When school started a month ago, this Doctor Mama found herself a little more overwhelmed than usual. This is the year we have been dreading. Three kids in three schools and a drop off circuit that takes an hour (before the forty-five minute commute to work) left me feeling underwater. And then there is the flood of fun extras, like theater, band, and soccer that kids crave and parents have to drive to. Add it all up, and sometimes things feel downright impossible. So I decided I had to make some improvements, or I wasn't going to hold it together for the school year.
After arriving home late, tired, I spend way too much time zoning out mindlessly on my smart phone. Yikes! And right before bed. Terrible sleep hygiene. Not doing that anymore.
Watching less TV. Most days, none at all.
And where am I sitting while staring at the smart phone? Parked in front of a Netflix binge-watch series. Between the phone and the TV, I'm missing most of the input coming in to my brain. What kind of "relaxing" is this? So, nope, no more of that.
Going to bed earlier. Getting up earlier.
Without the flashy screen-zone-out-time in the evening, I realize I'm tired. I'll start reading a book in bed and doze off and hour earlier than my previous bedtime. Good plan, I think I'll keep it.
Walking around the grounds or reading in the car while waiting to pick up at theater or sports practice.
On the days when I head straight from work to shuttle kids to and from extras, sometimes there is a period of waiting around. Tired from the day, my habit has been to sit and (shocker) stare at my phone. Lately I have been catching up on nonmedical reading, or taking a brisk walk. Now that's a better use of my time.
Eating better. (Except on weekends).
I'm skipping the fast food, and trying to eat whole and healthy. Except on weekends. I can be "good," but I have my limits.
Working on my listening skills.
With the pace extra hectic, misunderstandings abound in hurried interactions with kids and spouse. I've been trying to slow down and listen.
When I catch an unexpected moment alone, I have been trying to be mindful. I might meditate, or just focus on being present for a bit. This is good practice, so I think I'll keep it up.
Letting Dad drop off twice a week.
In years past, the morning commute was joyful. We laughed and sang all the way, and the time was too precious to give up for a Doctor Mama who works until bedtime a lot of the time. But as kids get older, and transform from joyful children into brooding teens, the morning commute is quiet and surly. No need to covet what isn't much fun.
Saying no to extra projects.
Saying "no" is an art form. I'm still working on the finer points- especially big projects that benefit the community. But I'm trying to say no if it interferes with family time.
Taking advantage of unexpected breaks.
September is unofficial patient cancellation month. Back to school chaos leads to forgetful patients and parents. Using those free blocks to catch up instead of wander aimlessly is a better bargain.
I used to routinely schedule my first patient too early, or underestimate how much time I needed to block off to travel to and from a meeting or conference. I'm working on scheduling realistically, with a little bit of buffer time just in case.
Posted on September 26, 2016 by Melissa Deuter.


विदर्भातला पदवीधर मतदार अतिशय सावध आहे, चिकित्सक आहे, तो नेमके मतदान करतो, प्रसंगी त्याच्या पसंतीचे उमेदवार नसतील तर वर्हाडी मतदार मतदानाच्या दिवशी घरी बसणे पसंत करेल पण चुकीचा उमेदवार त्याने निवडला असे होत नाही म्हणून बी टी देशमुख हे तसे मधू दंडवते सारख्या आदर्शाच्या रांगेतले नेते वर उल्लेख केलेले पाचही जिल्ह्यातले सुशिक्षित मतदार त्यांना नेहमी पदवीधर विधान परिषद मतदार संघातून निवडून पाठवायचे पण अशी वेळ आली कि याच मतदारांनी त्यांना पराभूत केले आणि रणजित पाटलांना निवडून दिले. याच चिकित्सक मतदारांनी मागल्या वर्षी पुन्हा एकदा रणजित पाटील यांना तब्बल ५५००० हजार मतांच्या फरकाने निवडून दिले, त्यांच्या विरोधातल्या उमेदवाराला म्हणजे काँग्रेस च्या संजय खोडके यांना भाजपमधले नेमके हेच अकोल्यातले नेते अगदी उघड मदत करीत असतांनाही...थोडक्यात एकही संधी धोत्रे आणि कंपूने सोडली नाही जेथे रणजित पाटील यांची छळवणूक किंवा अडवणूक झाली नाही मात्र त्याचवेळी रणजीत पाटलांनी वागण्यातली बोलण्यातली सभयता कधीच सोडली नाही. त्यांनी राज्यमंत्री म्हणून शपथ घेतल्या घेतल्या थेट खासदाराचे घर गाठले, पाया पडून म्हणाले, संजयजी आपण बुजुर्ग आहेत, ज्येष्ठ नेते आहेत, आपण विकासाचे कोणतेही काम सांगावे आणि मी ते ऐकावे, करावे असे सतत माझ्याकडून घडेल, तरीही द्वेषाचे राजकारण वाढत गेले आणि आता भाजपाचे नुकसान झाले तरी बेहत्तर, रणजित पाटलांची हकालपट्टी करण्यासाठी धोत्रे आणि कंपू रुसून फुगून बसला आहे..
If world is moving towards the digital age, how could our Shirdi Sansthan be left behind? The CEO took drastic & quick steps towards revamping of the old website and introducing devotee oriented mobile App launching for all types of bookings and information.
One of the giant steps Agarwal initiated was the Paduka Yatra all across India. The devotees from Goa, Pondicherry, Delhi Surat Ahmedabad & all Vidharbha districts were able to experience this. A record number of 2 crore devotees visited Shirdi in 2017 and it being a Cenetary Year Shirdi Sansthan is equipped to welcome more than 3.5 crore devotees. Blood donation camps, Free Jaipur Foot camp, Free Medical camps are part of the Sanasthan every now & then. Being the fire brand lady and lot of monies to be exchanged via tendering process, Rubal has kept an eye of a vigilante too...The entire focus on procedures of procurement, requirement and work culture of Sansthan remains her top most agenda.
It was an event in the history of Sansthan when on 1st October 2017 Hon'ble President of India innnaugrated the Cenetary Year and hosted the Cenetary Flag in Lendi baugh. Hon'ble Vice President of India inaugurated the second International Sai Submit in 23rd December 2017. In middle of all the works happening, just imagine the pressure these people along with the police department to host so many VVIP's.
I have personally seen the construction of Tensile Fabric Sheet big mandap for Cultural & Social Programmes & Bhajan Sandhya. This has a capacity of occupying more than 1500 people at one time. Being the cenetary year, every corner of the Mandir is clean, neat & renovated. For devotee's there is free prasad, free medical facility, free tea-coffee for senior citizens and arrangement for special & free darshan for the physically challenged. Also those intending to flex some muscle, there is a free gym in the gardens. Then there are 3D diaries, & New year Calendars with Sai Charitra avaibale in more than 20 languages.
It is not only the Mandir or Sastha that has caught the eye of Agarwal. She has extended support to the Nagar Panchyatas too wherein the Amrut Water Supply Scheme will distribute Rs. 6.58 crore for cleaning of Shirdi Nagar Panchayat area. The proposal for the same has been sent to give Rs. 35 lakhs per month and BVG group has been given the responsibility for Shirdi Cleanliness Project.
Rs. 55 crore Medicine Tender is finalised for people living below poverty line and needy patients. Medical facility is free of cost at the Sainath Hospital. There is focus on new machinery instalment. The same has been put under tender have been invited for installations of 220 machines of Saibaba & Sainath Hospital worth Rs. 30 crore. The Sansthan released fund for Shirdi Airport and help in inauguration of the same on the 1st October. Then there is Smart Shirdi Project. They are working very closely with the IT department for installation of CCTV's for security & surveillance. Sai Shrusti Project which is very prestigious will be done on the (Built Operate Transfer) BOT basis. Also on the same basis there is SAi Virtual Reality Show is ready and ready to be implemented. Immersity Infotect Pvt Ltd. from Mumbai will be the agency incharge.
A project has been initiated for renovation of the 500 room Bhaktniwas for Rs. 18 crore. New Laddu & Bundi Processing unit of Rs. 15 crore and renovation of Sai Prasadalaya are on the way. Then there is New education Complex proposed for Rs. 120 crore and latest a New Senior College of Arts, Science & Commerce has been given the nod by the Government. For the New Education Complex 28 Hectare Land has been identified and Zone has been changed.
The above achievements, or whatever Rubal Agarwal could do in one year, speaks for itself; and yes it wasn't a cake walk. But today we are celebrating Women's Day; the opposition from the Trust & their foul play some other time in my own style. But for now, Hats Off to Rubal Agarwal, her husband Prakher, in particular, who is working at Pune and does not get to see his family for weeks together if time and distance does not permit. This is the only negative thing I could sense whilst talking to Rubal ji. After all, after the hard day's work if you don't have your family to get back to, it alls seems to be a bit futile... May our state get more of such able officers!!
Wishing one & all A very Happy Women's Day!!
PS: The picture of Mine with Rubal ji is 4 months ago, hence please do not talk about weight gain when any of you meet me, I know I'm young & need to do something but friends, chill!!..Have a good one!!
Bura Na Mano, Holi Hai--OFF THE RECORD special !!


text:
Art Appreciation Chapter 16
tharakadesilva
___-named for the Italian word meaning "style" or "stylishness"-is the school of painting suggesting that the painters practiced an art of grace and sophistication.
What are three characteristics demonstrated in Robert Campin's Merode Altarpiece that would help one classify it as a Northern Renaissance painting?
The use of rich detail and precise brush strokes
The use of oil paint on wood panel
The combination of everyday life and the supernatural
What can be concluded about the period known as the Renaissance based on the role of the arts during that time?
The identities and influences of patrons played a larger role in the production of art.
What demands did the Counter-Reformation reformers make of artists?
The insisted that every depiction of sacred subject matter when directly commissioned by the Catholic Church.
They demanded that compositions be arranged to make the lessons of Church teachings immediately evident.
The word renaissance refers to the revival of the ancient ___ and ___ cultures.
What was the cause of the Northern Renaissance?
It developed from the growing fascination with the details of the visible world.
Why did Italy emerge as the home of the Renaissance?
The Christian Church was centered in Rome
Humanism first arose in Italy
Powerful banking families and economic prosperity emerged
Which of the following are not characteristics of Venetian Renaissance painting?
Emphasis on classical models and mathematican organization
Which of the following characteristics would not be classified as a trait of Nothern painting from the Renaissance period?
Use of linear perspective
Why did the Counter-Reformation Catholic church see an art as one of their strongest weapons?
They understood arts ability to engage the emotions and intellect of the faithful.
Which of the following were patrons of the arts during the Renaissance?
Merchant-rulers
Agnolo Bronzino's painting Allegory ("Venus, Cupid, Folly and Time") demonstrates with Mannerist traits?
A forbidden or erotic undercurrent.
Shallow, compressed, or illogical space.
Classical subject matter and symbols.
Elongated forms and twisted poses.
Fondness for elaborate or obscure subject matter.
The frescoes of the Sistine Chapel were completed with the help of
many assistants
In 1401, what artist wwon a high-profile competition to design a new set of bronze doors for the Florentine baptistery?
How is Mechelangelo's David similar to ancient Greek sculptures, such as Warrior A?
Use of contrapposto
Knowledge of human physique
What does the term renaissance mean?
Who are two famous High Renaissance artists?
The Renaissance was when the concept of "___" arose.
How does Pieter Bruegel the Elder's painting The Harvesters illustrate the changes in art that were brought about by the Protestant Reformation?
The painting depicts scenes from everyday life and landscape rather than scenes of saints or religious subjects.
Michelangelo envisioned St. Peter's Basilica as
an organic whole with a powerful upward thrust.
What is sfumato?
Layers of glaze that produce a soft, hazy ambiance
Italian word for "smoke"
How can scholars tell that Rogier van der Weyden's St. Luke Drawing the Virgin is, at least in part, a painting about looking?
Everyone in the painting in act of looking at something
The artist's careful rendering of precise detail
What did Renaissance humanists believe to be true?
People's obligation to God is to realize their full intellectual and creative potential
To combine the teachings of Christianity with the reason and intellect of ancient cultures
Which of the following was a patron of the arts in the Renaissance but not a patron in earlier times?
What is a Renaissance person?
Someone with a diverse skill set
How does Tintoretto's painting The Last Supper draw the focus of the viewer to Christ?
Dramatic diagonal lines direct the viewers eye to Christ's figure in the foreground.
Christ's figure is placed near the center of the composition.
What is unusual about Sandro Botticelli's The Birth of Venus?
It uses unusual linear style and shallow modeling
The background acts as a backdrop, as for a play
What do the paintings in the prayer book constructed from the Limbourg Brothers' paintings represent?
A calendar illustrated with activities of the wealthy and peasants
Which of these themes are commonly seen in Renaissance art?
Detailed depictions of the physical world
Idealized and proportioned human figures
Interest in ancient Greek and Roman subject matter
What is the accepted interpretation of the lute with a broken string depicted in Hans Holbein's The Ambassadors?
It represents discord, which ties to the recent Protestant Reformation.
During which 25-year period did the High Renaissance take place?
How is Michelangelo's David different from ancient Greek and Roman sculpture?
Has tension and energy
Knowledge of human anatomy
Expression is communicated on the face
How did Renaissance artists obtain ideal beauty?
They borrowed beautiful features from everywhere
Which Venetian painter created the painting The Annunciation?
How does Leonardo da Vinci organize the forms in his painting Madonna and Child with Saint Anne?
He uses a soft gentle light to dissolve the edges of the forms.
He organizes the forms into a triangular shape.
He balances the composition with dark shadows in one corner and a dark tree in the other.
The plan of Leon Battista Alberti's church Sant'Andrea recalls examples found in the architecture of which ancient culture?
The philosophy of humanism
revived interest in ancient Greek and Roman scholars.
focused on the abilities and accomplishments of mankind.
To accurately portray the human body, what did some artists do to study human form?
Dissected cadavers
Installed in a hospital for illnesses of the skin, the graphic depiction of pain and suffering in Matthias Grunewald's Isenheim Altarpiece was intended to
increase the faith of the patients, inviting them to identify their own suffering with Christ's.
Why is The Last Supper by Tintoretto considered an excellent example of Counter-Reformation artwork?
It conforms to the teachings of the Church.
Even though Michelangelo was an accomplished artist in a variety of media, he considered himself to be a)n)
sculptor.
Which shapes did Michelangelo use as a basis for the floor plan of St. Peter's Basilica?
A square
Renaissance ___ held that people should pursue knowledge for its sake.
During the Renaissance, works of art with Classical Greek and Roman subject matter were
especially popular and were commissioned for both secular and religious spaces.
Who created this statue of Saint Mark?
What did Michelangelo feel summarized the noblest of creations worth of art?
The nude body
What is the diagonal shape at the bottom of Hans Holbein's The Ambassadors, and what did it represent?
A skull representing that everyone dies
Matthias Grunewald's Isenheim Altarpiece is an example of the ___ often found in Northern Renaissance art.
Which of the following Greek philosophers inspired the idea of ideal beauty, which was equated with moral goodness?
What Northern Renaissance quality is evident in the Limbourg Brothers' Les Tres Riches Heures from the late Middle Ages?
careful attention to detail
What Renaissance convention did Lorenzo Ghiberti use to arrange space in his composition of The Story of Jacob and Esau for the Flortine batistery doors?
Linear perspective
Based on what scholars know about Giorgione's The Tempest, what do they believe to be the meaning of its content?
The focus is on the power of nature that brings opposites together.
Titan's style of painting, especially late in his life, incorporated ___ that made the image indistinct when seen close up but clear when viewed from a distance.
frenzied brush strokes
Where is the vanishing point in Masaccio's The Trinity?
Directly under the cross on the mid-point of the ledge where the donors are kneeling
Which of the following is not a characteristic of the Renaissance style?
Complex, abstract forms that represent an idea rather than an observed form
What Renaissance artist is most closely associated with the fusion of Italian concepts of math and science and Northern methods of meticulous detail and observation?
art 100 chapter 17
hannahhardison24
Chapter 17: The 17th and 18th Centuries
Alina__Tran
Ch. 16 The Renaissance
camillejonesxo
karinaruiz24
ARTF 111 CH22-25 Q&A
jdrc524
Art 101 Ch16&17
Raegan_Loftis
Prebles' Artforms (Ch 16)
mlp3691

redpajama_set_name: RedPajamaCommonCrawl


text:
AbstractIntroductionConclusionsConflicts of InterestAcknowledgmentsReferencesCopyrightRelated Articles
Uncoupling Protein 2: A Key Player and a Potential Therapeutic Target in Vascular Diseases
Giorgia Pierelli,1Rosita Stanzione,2Maurizio Forte,2Serena Migliarino,3Marika Perelli,3Massimo Volpe,2,3and Speranza Rubattu2,3
Academic Editor: Ryuichi Morishita
Revised19 May 2017
Accepted10 Sept 2017
Published15 Oct 2017
Uncoupling protein 2 (UCP2) is an inner mitochondrial membrane protein that belongs to the uncoupling protein family and plays an important role in lowering mitochondrial membrane potential and dissipating metabolic energy with prevention of oxidative stress accumulation. In the present article, we will review the evidence that UCP2, as a consequence of its roles within the mitochondria, represents a critical player in the predisposition to vascular disease development in both animal models and in humans, particularly in relation to obesity, diabetes, and hypertension. The deletion of the UCP2 gene contributes to atherosclerosis lesion development in the knockout mice, also showing significantly shorter lifespan. The UCP2 gene downregulation is a key determinant of higher predisposition to renal and cerebrovascular damage in an animal model of spontaneous hypertension and stroke. In contrast, UCP2 overexpression improves both hyperglycemia- and high-salt diet-induced endothelial dysfunction and ameliorates hypertensive target organ damage in SHRSP. Moreover, drugs (fenofibrate and sitagliptin) and several vegetable compounds (extracts from Brassicaceae, berberine, curcumin, and capsaicin) are able to induce UCP2 expression level and to exert beneficial effects on the occurrence of vascular damage. As a consequence, UCP2 becomes an interesting therapeutic target for the treatment of common human vascular diseases.
Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins and are important for lowering mitochondrial membrane potential and dissipating metabolic energy as heat, maintenance of respiration, glucose disposal rate, insulin secretion, and prevention of reactive oxygen species (ROS) accumulation [1, 2].
Five UCPs have been characterized in mammals: UCP1–UCP3 that are evolutionary related and UCP4 and UCP5 (also known as BMCP1) that are more divergent [3]. UCP2 is a member of the mitochondrial anion carrier family and displays 60% sequence identity with the well-known thermogenic UCP1 present in the brown adipose tissue [2]. The genes encoding UCP2 and UCP3 are adjacent in all species, and they map on mouse chromosome 7, rat chromosome 1, and human chromosome 11 [3]. UCP1–UCP3 genes share six coding exons and have two additional nontranslated exons [4]. UCP2 is highly conserved across species with a 95% homology in the amino acid sequence between rat and human [4]. The UCP2 promoter contains putative response elements for peroxisome proliferator-activated receptor (PPARγ, PPARα, and PPARδ), sterol-responsive element-binding protein (SREBP), and cyclic AMP response element-binding protein (CREB) [5–7].
Several regulatory factors of UCP2 act at both transcriptional and posttranscriptional levels. Purine nucleotides have been recognized to negatively regulate UCP2, whereas unsaturated free fatty acids (FFA), glucose, retinoic acid, lipopolysaccharides, and ROS have been reported to activate UCP2 [8, 9]. In particular, FFA have been demonstrated to strongly enhance UCP2 mRNA expression acting on either PPAR or SREBP element [10].
UCP2 is highly expressed in human white adipose tissue. Considerable amounts are also expressed in the skeletal muscle, heart, lung, spleen, thymus, cells of the immune system, and vascular cells, whereas lower amounts are expressed in the brain, liver, and kidney [11]. All members of the UCP family are integral transmembrane proteins, located within the inner mitochondrial membrane. They are characterized by three repeat domains each formed by two α-helix regions in the lipid bilayer. The carbossi and aminoterminal regions reside into the mitochondrial intermembrane space whereas the α-helix regions are connected by long hydrophilic loops in the matrix side (Figure 1) [12, 13].
Overview of UCP2 localization and function. UCP2 is located within the inner mitochondrial membrane where it uncouples proton flux with the consequent regulation of ATP synthesis. ROS activates UCP2. The latter, through a negative feedback mechanism, decreases ROS and protects vascular cells from the oxidative stress-dependent damage. See text for details. OMM: outer mitochondrial membrane; IMS: intermembrane space; IMM: inner mitochondrial membrane.
UCP2 is involved in the control of uncoupling of proton flux within the mitochondria. In particular, protons generated across the inner mitochondrial membrane during oxidation of substrates reenter in the matrix through UCPs instead of the ATP synthase [14]. Therefore, the proton gradient is converted into heat energy and not in ATP (Figure 1). The involvement of UCP2 in ATP production was demonstrated for the first time in pancreatic β-cells [15]. UCP2, unlike UCP1, appears to contribute mainly to the regulation of ATP [16], mitochondrial membrane potential (Δψ) [17], cellular calcium homeostasis [17], cell survival [18], lipid metabolism [19], and the generation of ROS [19, 20]. UCP2 belongs to the mitochondrial antioxidant mechanisms [21], and as such, it contributes to maintaining the balance between production and clearance of ROS.
Due to the roles that UCP2 plays within the mitochondria, it is clear that a decrease in UCP2 expression may be strongly implicated in the genesis of mitochondrial dysfunction, ROS accumulation, and cell death and, therefore, in the pathogenesis of several diseases.
Whereas controversial evidence exists, within the cardiovascular system, in regard to the role that UCP2 plays in the pathogenesis of left ventricular hypertrophy [22, 23], more robust and convincing findings were reported in relation to UCP2 and its contribution to vascular damage.
The present article will review the available evidence demonstrating the direct contributory role of UCP2, through an increased rate of ROS generation, in the pathogenesis of vascular diseases, particularly within the context of diabetes and hypertension, therefore supporting it as an attractive therapeutic tool for the treatment of the vascular complications associated with these common pathological conditions.
2. UCP2 and the Pathogenesis of Vascular Diseases
An increased ROS accumulation is an important mechanism involved in the development of vascular diseases. At physiological concentrations, ROS, produced from both cytoplasmic and mitochondrial sources, represent an intracellular and intercellular second messenger that modulates several downstream signaling molecules leading to vascular reactivity [24], vascular smooth muscle cell growth and migration, expression of proinflammatory mediators, and remodeling of the extracellular matrix [25]. On the other hand, an accumulation of ROS is dangerous. At the level of mitochondria, it leads to damage of mitochondrial proteins, lipids, and DNA with consequent alteration of the mitochondrial function, a further increase in ROS, and, at the vascular level, development of endothelial oxidative stress [26]. In fact, mitochondrial dysfunction causing excessive ROS production contributes to the pathogenesis of several diseases including cardiovascular diseases [27]. It has been demonstrated that UCP2 proton leak is activated directly by superoxide and ROS by-products [9], thus creating a local feedback circuit. Although the mechanism by which UCP2 is activated by ROS is not completely understood, reactive aldehydes derived from lipid peroxidation have been suggested to be the ROS able to induce UCP2 activation [28]. The known intracellular signaling pathways mediating UCP2 gene activation are the AMPK/SIRT1/PPARα axis [29] and the cAMP-dependent protein kinase [30, 31].
Once activated, UCP2 modulates several proinflammatory and proatherogenic signals working in the vasculature and involved in the pathogenesis of diseases. Among them, tumor necrosis factor α (TNFα) is the most relevant. Thus, the relationship between TNFα and UCP2 expression levels appears to be of importance in assessing the risk of vascular damage. It has been reported that TNFα directly downregulates adiponectin [32] thus contributing to the development of vascular insulin resistance and to decreased UCP2 levels in the aorta. On the other hand, higher levels of adiponectin might induce UCP2 overexpression in the aorta attenuating the vascular damage [33]. Another mechanism involved in the inhibitory effect of TNFα on UCP2 expression is the nitric oxide- (NO-) dependent pathway that involves the inducible nitric oxide synthase (iNOS) expression in both endothelial and vascular smooth muscle cells [34]. Thus, based on the evidence that TNFα downregulates UCP2 expression level, a pretreatment with an anti-TNFα antibody has been attempted in vivo [33]. TNFα and insulin share an antagonistic effect on UCP2 expression level in vascular cells and also in the aorta in vivo. Moderate hyperinsulinemia in response to insulin resistance or lowering of TNFα levels within the aorta attenuated vascular damage [33]. This protective effect was mediated by increased UCP2 expression level through a decrease in iNOS expression. Insulin might also reduce NF-κB activation in the aorta, and as a consequence, it may favor UCP2 overexpression and may protect against the vascular damage.
A part from TNFα, UCP2 modulates the expression of other inflammatory cytokines within the vascular tissue. In fact, a significant increase in the protein levels of cutaneous T-cell-attracting chemokine (CTACK), chemokine (C-X-C motif) ligand-16 (CXCL16), eotaxin-2, fractalkine, and B-lymphocyte chemoattractant (BLC) was reported in the UCP2 gene-knockout mice [35]. The upregulation of these inflammatory mediators contributed to the ischemic brain damage and to the neuronal death after transient focal ischemia in the UCP2-knockout model. On the other hand, UCP2 overexpression in monocytes led to a significant reduction of β2 integrin level with a consequent decrease in monocyte adhesion and transendothelial migration [36]. The latter phenomena can contribute to the reduction in atherosclerotic plaque formation in the presence of higher UCP2 level.
UCP2 has also been reported to prevent mitochondrial-induced cell death [18]. Although the precise mechanism is not completely understood, several authors suggested that UCP2, acting on multiple aspects of mitochondrial functions (Δψ, ATP/ADP ratio, calcium transport, and levels of ROS), may reduce the activation of the mitochondrial permeability transition pore (mPTP), the main activator of mitochondrial death cascade [17].
2.1. Atherosclerosis
Atherosclerosis is a disease of the large vessels where it leads to plaque deposition and narrowing of the lumen with distal ischemia. Microvascular disease affects the small blood vessels of highly perfused organs with low vascular resistance such as the retina, kidney, heart, and brain [37]. The pathogenesis of both macro- and microvascular diseases is associated with several risk factors and common pathological conditions such as hypertension, diabetes, obesity, and dyslipidemia [38, 39]. This process involves multiple molecular mechanisms, primarily oxidative stress and inflammation.
Evidence of a direct role of UCP2 in the promotion of atherosclerosis in vivo was first obtained in the UCP2 gene-knockout mice that developed multiple atherosclerotic lesions in several districts, with a significantly shorter lifespan [40, 41]. Moreover, the bone marrow transplantation from UCP2-deficient mice to low-density lipoprotein receptor (LDLR−/−) mice markedly increased atherosclerotic lesion size [42]. An indirect evidence of the pathogenic link between UCP2 and vascular damage was provided by the high-fat diet-fed BATIRKO mice that manifested higher oxidative stress in the aorta in association with lower UCP2 expression level [33]. The decrease in UCP2 level in the aorta was strongly inversely correlated with lipid accumulation and lesion area in the normoinsulinemic BATIRKO mice [33].
On the other hand, UCP2 overexpression has been shown to ameliorate both hyperglycemia and obesity-induced endothelial dysfunction [43, 44], and it may help to prevent the development of atherosclerosis in patients with increased ROS, such as those with diabetes, obesity, or hypertension [45].
2.2. Diabetes
The pathogenetic link between UCP2 and metabolic diseases, involving the associated vascular damage, is complex. First of all, UCP2 might play an important role in the regulation of energy expenditure and it is likely to contribute itself to obesity and type 2 diabetes mellitus (T2DM). In fact, reduced UCP gene expression was found in tissues of obese subjects and in the kidneys of T2DM patients [46, 47]. Furthermore, few case-control genetic association studies reported significant associations between UCP2 gene polymorphisms and obesity and diabetes in humans [47–52]. On the other hand, both obese and diabetic patients have associated vascular complications such as atherosclerosis [53] and retinopathy [54] where UCP2 may play a direct contributory pathogenetic role. In this regard, the early stages of diabetic retinopathy, the most common complication of diabetes, are characterized by microvascular cell damage [54] associated with the thickening of the capillary endothelial basement membrane and pericyte apoptosis induced by hyperglycemia [55]. Previous investigations into the molecular mechanisms that cause this common vascular complication of diabetes focused on the vascular endothelial growth factor (VEGF) [56, 57]. Recently, the important role played by increased mitochondrial ROS production in the complications of diabetes, including retinopathy, has been emphasized [58]. Of note, UCP2, as a mediator of the mitochondrial ROS pathway, appears to be involved [59].
Recent studies investigated the possible inhibition of high glucose-induced apoptosis by UCP2 in human umbilical vein endothelial cells (HUVEC) [60] and demonstrated that UCP2 plays an antiapoptotic role in this experimental setting. The beneficial effects of UCP2 on the vascular consequences of hyperglycemia are interesting based on the known observation that glucose itself is responsible for the vascular complications and that, as a downstream effector of hyperglycemia, oxidative stress is involved in the development of vascular dysfunction. Glucose can induce ROS generation by multiple mechanisms including the mitochondrial respiratory chain [61]. The endogenous antioxidant system should counterbalance the ROS production in the vasculature, but it fails to do so in diabetes, leading to oxidative stress accumulation and damage [62]. Consequently, the restoration of the mitochondrial antioxidant mechanisms can represent a useful approach for the prevention and treatment of diabetic vascular complications and of the consequent clinical events. The potential beneficial effect of this strategy is supported by evidence that a common −866G>A variant in the promoter of the UCP2 gene, where the A allele associates with increased gene expression [49], decreased the risk of myocardial infarction, angina pectoris, coronary artery bypass grafting (CABG), and sudden death in TDM2 patients [52, 63].
2.3. Hypertension
A tight link exists also between UCP2 and vascular damage in hypertensive disease, particularly in the presence of excess salt intake. Abundant evidence in the literature demonstrates that high salt (HS) intake is a major factor increasing systemic blood pressure (BP) levels and thereby vascular damage [64, 65]. HS diet plays also direct harmful effects independent of its impact on BP levels [66]. The mechanisms underlying the direct deleterious effect of HS intake on the vascular bed have not been fully understood. Recent studies demonstrated an important role of UCP2 in the salt sensitivity and its vascular consequences. In this regard, it has been shown that HS diet caused enhanced BP levels and an impairment of vascular function (reduction in endothelium-dependent relaxation) in UCP2−/− mice [67, 68]. On the other hand, overexpression of UCP2 was able to ameliorate the salt-induced vascular dysfunction [69]. The beneficial effect of UCP2 was mediated by decreased superoxide production and increased NO bioavailability. In fact, UCP2 deficiency exacerbated the HS-induced reduction of NO bioavailability and increased superoxide production.
Consistent with the above-mentioned evidence, the gene encoding UCP2 has been underscored as a contributory factor to the HS diet-dependent vascular disease in an animal model of spontaneous hypertension, renal damage, and stroke. In fact, it was found that UCP2 maps nearby the lod score peak of a quantitative trait locus for stroke (STR1) in the HS-fed stroke-prone spontaneously hypertensive rat (SHRSP), a strain with increased susceptibility to vascular damage [70]. Recent studies performed in this animal model, aimed at the further dissection of the pathogenetic contributory role of UCP2 in the vascular disease of the strain, showed that a differential regulation of UCP2 expression, and of all proteins that lie upstream in the UCP2 regulatory pathway, was present in the kidneys of SHRSP, but not in those of the stroke-resistant SHR (SHRSR) upon the stroke-permissive HS dietary regimen. In particular, we obtained evidence of reduced UCP2 gene and protein expression in the kidneys of stroke-prone rats and of increased expression in the kidneys of stroke-resistant rats. Moreover, knocking out the UCP2 gene in mesangial renal cells led to increased oxidative stress, reduced ATP synthesis, and increased cell necrosis [71, 72]. Furthermore, a recent study demonstrated that proximal tubular epithelial cells from the SHRSP strain, once exposed to the high-NaCl medium, showed a significant UCP2 downregulation with an increased rate of cell inflammation and necrosis. Notably, the renal tubular epithelial cells recovered their healthy status after exposure to exogenous recombinant UCP2 despite the presence of high-NaCl medium [73]. These results strongly suggest that changes in UCP2 expression contribute to the higher predisposition of HS-fed SHRSP to renal damage development.
Similar findings were more recently obtained in the brain of the SHRSP, compared to the SHRSR, with evidence of a significant contributory role of reduced UCP2 gene and protein expression in the higher stroke predisposition of the strain [74].
Moreover, a striking downregulation of UCP2 gene and protein expression was found in relation to both hypertension and ageing in the brain, heart, and kidneys of the SHRSP, but not of the SHRSR [74]. In fact, the age- and hypertension-related UCP2 suppression in SHRSP associated with a higher oxidative stress accumulation and inflammation in all tissues examined, along with an increased rate of interstitial, perivascular, peritubular, and glomerular fibrosis in the kidneys; with increased percentage of perivascular and myocardial interstitial collagen accumulation in the heart; and with higher occurrence of ischemic and hemorrhagic lesions in the brain [75]. The latter study supported the concept that, through greater oxygen consumption, reduced mitochondrial membrane potential, and reduced ROS generation, all underlying positive influences on biological ageing, UCP2 may also contribute to expand lifespan, as stated in the "uncoupling-to-survive" hypothesis [76].
Thus, HS diet, high BP levels, and ageing are able to turn off tissue UCP2 gene expression only in the SHRSP animal model through still unexplained mechanisms, therefore contributing to the higher susceptibility to vascular disease of the strain. Interestingly, an epigenetic regulation may be involved in the selective UCP2 gene downregulation upon HS diet in SHRSP, as suggested by the evidence obtained in our studies in relation to both kidney injury [71] and brain damage [74]. Based on the above-reported evidence, an increase in UCP2 expression may play a compensatory role to offset, at least in part, the salt-induced endothelial dysfunction and vascular damage in hypertension with a consequent net reduction of adverse outcomes.
2.4. Stroke
Several findings provide evidence that UCP2 is directly involved in the development of cerebral ischemic damage, independent of hypertension. In fact, consistent with its ability to decrease endogenous mitochondrial ROS production and to maintain normal mitochondrial membrane potential and ATP levels, a neuroprotective effect of UCP2 has been described both in vitro and in vivo [18, 35, 77–80]. In this regard, both the enhanced levels of ROS and the apoptosis of neuronal cells are considered important contributory factors to the cerebral ischemia/reperfusion injury (I/R), a condition of great importance among all types of stroke [81]. Of note, it has been reported that sestrin2 (Sesn2), a powerful free radical scavenger, exerts a neuroprotective effect during cerebral I/R injury possibly by increasing mitochondrial biogenesis. Sesn2 is a member of the sestrin family, which is a group of highly conserved proteins that are induced by environmental stresses, including DNA damage, oxidative stress, and hypoxia [82]. Importantly, Sesn2 silencing suppressed AMPK activation, leading to downregulation of UCP2, superoxide dismutase 2 (SOD2), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α, and the downstream signaling factors with resulting decreased mitochondrial biogenesis and enhanced intracerebral oxidative stress. Thus, Sesn2 provides useful indirect evidence of the beneficial role of UCP2 in stroke.
2.5. Peripheral Vascular Disease
Evidence obtained by a microarray approach in human aortic specimens demonstrated that the UCP2 gene is markedly downregulated in the aortic occlusive disease [83], a common cause of morbidity and mortality in elderly population. Moreover, a study performed in a Caucasian general population revealed that the −866G>A variant of the UCP2 promoter was modestly associated with asymptomatic carotid atherosclerosis in middle-aged women [84].
3. UCP2 as a Potential Therapeutic Target for the Treatment of Vascular Diseases
Several studies suggested that excessive ROS production is involved in the atherosclerotic plaque formation [85] and that all plaque cellular components may respond to and be damaged by ROS. The latter contribute to plaque progression and finally to plaque rupture [86]. Thus, several approaches to stop ROS production and to modify disease progression may be used to treat atherosclerosis and its dreadful consequences.
Although UCP2 negatively regulates intracellular ROS production and protects vascular function, its contribution to the vascular benefits of drugs used to treat cardiometabolic diseases is not completely known. Both in vitro and in vivo studies reviewed herein strongly highlight the role of UCP2 as a potential therapeutic target for the treatment of vascular diseases. In particular, UCP2 might function as an adaptive antioxidant defense to protect against the development of atherosclerosis in response to high-fat and cholesterol diets [40, 87] and to improve hyperglycemia-induced endothelial dysfunction [43]. In this regard, diabetes might derive a major benefit from UCP2-targeted therapies. In fact, despite considerable evidence showing beneficial effects of antioxidants, results from large-scale clinical trials led to the conclusion that classic antioxidant scavengers may not be appropriate therapeutics in diabetes [88]. Therapeutic approaches specifically designed to counteract glucose-induced mitochondrial ROS production in the vasculature are expected to show major efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species.
The following paragraphs will discuss the available indirect evidence documenting the role of UCP2 as a mediator of the vascular protective effects exerted by either drugs or vegetable extracts.
3.1. UCP2 and Its Involvement in the Effects of Pharmacological Therapy
It has been recently shown that glucocorticoids induce the expression of the UCP2 protein [89]. In fact, UCP2 silencing prevented the protective effect of glucocorticoids on ROS production. UCP2 induction upon glucocorticoids increased the oxygen consumption and the proton leak in microvascular hyperglycemic endothelial cells [89]. Thus, UCP2 activation may represent an attractive experimental therapeutic intervention for the treatment of diabetic vascular complications. While direct use of glucocorticoids may not be feasible for the treatment of diabetic complications, due to the significant side effects that develop during their chronic administration, the UCP2 pathway may be therapeutically targetable by other glucocorticoid-independent pharmacological tools.
A recent study demonstrated that a highly selective dipeptidyl peptidase-4 inhibitor, sitagliptin, used for the treatment of diabetes, protected endothelial function in hypertension through the upregulation of UCP2 expression and the subsequent scavenging of mitochondrial ROS [90]. The latter phenomenon, in turn, downregulated cyclooxygenase- (COX-) 2 expression via the stimulation of the glucagon-like peptide- (GLP-) 1/GLP-1R/AMPK cascade. UCP2 inhibited oxidative stress and downregulated COX-2 expression through the GLP-1/GLP-1R/AMPK axis. In humans, dipeptidyl peptidase-4 inhibitors appear to have unique and/or additive antiatherosclerotic effects as add-on therapy to statins and/or angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers [91]. Thus, UCP2 is revealed as an effective molecular target for drug intervention to combat both diabetes- and hypertension-related vascular diseases.
In the context of hypertension, the mitochondrial dysfunction contributes to the promotion of target vascular damage [92]. Mitochondrial abnormalities were described in the heart and in the brain of SHR [93, 94], in the kidneys of both renovascular and essential hypertensive animal models [95, 96], and in the brain of SHRSP [97, 98]. Interestingly, a significant protective effect on both renal and cerebrovascular damage was described with fenofibrate in salt-loaded SHRSP [97]. This beneficial effect may be mostly mediated by the peroxisome-proliferator activated receptor alpha (PPARα) agonist action of fibrates with the consequent stimulation, among other properties, of UCP2 expression [99]. The latter may exert protective effects on target organ damage through its action on mitochondrial biogenesis and function. In fact, we recently obtained evidence that fenofibrate stimulates brain UCP2 expression, reduces tissue oxidative stress and inflammation, and exerts full protection from stroke occurrence in salt-loaded SHRSP [74]. At the cellular and tissue levels, PPARα activity mitigates atherosclerosis by blocking macrophage foam cell formation, vascular inflammation, vascular smooth muscle cell proliferation and migration, plaque instability, and thrombogenicity [100]. Interestingly, clinical use of the synthetic PPARα agonist fibrate has been reported to reduce cardiovascular risk particularly in high-risk patients [101].
3.2. The Effects of Vegetables and Plant Extracts on UCP2 Gene and Protein Modulation
We obtained evidence of a significant stimulation of renal UCP2 expression by the administration of a vegetable extract obtained from Brassica oleracea sprouts in the animal model of salt-loaded SHRSP. In fact, the latter was able to counteract the HS diet-induced renal damage of SHRSP, independent of BP levels [102], and to reduce the stroke occurrence of the strain [74]. The key role of UCP2 stimulation in mediating the positive effects of Brassica oleracea sprout extract was reinforced by evidence that parallel blockade with a selective inhibitor of PPARα did not allow any further protection from both cerebrovascular and renal damages in HS-fed SHRSP [74, 102]. Therefore, restoring UCP2 expression levels, as observed under the Brassica oleracea sprout extract, appears to be a critical step to prevent target organ damage development in hypertension.
Of note, the beneficial cardiovascular effects of vegetable compounds, including extracts from Brassica oleracea, were also reported in humans, thus underscoring the potential useful role of this vegetable as an adjuvant to conventional cardiovascular therapies [103].
Interestingly, the improvement of mitochondrial function by the vegetable administration is often mediated through UCP2 upregulation. Curcumin is an extract from the Curcuma longa (turmeric) plant rhizome that has been widely used worldwide as a spice and an herbal medicine. Curcumin has many biological activities, including the amelioration of ischemic stroke and antioxidant, anti-inflammatory, and antineurodegenerative properties [104, 105]. Chronic dietary curcumin administration significantly reduced ROS production and improved cerebrovascular endothelium-dependent relaxation in ageing wild-type mice, but not in ageing UCP2−/− mice [106]. Dietary curcumin administration for one month remarkably restored the impaired cerebrovascular endothelium-dependent vasorelaxation in ageing Sprague Dawley rats. In cerebral arteries from this rat model and in cultured endothelial cells, curcumin promoted endothelial nitric oxide synthase (eNOS) and AMPK phosphorylation, upregulated UCP2, and reduced ROS production. The effects of curcumin were abolished by either AMPK or UCP2 inhibition [106]. Thus, the curcumin-mediated UCP2 upregulation involved AMPK activation in the cerebrovascular endothelium. This activation antagonized superoxide anion production and prevented the NO reduction in endothelial cells [106].
Berberine, a botanical alkaloid purified from Rhizoma coptidis and a constituent of many medicinal plant extracts, improves metabolic conditions in dyslipidemia, obesity, and T2DM [107]. Berberine reduces body weight and improves glucose tolerance and insulin action in obese and/or diabetic mice by activating the AMPK [108]. Notably, berberine increases AMPK1α and UCP2 mRNA in visceral adipose tissues and livers of high-fat diet-fed mice [109]. In cultured HUVECs, berberine significantly increased UCP2 mRNA and protein expression in an AMPK-dependent manner with promotion of mitochondrial biogenesis [110]. Transfection of HUVECs with nuclear respiratory factor 1- (NRF1-) specific siRNA attenuated berberine-induced expression of UCP2. Through the same mechanism, a significant reduction of atherosclerotic aortic lesions was observed in both ApoE−/− and ApoE−/−/AMPK alpha 2−/− mice [110].
Capsaicin is a phytochemical responsible for the spiciness of peppers [111]. It has the potential to modulate the metabolism via activation of one of the components of the transient receptor potential (TRP) channel family, the TRP vanilloid 1 (TRPV1). The TRP channel family plays a key role in the regulation of cellular calcium signaling and of cardiometabolic functions [112]. In particular, activation of TRPV1, found not only on nociceptive sensory neurons but also in a range of other tissues [112, 113], induces calcium influx, and in certain tissues, this is associated with increased activation or expression of key proteins such as eNOS, UCP2, Krüppel-like factor (KLF2), PPARδ and PPARγ, and liver X receptor alpha (LXRα) [113]. The increased expression of UCP2 induced by TRPV1 activation exerts a protective antioxidant effect in the liver in the nonalcoholic fatty liver disease and in the vascular endothelium in the context of hyperglycemia. In rodent studies, capsaicin-rich diets have shown favorable effects on atherosclerosis, metabolic syndrome, diabetes, obesity, nonalcoholic fatty liver disease, cardiac hypertrophy, hypertension, and stroke [114]. The upregulation of protein kinase A/UCP2 via TRPV1 activation ameliorated coronary dysfunction and prolonged the lifespan of atherosclerotic mice by improving endothelial mitochondrial function. On the other hand, either TRPV1 or UCP2 deficiency exacerbated high-fat diet-induced coronary dysfunction, and this result was associated with increased ROS generation and reduced NO production [114]. Topical application of capsaicin via patch was found to increase exercise time to ischemic threshold in patients with angina [115]. Thus, dietary capsaicin supplementation may represent a promising intervention for the primary prevention of coronary heart disease [115]. Further clinical studies with capsaicin administered in food and capsules, or via patch, are needed to establish protocols that are tolerable for most patients and to evaluate the potential of capsaicin for promoting vascular and metabolic health.
Mitochondrial dysfunction is an emerging contributory mechanism into the pathogenesis of human vascular diseases. For these reasons, novel targeted approaches, designed towards mitochondrial-dependent pathogenic mechanisms, may reveal a useful therapeutic strategy through their ability to improve mitochondrial function and therefore to protect patients from cardiovascular disease occurrence [116]. Among the mitochondrial proteins, UCP2 has been revealed as a significant player in the protection from vascular damage since lack of UCP2 leads to increased micro- and macrovascular damage in distinct pathological contexts. The fine molecular mechanisms dependent on the lack of the UCP2 protein, such as ROS accumulation, upregulation of inflammatory cytokines, increase in monocyte adhesion and transendothelial migration, and increased cell death, may well explain the observed increased rate of atherogenesis and related clinical consequences, as well as the shorter lifespan. Therefore, UCP2 may represent an attractive and promising therapeutic tool in cardiovascular therapeutic. Based on the current knowledge that has been reviewed herein, particularly on the effects of sitagliptin, fibrate, and vegetable extracts, it is likely that overexpression of UCP2, with a consequent improvement of mitochondrial biogenesis and function, may represent a mechanism by which a therapeutic agent can modulate vascular oxidative stress and exert vascular protection (Figure 2). However, the regulation of UCP2 expression is still a complex and incompletely understood process, and there is no specific pharmacological tool available yet to induce UCP2 gene transcription.
Schematic representation of UCP2 gene upregulation. Schematic representation of the pharmacological, vegetable, and humoral factors known to positively modulate UCP2 gene transcription. As a consequence of the UCP2 protein overexpression, several beneficial effects are observed in the vascular system with a significant reduction of the vascular disease occurrence.
This work was funded by the Italian Ministry of Health and the 5‰ grant.
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I support the second amendment. Gun laws and school safety measures should be established by each state, not imposed by the federal government. I do not support newly proposed federal gun legislation with the exception of the removal of bump stocks for public sale and an updated background check system promoted by Congress and President Trump.


GRAPE EXPECTATIONS: In 1986, the Spokane Winery Association (SWA) was formed with Arbor Crest Wine Cellars, Latah Creek Wine Cellars, Mountain Dome Winery, Caterina Winery and the no longer Worden Winery. Four of the five founding wineries are still blazing the Washington Wine trail and actively contributing to our bustling wine scene. There are currently over 700 wineries in Washington State and at the time of the inception of the SWA in the mid 80's there were less than 25 Washington wineries.
Spokane has become a destination for WINE and local winemakers are thrilled to invite you to taste why. 2012 marks the 26th annual Spring Release Tasting event. This highly anticipated indulgence takes place on Mother's Day Weekend (May 11-13) from 12-6pm at 18 local wineries and 2 affiliate tasting rooms.
Spring finds wineries everywhere celebrating the releases of their liquid art, which marks the finale of wine making season and the start of a new wine year. Locally, our area wineries invite locapours (lovers of local wine) in on the festivities of their annual Spring Barrel Tasting. You can expect the welcoming tasting rooms to provide samples of new wines which include current vintages and in some cases wines still in the wine making process with your taste coming directly from the barrel or tank.
Today with all the local wineries and tasting rooms that are participating, you'll need a plan of stopping by more than a few wineries a day to complete the mission of not missing a single one during this premier wine event.
Downtown 1 (12-13 wineries total, 7-*8 stops).
Barrister Winery, Barili Cellars, Whitestone Winery, Grande Rhone Cellars, Caterina Winery/Lone Canary Winery/Mt Dome. *Arbor Crest Wine at their Riverpark Square, Cougar Crest, Nectar Tasting Room.
Robert Karl Cellars, Overbluff Cellars, EMVY Cellars/Bridge Press Cellars and Vintage Hill Cellars with either before or after hitting Townshend in Greenbluff.
Knipprath Cellars, Latah Creek Wine Cellars, Nodland Cellars, *Arbor Crest Wine Cellars (Cliff House) with either before or after jetting to Liberty Lake Wine Cellars.
Note: *Arbor Crest Wine Cellars has both a downtown tasting room at Riverpark Square and the historic Cliff House located in the Spokane Valley.
No, you really can't taste it all. So here's some SIP TIPS.
Sip Tips: Go for the Syrah, Malbec or Sauv Blanc.
Sip Tips: Take a CAB.
Sip Tips: New release of Rough Justice BABY! and the coveted Barrister Block or you can always rely on the remarkable Cab Franc.
Sip Tips: Caterina Winery will both be pouring a selection of complimentary sips. The viognier is a victory.
Sip Tip: EMVY's pride is the Devotion Red Blend wine and the Bridge Press Merlot is marvelous..
Sip Tips: Au Chocolat! and "V" are a treat.
Sip Tips: Latah Creek always take the best host award. The Monarch series is a standout. The magnificent winery gift shop provides a serious shopping opportunity.
Sip Tips: You had me at Merlot. Liberty Lake Merlot is marvelous. LL is debuting their 2009 Tempranillo.
Anelare Winery, Hard Row to Hoe Vineyards, Northwest Cellars, Skylite Cellars, and Terra Blanca Winery. With so many options, let your flight attendant be your guide.
Sip Tip: A Bad Attitude is not only recommended, it's encouraged.
Sip Tips: A stellar cellar line up. Overbluff tends to sell out quickly. Encourage them to make more. Overbluff is debuting Defiance Syrah and their coveted Reserve.
Sip Tips: Crushing on the Claret which the 2009 is being released and the Sauv Blanc is spectacular.
Sip Tip: Vintage Hill provides a SIP then SHOP opportunity as its nestled amongst 2nd Ave boutiques.
Sip Tip: Pieces of Red (Version 9 is out) is always a winner but St Vincent is Sip's all time WS fave.
***Be safe. Remember, it's HIP TO SPIT. Taste responsibly by pacing yourself, nibbling throughout your winescapade and having a designated driver. CHEERS!