role of PUFAs and eicosanoids in hepatic steatosis, microcirculation and ischemia/reperfusion injury.

Prevention of reperfusion injury and microcirculatory failure in macrosteatotic mouse liver by omega-3 fatty acids.

UNLABELLED: Macrovesicular hepatic steatosis has a lower tolerance to reperfusion injury than microvesicular steatosis with an abnormally high ratio of omega-6 (n-6): omega-3 (n-3) polyunsaturated fatty acids (PUFAs). We investigated the influence of PUFAs on microcirculation in steatotic livers and the potential to minimize reperfusion injury in the macrosteatotic liver by normalization of PUFAs. Ob/ob mice were used as a model of macrovesicular hepatic steatosis and C57/Bl6 mice fed a choline-deficient diet for microvesicular steatosis. Steatotic and lean livers were subjected to 45 minutes of ischemia and 3 hours of reperfusion. Hepatic content of omega-3 and omega-6 PUFAs was determined. Microcirculation was investigated using intravital fluorescence microscopy. A second group of ob/ob mice was supplemented with dietary omega-3 PUFAs and compared with the control diet-fed group. Microcirculation, AST, and Kupffer cell activity were assessed. Macrosteatotic livers had significant microcirculatory dysfunction correlating with high omega-6: omega-3 PUFA ratio. Dietary omega-3 PUFA resulted in normalization of this ratio, reduction of intrahepatic lipids, and decrease in the extent of macrosteatosis. Defective microcirculation was dramatically ameliorated with significant reduction in Kupffer cell activity and protection against hepatocellular injury both before ischemia and after reperfusion. CONCLUSION: Macrosteatotic livers disclosed an abnormal omega-6: omega-3 PUFA ratio that correlates with a microcirculatory defect that enhanced reperfusion injury. Thus, protective strategies applied during or after ischemia are unlikely to be useful. Preoperative dietary omega-3 PUFAs protect macrosteatotic livers against reperfusion injury and might represent a valuable method to expand the live liver donor pool.

Effect of metal ions and EGTA on the optical properties of concanavalin A at alkaline pH.

In our earlier communications, we reported the effect of salts and alcohols on alpha-chymotrypsinogen [1] and the existence of stable intermediates at low pH in bromelain [2] and glucose oxidase [3]. In the present study, the role of metal ions and EGTA on the conformation of concanavalin A at alkaline pH was studied by near- and far-UV circular dichroism, fluorescence emission spectroscopy and binding of a hydrophobic dye, 1-anilino-8-naphthalene sulfonate (ANS). Far-UV CD spectra showed the transition from an ordered secondary structure at pH 7 with a trough at 223 nm to a relatively unordered state at pH 12. Near-UV CD spectra showed the loss of signal at 290 nm, thereby indicating the disruption of native three dimensional structure. Maximum ANS binding occurred at pH 12 suggesting the presence of an intermediate or molten globule-like state at alkaline pH.