Redox Biology 2016: Redox enzymes and Redox physiology Air date: Tuesday, October 25, 2016, 4:00:00 PM Category: Redox Biology Runtime: 01:50:54 …
TODAY WE HAVE LISA RIDNOUR
SHE GOT HER Ph.D. UNIVERSITY OF
IOWA.
>> THAT'S RIGHT.
>> THEN YOU WENT TO ARIZONA.
>> THEN WASH U.
THEN SHE CAME TO NCI, NOW IN THE
CANCER INVESTIGATION PROGRAM SO
SHE WORKS UP IN FREDERICK.
SHE DARED 270 AND GOT HER EARLY.
PLEASED TO HAVE LISA TO ARRIVE
IN MECHANISM DISEASE
PROGRESSION.
>> ALL RIGHT, FOLKS.
TODAY, I'M GOING TO TALK ABOUT
TWO DIFFERENT DISEASES,
ACTUALLY.
I'LL TALK MOSTLY ABOUT CANCER
BUT I'M GOING TO TALK ALSO A
LITTLE BIT ABOUT ALZHEIMER'S
DISEASE WHERE WE KNOW THAT IN
DISEASE PROGRESSION.
TO START OUT TALKING ABOUT
BREAST CANCER, BREAST CANCER
REMAINS SECOND-LEADING CAUSE OF
DEATH AMONG WOMEN WITH
MALIGNANCIES.
DIAGNOSIS IS GENERALLY
DETERMINED BY THESE CLASSICAL
INDICATORS — LET'S SEE.
— THESE ON THE TOP OF THE
SLIDE, BUT WE THINK THAT WE CAN
IMPROVE DISEASE MANAGEMENT AND
SURVIVAL BY IDENTIFYING NEW
BIOMARKERS THAT COMPETE IN
MANAGING THE DISEASE AND
IMPROVING PATIENT SURVIVALS.
AND SO, SINCE WE'RE GOING TO
TALK ABOUT NOs, THE PAST 10-15
YEARS WE SAY THE LAB HAS SPENT A
LOT OF TIME EXAMINING SIMILAR
EFFECTS OF NIGH TRUST OXIDE AND
CHEMICALS KNOWN FOR NIGH
NITROOXIDE.
AS CONCENTRATIONS BEGIN TO RISE,
WE SEE STABILIZATION AND
PHOSPHORYLATION OF KINASE AS
WELL AS AKT.
IN HIGHER LEVELS, WE SEE PEOPLE
SEE PHOSPHORYLATION AND EVEN
HIGHER LEVELS AROUND ONE STUDY
SAVING NOTE THAT IS CONSISTENT
WITH NITRO-STATED LEVELS.
SO THESE INTERMEDIATE AND HIGHER
LEVELS CAN BE PRODUCED BY THE
INDUCIBLE MOUTH SEW PLAN MOUTH
TWO.
WE KNOW THAT THE COMPONENTS OF
THE TUMOR MICRO AND BIOME, WE
KNOW THE TUMOR MICRO ENVIRONMENT
IS COMPLEX AND CONSISTS OF
CANCER CELLS, IMMUNE CELLS AND
FIE SEW BLASTS AS WELL AS EXTRA
CELLAR MATRIX.
ALL F OF THESE WITHIN THE
ENVIRONMENT COMMUNICATES WITH
EACH OTHER TO PROMOTE TUMOR
PROGRESSION.
REDOX BIOLOGY DERIVED AND
COMMUNELATING FACTOR IN THESE
COMMUNICATION PROCESSES.
WHILE OVER THE YEARS WE'VE
DETERMINED QUITE A LOT INTERCIG
WILLING AND CANCER CELLS, LESS
IS KNOWN ABOUT INTERSIGNALING IN
EXTRA CELLARER MATRIX.
WHEN I FIRST JOINED THIS GROUP,
THAT WAS ONE OF THE FIRST
QUESTIONS WE WERE INTERESTED IN
ADDRESSING.
SO BECAME INVOLVED WITH DAVE
ROBERTS HERE AT NCI AND WE BEGAN
A COLLABORATION LOOKING AT CROSS
TALK SIGNALING EFFECTS BETWEEN
NITROOXIDE AND SOUND RESPONDING
ONE WHICH WAS LARGE EXTRA CELLAR
MATRIX PROTEIN AND IT'S GENERAL
HLY THOUGHT TO BE ANTIANT KNOW
GENIC WHERE IN CONTRACT WE KNOW
NO IS COANGIOGENIC.
WHAT THIS PROJECT DETERMINED —
ALSO WE USED FUNCTIONAL ASSAYS
INCLUDING UX PROLIFERATION AND
VASCULAR GROWTH MUS KAL CUE LAR
ASSAY TO LOOK AT NEGATIVE
EFFECTS.
WHAT WE FOUND WAS THAT AT LOW
FLEX NO WE SEE INCREASED
PROLIFERATION WHICH ABOUT ONE
MICROMOLAR AND IN THE PROCESS OF
INDUCING THAT THROUGH THAT
PROLIFERATION, WE SEE
NO-INCLUSED SUPPRESSION OF
FONDING ONE AT VERY LOW LEVELS
OF NITROOXIDE.
SIMILARLY IN THE X PLANT ASSAY,
WE SEE THAT IN THE CONTROL
TISSUE, UM, YOU SEE A SMALL
AMOUNT OF VASCULAR CELLS
MIGRATING OUT AND AWAY FROM THE
PERIMETER OF THE TISSUE, BUT IF
YOU ADD INHIBITOR L-NAME YOU
BLUNT THE OUTGROWTH OF THESE
VASCULAR CELLS.
IN CONTRAST, IF WE ADD A LITTLE
BIT OF TRY TRO OXIDE TO —
NITROOXIDE TO THESE TISSUES WE
SEE ABUNDANT OUTGROWTH OF
VASCULAR CELLS.
THIS IS VERY CONSISTENT IN THIS
INCLUSED RESPONSE ASSAY.
— INDUCED RESPONSE ASSAY.
THIS GOES ON TO SHOW THAT ALL
THESE PROCESSES CAN BE INHIBITED
BY THE ADDITION OF ENDOGENOUS
RESPONDING ONE.
SO IN SUMMARY, THIS PROJECT WENT
ON, IT BECAME A FRUITFUL
COLLABORATION AND WENT ON TO
GENERATE A NUMBER OF VERY NICE
PAPERS FOR DAVE ROBERTS' GROUP.
ANOTHER GROUP OF EXTRA CELLAR
MATRIX PROTEINS THAT THEY WERE
INTERESTED IN EXAMING FOR MATRIX
AND POWER PROTEIN.
THESE ARE SE KROOED CRETED
PROTEASES, THEY CAN PROCESS
COMPONENTS OF EXTRA CELLAR
MATRIX AND THE REASON WE WERE
INTERESTED IN THEM IS BECAUSE
THE A ACID SITE CONTAINED
VIOLATES WHICH TARGETED BY
NITROGEN SPECIES.
SO WE FIRST STARTED EXAMINING
REGULATION AND ENDOGENOUS
INHIBITORS [INDISCERNIBLE] IN
MACROPHAGE CELLS THAT WE EXPOSED
LOW DOSES OF NO STERNO.
WE SEE INCREASE IN ACTIVITY AND
WE ALSO SEE SUPPRESSION OF
SECRETION AT THESE LOWER LEVELS.
SO WE TOOK THE CONDITIONED MEDIA
FROM THESE CELLS WHERE WE SAW
PEAK ACTIVATION OF NPs AND WENT
ON AND PUT THIS MEDIA ON TISSUE
EXPLANT A ASSAY AND WHAT WE
FOUND WAS THAT THE MEDIA FROM
CELLS THAT WERE TREATED WITH
MICROMOLARS SHOWED OUTGROWTH OF
VASCULAR CELLS AWAY FROM THE
PERIMETER OF THE THE TISSUE BED.
THEN WHEN WE WENT ON TO KNOCK
DOWN MNP 9 WE SAW THIS PROCESS
WAS DEPENDENT UPON MNP 9
ACTIVITY.
THIS WAS DEMONSTRATED THAT THE
WAS IN PART BY DEPENDENT AND
INVOLVED ONE SECRETION OF TIP
ONE AND INCREAMNP 9 ACTIVITY.
WE WANTED TO GO ON AND LOOK AT
THIS REGULATION PROCESS AND
FIGURE OUT RELEVANT MODELS.
SO WE PROCEEDED TO EXAMINE THESE
E EFFECTS IN CANCER AND ALL
RECIPES.
BEFORE WE TALKED ABOUT WHAT WE
FOUND IN CANCER I'LL TELL YOU
WHAT WE FOUND IN ALZHEIMER'S
MODELS.
THIS MODEL WAS DEVELOPED AT DUKE
UNIVERSITY BY A COLLABORATOR OF
OURS, AND SHE MADE THIS MOUTH
THAT OVEREXPRESSES ATP PROTEIN
WHICH IS THE TRANS MEMBRANE
PROTEIN AND WHEN IT'S CLIPPED IT
CAN MAKE A BETA.
OKAY.
SO THESE MICE, SHE THEN CROSSED
THESE MICE WITH THREE KNOCKOUT
ANIMALS.
SHE HAD MICE THAT HAD FUNCTIONAL
MOUSE TWO AS WELL AS MICE THAT
LACKED MOUSE TWO IN ALL CELL
TYPES THAT MAKE IT, OKAY.
SO WHAT SHE FOUND WAS THAT THE
MICE THAT LACKED FUNCTIONAL
MOUSE TWO HAD A LOT OF INSOLUBLE
PLAQUE.
WHERE AS, MICE THAT CONTAINED
FUNCTIONAL MOUSE TWO DID NOT,
AND CERTAINLY WHEN SHE LOOKED AT
THE STATE OF THE NEURONS IN
THESE ANIMALS, MICE THAT HAD
MOUSE TWO DID NOT EXHIBIT
NEURONS BUT THE MICE THAT LACKED
MOUSE TWO DID HAVE QUITE A LOT
OF DEAD NEURONS WHEN THEY
COMPARED TO A CONTROL.
SO ONE THING THAT WE KNOW FROM
THE LITERATURE IS THAT A BETA IS
A SUB STRAIGHT FOR MNP 9 AND
THIS WAS DEMONSTRATED BY A GROUP
AT WASHINGTON UNIVERSITY AND
THEY SHOWED THAT ACTIVE MNP 9
COULD CLIP A BETA AT THESE
SPECIFIC SITES IN THIS SEQUENCE,
SO WE BEGAN TO EXAMINE WHETHER
OR NOT NO REGULATION OF MNP 9
AND ONE MAY BE ATTRIBUTED TO
THIS DIFFERENCE IN GENOTYPES OF
MOUSE.
SO THE FIRST THING WE DID WAS WE
LOOKED AT MNP 9 AND TENT ONE
EXPRESSION IN THESE MICE AND WE
COULD SEE THAT IN THE ANIMALS
THAT LACKED FUNCTIONAL MOUSE
TWO, THEY HAD LOWER LEVELS OF
MNP 9 EXTREGS, AND THEY ALSO
HAVE HIGHER LEVELS OF TENT ONE
EXPRESSION.
WE EXAMINED MNP 9 AND TENT TWO
LEVELS IN THESE MICE AND THEY
DID NOT APPEAR TO HAVE ANY
DIFFERENCE IN THEIR EXPRESSION
LEVELS.
SO THEN WE WENT ON AND LOOKED AT
SIGNOGRAPHY OF THESE MICE, WE
USED GELATIN SIGNOGRAPHY ASSAY.
THIS WOULD MEASURE MNB 9 AND MNP
2.
THE ANIMALS THAT HAVE FUNCTIONAL
HAVE HIGHER MNP ACTIVITY IN
THESE THE TISSUES.
THIS ACTIVITY SEEMS TO BE
RESTRICTED TO MNP 9 BECAUSE WE
DON'T SEE — REALLY, WE SEE
MINIMAL LEVELS OF MNP 2 IN THESE
ANIMALS.
SO UNFORTUNATELY, THIS PART OF
THE ASSAYS WASN'T ABLE TO GIVE
US A DIFFERENCE IN ACTIVITY
LEVELS, SO WE WENT ON AND
DEVELOPED AN ANTIBODY-BASED MRN
A ASSAY TO EXAM THE ACTIVITY IN
THESE TISSUES.
AND SO WE MADE AN ANTIBODY THAT
RECOGNIZED A FRAGMENT OF MNP 9
CLIPS INSOLUBLE A BETA.
MANY ENZYMES CAN BE GREAT
SOLUBLE BETA, BUT MNP 9 IS THE
ONLY ENZYME THAT CAN LOOK THE
ENSOLUBLE FORM.
IT CAN CLIP IT AT THESE POINTS
IN THE SEQUENCE AND WE MADE AN
ANTEAGAIN FOR THE ONES 16
FRAGMENT.
THIS ANTIBODY WAS EXTENSIVELY
CHARACTERIZED USING MASS SPECK.
WE IMMUNO PRECIPITATED MATERIAL
FROM MNP 9 DESTRAITED INSOL BETA
AS WELL AS THE WHOLE GRAIN HA
KNOWLEDGE NATE OF THE MICE THAT
CONTAINED NOS TWO AND WE ALSO
USED A BETA ONE TO 16 THAT WE
PURCHASED.
WHAT YOU CAN SEE IS THAT THESE
MRNs ARE ALL THE SAME AND THAT
TELLS US THAT THIS PROGRESSMENT
IS ABUNDANT IN THESE ANIMALS AND
WE CAN MEASURE IT.
AND SO WE DID THAT IN THE BRAINS
OF THE MICE WHICH IS SHOWN ON
THIS TOP PANEL HERE, PANEL A,
AND WHAT THIS SHOWS US IS THAT
MICE THAT CONTAIN FUNCTIONAL NOS
TWO HAVE A LITTLE BIT MORE THAN
TWO-FOLD INCREASE IN THE AWAY TA
16 FRAGMENT AND WE USE THAT AS
AN INDEX OF MNP 9 ACTIVITY AND
THESE DATA SUGGEST THAT THESE
ANIMALSES DO HAVE HIGHER MNP 9
ACTIVITY, WHEREAS IN THE ABSENCE
OF NOS TWO, IT'S REDUCED.
SO WE WENT AHEAD AND LOOKED AT
HUMAN ALZHEIMER'S BRAIN AND
HUMAN CONTROL BRAIN AND WE SEE
THE SAME TWIN IN THESE TISSUES
AS WELL.
SO TOGETHER THESE DATA TELL US
THAT PERHAPS NITRIC OXIDE IS
PROTECTING AGAINST DISEASE
PROGRESSION OF A ALZHEIMER'S, IN
PART, BY INCREASED MNP 9
ACTIVITY AND LOWERING TENT ONE
WHICH FACILITATED THE
DEGRADATION AND CLEARANCE OF
ANDROID FAT TO NON-TOXIC PEPTIDE
FRAGMENTS.
NOW WE'LL TALK ABOUT CANCER, AND
SO ON THIS SLIDE ANYTHING THAT
IS HIGH LIGHTED IN GREEN ARE
CANCER TYPES THAT HAVE PUBLISHED
THE ABILITY OF NOS TWO TO
PREDICT PROGNOSIS.
AMONG THEM ARE BREAST CANCER,
WHICH YOU CAN SEE ON THE RIGHT
SIDE OF THE SLIDE, AND SO WE
WENT ON TO EXAMINE NOS TWO AS A
PREDICTOR OF BREAST CANCER
SURVIVAL.
WE DID A COHORT STUDY WITH NCI
FREDERICK AND WHAT THEY SHOWEDED
IN THIS STUDY WAS THAT NOS TWO
DID, IN FACT, PREDICT SURVIVAL
IN PATIENTS THAT HAD BR 2 BREAST
CANCER WHICH WAS A AGGRESSIVE
FORM OF BREAST CANCER.
IT DID NOT PREDICT SURVIVAL IN
THE LESS.
INTERESTINGLY, AMONG THE
PATIENTS THAT BECOMES TO
DISEASE, HIGH NOS TWO EXPRESSING
GROUP, 92% OF THOSE PATIENTS
EXPRESSED ELEVATED TUMOR NOS
TWO.
SO ANOTHER IMPORTANT THING THAT
I WANTED TO SHOW FROM THIS WORK
IS THAT NOS TWO EXPRESSION DID
CORRELATE POSITIVELY WITH BRAVE
THREE.
IT ALSO CORRELATED POSITIVELY
WITH 253 MUTATION AS WELL AS CD
31 WHICH IS AN INDEX OF
VASCULATURE.
SO IN THIS STUDY, THEY USED
LASER CAPTURE OF HIGH NOS TWO
AND LOW NOS TWO TUMOR TISSUES
AND DID A GINA RAY ANALYSIS AND
FOUND SIGNATURE OF ABOUT 44
GENES THAT WERE UP REGULATED IN
TUMORS THAT HAD HIGH NOS TWO.
WE WERE INTERESTED IN A SET OF
THESE PROTEINS INCLUDING IL 8
WHICH IS BASIL-LIKE MARKER AND
INVOLVED IN PROLIFERATION,
ANGIOGENESIS AND CELL MIGRATION.
IN ADDITION, THE PEAK HEARING IS
ALSO LIKE MARKER 108 A IS COAL
RECEPTOR AGONIST INVOLVED IN
INFLAMMATORY PROCESSES AND CD 44
IS A STEM CELL MARKER IN THESE
WERE ALL ELEVATED.
INTERESTINGLY, I THINK PROTEIN
[INDISCERNIBLE], THIS H IS VERY
INTERESTING TO ME BECAUSE THIS
TELLS ME BASICALLY CATALYZED
RECYCLING OF SIT LIEN WHICH IS
ALSO A BY-PRODUCT OF THE
NOS-MEDIATED OXIZATION OF L
LARGENEN.
— — KEEPING LEVELS HIGH ENOUGH
IN THE TUMORER TO GENERATE NO.
THAT WAS VERY INTERESTING.
ONE THING YOU DON'T SEE ARE MNP
9 AND TEMPS ON THIS TABLE, BUT
THERE ARE SOME OTHER CONNECTIONS
HERE BECAUSE MNP 9 HAS BEEN
SHOWN TO PROCESS IL 8 TO
INCREASE ITS BIOACTIVITY AND
ALSO CD 44 CAN SERVE AS A
DOCKING PORT FOR MNP 9 SO IT ARE
RESIGNED TO IT AND IT'S BEEN
IDENTIFIED AS LEADING EDGE OF
MIGRATING CELLS AND IT'S BEEN
SHOWN IN SOME STUDIES TO BE
ASSOCIATED WITH INCREASED
METASTASES.
OKAY.
UM, SO, OTHER GROUPS HAVE ALSO
DEMONSTRATED THAT MNP 9 PREDICTS
OVERALL SURVIVAL AND
RELAPSE-FREE SURVIVAL.
TEMP TENT ONE DOES AS WELL.
TENT ONE IS GENERALLY THOUGHT OF
AS AN INHIBITOR FOR MNP 9 BUT IT
DOES HAVE OTHER MNP-INDEPENDENT
FUNCTIONS.
WE ASKED THE QUESTION OF WHETHER
OR NOT NO MIGHT ELUCIDATE
PROTUMOR EFFECTS BETWEEN MNP 9
AND TENT ONE.
TO DO THIS, WE WENT BACK TO STE
FAN'S COHORT AND WE STAINED FOR
TEMP ONE EXPRESSION IN THESE
TUMOR TISSUES AS WELL AS PD 63
WHICH IS A CELL SURFACE PROTEIN
WHICH IT BINDS TO.
WHAT YOU SEE IS THAT THESE
TUMORS — THESE ARE JUST TWO
EXAMPLES — WE SEE DIFFERENTIAL
EXPRESSION IN THESE TUMORS.
SOME HAD HIGH, SOME
INTERMEDIATE, AND SOME HAD LOW
OR NO LEVELS OF TENT ONE AND CD
63.
WE EXAMINED THE SURVIVAL EFFECTS
OF TENT ONE IN OUR MODEL AND
SHOW THAT TENT ONE DOES PREDICT
SURVIVAL IN OUR COHORTS, AND
WHEN WE STRATIFIED FOR TIEING
OFF TWO, THIS EFFECTS SEEMED TO
BE RESTRICTED TO TUMORS THAT
ALSO EXPRESSED KINASE TWO
BECAUSE TEMP ONE DID NOT PREDICT
SURVIVAL IN TUMORS THAT EXPRESS
LOW NOS TWO.
WE THOUGHT THAT THIS MIGHT BE
TELLING US SURVIVAL EFFECTS OF
HIGH NOS TWO AND HIGH TENT ONE
MAY BE MECHANISTICALLY
INTERRELATED.
WHAT MIGHT A COMMON SIGNALING
PATHWAY BE?
AKT SIGNALING MAY BE COMMONLY
SHARED AS A MECHANISM.
SO AGAIN, WE KNOW FROM THE
LITERATURE THAT TENT ONE
COMBINES TO CD 63 TO INITIATE
PROSURVIVAL SIGNALING THAT GOES
TO PAP KINASE, AKT BAD
PHOSPHORYLATION.
WE ALSO KNOW FROM PREVIOUS
STUDIES THAT FROM STEFAN'S LAB
THAT NOS TWO CORRELATES WITH
PHOSPHOR AKT AND THAT IS SHOWN
BY THIS ODD RATIO OF 4.49.
RATIO DESCRIBES STRENGTH AND
SOESHUATION BETWEEN TWO
MOLECULES AND THE ODDS OF THAT
EVENT OCCURS IN ONE GROUP
COMPARED TO ANOTHER.
HUMANS THAT HAVE HIGH NOS TWO
AND HIGH TAKT EXHIBIT AN ODDS
RATIO OF THAT 4.5.
WE THEN STRATIFIED FOR HIGH AND
LOW TENT ONE AND ALSO EXPRESSED
HIGH TENT ONE RATIO GOES FROM
4.5 TO NEARLY 13.
IN CONTRAST, LOW TENT ONE
EXPRESSED, ODDS RATIO GOES DOWN
BY NEARLY HALF.
SO WE THEN LOOKED AT TENT SNF
TEMP] CORRELATION WITH NOS TWO
AND FOUND THAT TEMP ONE ONLY
CORRELATED WITH NOS TWO AND CR
NEGATIVE PATIENTS.
SO WE WENT FORWARD WITH OUR
CULTURE EXPRERMENTS USING ER
NEGATIVE BREAST CANCER CELLS AND
WE TREATED THESE CELLS WITH AN
INNER DONOR DETAINER AND WE
FOUND THAT AT HIGH
CONCENTRATIONS OF NO, WE SEE
INCREASED AKT PHOSPHORYLATION
AND BAD PHOSPHORYLATION, BUT
WHEN WE KNOCKED OUT TEMP ONE,
THESE PHOSPHORYLATION PATTERNS
WERE DIMINISHED AND WE ALSO KNOW
THAT ON THE BOTTOM OF THE FIGURE
WHERE WE PRODDED NORMALIZED
PHOSPHORYLATION OF AKT TO TOTAL
AKT AND PHOSPHOR
TU[INDISCERNIBLE]
AND THE CELLS THAT HAD HIGH TEMP
ONE AND CELLS THAT DID NOT.
WE WENT ON TO LOOK AT THE
EXPRESSION, WHETHER OR NOT NO IS
INDUCING EXPRESSION IN TEMP ONE
OF THESE CELLS AND WE COULD NOT
IDENTIFY SIGNIFICANT INCREASE AT
THESE DONOR CONCENTRATIONS IN
TEMP ONE EXPRESSION.
P WE DO SEE SIGNIFICANT INCREASE
IN PROTEIN SECRETION AT 100 MIE
I KRO MOLAR, BUT THIS
ISN'T — — THAT INDUCED
PHOSPHORYLATION OF THE PROTEIN.
WE BEGAN TO THINK THAT WE WERE
LOOKING AT THIS WRONG BECAUSE
THIS IS ACTUALLY MEASURING THE
LEVELS OF TEMP ONE SECRETE INTO
THE MEDIA BUT IF IT HAS TO FIND
BIND TO THE CELLS AT CELL
SURFACE PRO TAN, YOU KNOW, MAYBE
WE'RE, YOU KNOW, NOT LOOKING AT
THE RIGHT PLACE HERE.
SO WE THEN LOOKED IN THE
LITERATURE AND FOUND A PAPER —
INTERESTING PAPER — WHERE THEY
MADE A MU TRANT FORM OF TEMP ONE
THAT WOULD NOT INHIBIT ACTIVE
NNC 9 AND FOUND THIS MUTANT
PROTEIN ACTUALLY BOUND TO A
HIGHER DEGREE TO CD 63 THAN
WILD-TYPE PROTEIN.
IN THEIR SYSTEM, IT DID AFFECT
THE PHENOTYPE OF THEIR SYSTEM.
SO WE ASKED THE QUESTION OF
WHETHER OR NOT NO CAN MODULATE
TEMP ONE FUNCTION AND TUFRP ONE
CD 63 COLOCAL LIE IIZATION.
TO DO THIS WE DID A STUDY OF
CONTROL AND NO-TREATED NDP 31
CELLS AND TEMP ONE IS IN GREEN
AND CD 63 IS SHOWN IN RED.
YOU CAN SEE THAT THE FLOAT THAT
GOT NO, THERE'S A LOT MORE GREEN
INDICATING THAT TEMP ONE IS
STUCK TO THE SURFACE OF THESE
CELLS AND THEN THERE DOES APPEAR
TO BE SOME COLOCALIZATION WITH
CD 63 AND TEMP ONE AS SHOWN BY
THESE OWE LEISH AND ORANGISH
REEDS ON THE BOTTOM PANELS HERE.
WE KNOW THAT TEMP ONE CAN — WE
KNOW THAT NO CAN CAUSE NIGH
GRAGS EVENTS IN PROTEIN SO WE
TREATED REKOFSH NANT TEMP ONE
PROTEIN WITH THESE SAME
CONCENTRATION OF NO DONOR AND
THEN WE DRIED TO PROTEIN DOWN
AND PUT ON MASS SPECK AND SEE
THAT THERE IS, INDEED, A 45
MATCH SHIFT IN THE PROTEIN THAT
WE EXPOSED TO NO.
THIS IS CONSISTENT WITH NIGH
TRAGS EVENTSES AND WE IDENTIFIED
TWO NIGH TRAGS EVENTS ON TWO
RESIDUES IN THIS PROTEIN.
WE WENT BACK AND
IMMUNOPRECIPITATED NC TWO 31
WITH TEMP ONE AND THEN BLOTTED
WITH 3 MP AND WE SEE THERE'S AN
INCREASE IN NITROTYROSINE IN THE
CELLS TREATED WITH NO, AND THERE
SEEMS TO ALSO BE AN INCREASE IN
PULL-DOWN OF CD 63 IN THESE AS
WELL.
SIMILARLY, WE WENT BACK AND WE
LOOKED AT DI 3 CHAIN SIGNALING
IN THESE CELLS AND WE SEE THAT
NO INDUCES INCREASE IN TO 3 K
PHOSPHORYLATION AT 500
MICROMOLAR WHICH IS REDUCED WHEN
WE KNOCKED OUT TEMP ONE.
SO TOGETHER, THESE DATA TELL US
THAT, UM, TEMP ONE PREDICTS POOR
SURVIVAL IN PATIENTS WITH HIGH
NOS TWO TUMOR EXPRESSION, THAT
ELEVATED TEMP ONE AUGMENTS NOS
TWO TAKP SOESHUATION IN THE
BREAST TUMORS AND THAT IF WE
SILENCED TEMP ONE WE CAN
SUPPRESS NO-INDUCED ASIMILAR PA
TICK SIGNALLING IN BREAST CANCER
CELLS.
THEN AN INTERESTING PAPER CAME
OUT ABOUT SIX MONTHS BEFORE WE
PUBLISHED OUR PAPER AND
BASICALLY THIS WORK THEY ALSO
SHOWED IDENTIFIED HIGH LEVELS OF
TEMP ONE NITRATINGS.
THEY EXPOSED TO LPS SO YOU SEE
BIG HIGH LEVELS OF TEMP ONE
NITRATION.
THEY WENT ON AND SHOWED THIS
NITRATED TEMP WAS NOT ABLE TO
BIND TO MMP 9 AND YOU SEE HIGH
LEVELS OF MNP 9 ACTIVITY IN
THESE DIAGRAM.
INTERESTINGLY, THEY USED THE
MOUSE MODEL OR A MATH MODEL TO
PREDICT WHAT TYROSINE LEVELS
RESIDENCE DUZ WOULD BE AND THEY
PREDICTED THE SAME CAIRO SCENE
RESIDUE WITH THEIR MATH MODEL
THAT WE SHOWED BY MASS SPECK
TROM PI.
GOING BACK TO OUR COHORT, WE
ALSO LOOKED AT MNP 9 SURVIVAL.
IT DOES PREDICT POOR SURVIVAL.
IT PREDICTS THE HAZARD RATIO
GOES UP A LITTLE BIT IN TUMORS
THAT HAVE LOW TEMP ONE
EXPRESSION.
TEMP ONE — MNP 9 DOES NOT
PREDICT SURVIVAL IN TUMORS THAT
HAVE HIGH TEMP ONE EXPRESSION.
SO WE KNOW THAT MNP 9 IN
ADDITION TO PROCESSING IL 8 AND
INCREASING BIOACTIVITY, IT CAN
ALSO INCREASE AVAILABILITY AND
BEEN ASSOCIATED WITH INCREASING
GENESIS AND THEN AGAIN DOWN HERE
WHERE I TOLD YOU THAT IT'S BEEN
SHOWN THAT IT CAN FWIEN CD 44
AND PROMOTE METASTASES.
PATIENTS IN HIGH MP 9 AND CD 44
EXHIBIT INCREASE HAZARD RATIO OF
2.49.
THAT MAYBE, YOU KNOW, THERE MAY
BE A SIMILAR EFFECT IN OUR
BREAST CANCER COHORT AS WELL AND
INVOLVEMENT OF NOS TWO.
SO, CAN NO ELUCIDATE PROTUMOR
EFFECTS IN MNP 9 AND TEMP ONE.
WE THINK WHAT THIS DATA MAY BE
TELLING US IS NITRATION MAY
SHIFT TEMP ONE SIGNALING AWAY
FROM MNP 9 INHIBITOR FUNCTIONS
TO FAVOR CD 63 PROSURVIVAL CIG
ISSALING WHILE MAINTAINING MNP 9
ACTIVITY TO PROMOTE OVER
PROHUMOR EFFECTS LIKE CELL
MIGRATION AND METASTASES.
SO WE WENT ON AND LOOKED AT
WHETHER OR NOT WE COULD TARGET
NOS TWO IN A MOUSE MODEL.
SO WE INJECTED MICE WITH ND 231
SPIRALS THAT HAVE A TAG AND THAT
WAY WE CAN LOOK AT FLUORESCENCE
OF TUMORS IN THE MOUSE.
THEN WE TREATED MICE WITH WATER
THAT HAD AMY KNOW I NOS
INHIBITORS.
GROWTH RATE OF THESE TUMORS IS
SIGNIFICANTLY LESS THAN THE
CONTROL MICE THAT DID NOT GET
THE INHIBITORS.
YOU CAN SEE FLUORESCENCE OF
THOSE TUMORS AS WELL OVER HERE.
BUT THE MOST STRIKING
OBSERVATION FROM THIS STUDY WAS
THAT THE CONTROL MICE HAD MORE
FLUORESCENCE THAN THE MICE —
THEIR BRAINS HAD MORE AND THEIR
LUNGS — WE DON'T SHOW THAT ON
THIS SLIDE HERE BUT WE DID LOOK
AT LUNGS — MICE THAT GOT
TREATED THE IMMY KNOW GAUN KEEN
HAD FAR LESS FLUORESCENCE IN
THEIR BRAIN TISSUE WHICH
INDICATED THAT THERE WAS LESS
METASTATIC EVENT IN THE BRAINS
OF THESE MICE.
JULIE WENT ON AND LOOKED AT SOME
OF OUR BIOMARKER EXPRESSION
LEVELS IN THE MICE AND LOOKED AT
CD 44, S 100 A 8 WHICH WE SHOWED
IN OUR TABLES OF OUR TUMOR
TISSUES, AND SHE ALSO LOOKED AT
COX TWO, PLS 4, AGONIST, AND IL
6.
IN ALL CASES, THE MICE THAT GOT
AMY KNOW GAUN DEAN HAD REDUCED
EXPRESSION OF THESE BIOMARKERS.
SO AN IMPORTANT QUESTION OF
THOSE AND WITH YOU OF THE JCI
PAPER OF THE COHORT, AND THEY
WANTED TO KNOW IF NOS TWO WAS
ACTUALLY MAKING NO, AND SO JULIE
WENT ON TO LOOK AT HOW NOS TWO
MIGHT BE REGULATED IN TUMORS AND
SO SHE USED COMPONENTS OF THE
TUMOR MICROENVIRONMENT INCLUDING
STARVATION, WITHDRAWAL, SHE HIGH
POX YEAH AND CYTOKINE WHICH CAN
MIMIC CHRONIC INFLAMMATION IN
TUMOR MICROENVIRONMENT, AND SHE
FOUND THAT WHEN SHE JUST SIMPLY
E TREATED THE CELLS WITH SERUM
WITHDRAWAL WHEN COMPARED TO
CONTROL SHE SAW HIGHER LEVELS OF
NOS TWO PROTEIN EXPRESSION AND
SHE ALSO QUANTIFIED NIGH TRITE
LEVELS IN THESE SAMPLES AS WELL
AND SHE SHOWED, I THINK ABOUT A
TWO-FOLD INCREASE IN NITRATE
LEVELS WHEN THE CELLS WERE
EXPOSED TO SERL WITHDRAWAL.
SERUM WITHDRAWAL.
INTERFERON WAS VERY, VERY HIGH.
WE TOOK THESE CELLS EXPOSED TO
INTERFERON AND WITHDRAWAL AND
SHE LOOKED AT TEMP EXPRESSION
AND TEMP IS INDUCED DRAMATICALLY
BY INTERFERON GAMMA AND WHEN SHE
IPED TEMP OUT AND THEN PMP SHE
SAW A LITTLE BMP STAINING WHICH
WAS MAYBE REDUCED A LITTLE BIT
IN THE PRESENCE OF AMY KNOW GAUN
DEAN.
AMY KNOW
MAY BE INDICATION OF GAUN DEAN
WITHIN THE KNEW TUMOR.
INDUCE POST SURVIVAL SIGNALING.
IT CAN INDUCE TUMOR GROWTH AND
ME IT'S A — IT CAN REDUCE
CHEMO RESISTANCE AS WELL.
FROM MD ANDERSON.
THEY LOOKED AT NOS TWO EX
EXPRESSION IN PATIENTS NEGATIVE
DISEASE AND SHE FOUND NOS TWO A
ALSO PREDICTED BOTH SURVIVAL IN
THESE PATIENTS AND THIS WAS
VERIFIED IN ANOTHER IN TWO OTHER
COHORTS THAT SHE EXAMINED.
SO SHE WANTED TO TARGET NOS TWO
IN MICE AND SHE GAVE THEM
ANOTHER A DIFFERENT INHIBITOR, L
MAIN WHICH IS A PAN INHIBITOR OF
NOS.
THESE ARE MP31 SEE KNOW GRAPHS.
WE CAN SEE THE MICE THAT GOT THE
NOS INHIBITOR HAS REDUCED STROKE
AND THEY ALSO HAVE REDUCED
LUMINESCENCE.
THESE ARE TAGGEDED WITH ARE
RESIF RACE.
REDUCED LUMINESCENCE IN THE
LUNGS OF THESE ANIMALS AS WELL.
THIS STUDY SUPPORTS OURS THAT
TARGETING NOS CAN REDUCE TUMOR
BUT CAN ALSO REDUCE ME IT'S A
SEES AS WELAS WELL.
SHOWED IT'S SUPPRESSED IN THE
ANIMALS THAT GOT L MAIN AND SHE
PROPOSED THAT SIGNALING PATHWAY
INVOLVING I KNOX GOING TO PGS
BETA INCREASE STICK ONE WOULD
PROMOTE TUMOR METASTISES.
THIS IS JUST A SLIDE THAT, THIS
IS NEW DATA THAT WE'VE HAD WHERE
WE TREATED MP 231 CELLS WITH
ARGENEN, AND ALSO TITRATED BACK
IN DETAIN NO AND THE CELLS THAT
GOT IMMUNOGAUN DEAN.
WE JUST LOOKED AT TRAJECTORY OF
DIE-LABELED CELLS.
COMPAREDED TO CONTROLLED THERE'S
A LOT MORE EVENT AND YOU CAN SEE
LONGER TRAJECTORIES IN THE CELLS
THAT GOT NO.
THAT'S P PRELIMINARY DATA FOR A
NEW PROJECT WE'RE TRYING TO
START, BUT TOGETHER I THINK BOTH
OF OUR STUDY AND THEIRS SUGGEST
THAT [INDISCERNIBLE] TARGETING
METASTISES BY NO.
SO WE WANTED TO KNOW IF WE COULD
TARGET NOS WITH CONVENTIONAL
THERAPY.
WE USED RADIATION MODEL.
WE HAD MICE THAT HAD
TUMOR-BEARING LEGS AND WE GAVE
THEM TEN GRAY OF RADIATION AND
WE TREATED THESE MICE EITHER
WITH GAUN DEAN OR GAVE THEM L
MAIN.
IN THIS CASE, THIS IS AN
IMMUNOCOMPETENT MICE AND THE
ANIMALS THAT GOT L MAIN
EXHIBITED TRAMATICALLY F-REDUCED
TUMOR GROWTH WITH L MAIN —
DRAMATICALLY-REDUCED TUMOR
GROWTH WITH L MAIN.
I NOS DID SIGNIFICANTLY REDUCE
TUMOR GROWTH BUT IT THE TUMOR
GROWTH DELAY INDUCED BY
RADIATION BUT NOT AS EFFECTED AS
L MAIN.
WE REPEATED THESE IN MICE USING
HE 29 CELLS.
BASICALLY THERE WAS NO
AUGMENTATION OF THE RADIATION
INDUCED.
THIS SUGGESTS TO US THAT T CELLS
ARE REQUIRED FOR TARGETING NOS
IN THIS SYSTEM.
THANK YOU.
OKAY.
WE WENT ON AND LOOKED AT
CYTOKINE EXPRESSION PRO ARE
FILES IN THESE TUMORS AND THE TU
UH MORES THAT GOT — TUMORS THAT
GOT RADIATION ALONE OVERALL
IMMUNOSUPPRESSES SIGNALING
PROFILE BUT THE TUMORS THAT GOT
TEN GRAY AND L MAIN EXPRESSED
HIGHER LEVELS OF PROINFLAMMATORY
CYTOTOXIC CYTOKINES.
SO IL 10 WAS ONE CYTOKINE THAT
REAL HI JUMPED OUT AT US BECAUSE
IT WAS UP REGULATED EARLY AND
THE MICE THAT GOT TEN GRAY AND
IT WAS SUPPRESSED WHEN WE GAVE L
MAIN, AND SO WE WANTED TO KNOW
IF WE COULD TARGET IL 10 AND
INCREASE RADIATION-INDUCED.
WE WERE ABLE DO THAT WHICH IS
SHOWN HERE.
UM, SO WE WENT ON TO LOOK AT THE
TUMORS OF THESE MICE AND WE
ISOLATED LEUKOCYTES FROM THESE
TUMORS AND FOUND THAT IN THE
ANIMALS THAT GOT THE TEN
RADIATION AND L MAIN, THEY HAD
HIGHER NUMBER OF CDA POSITIVE T
CELLS AND HIGHERER NUMBER OF
ACTIVATED CD 8 POZ T CELLS AS
WELL.
— POSITIVE.
THIS DATA SUGGESTS THAT IF WE
TARGET NOS IN A RADIATION
THERAPEUTIC MODEL, WE CAN REDUCE
IMMUNOSUPPRESSANT CRY TO FINE,
INCREASE PROINFLAMMATORY
CYTOKINE AND INCREASE THE NUMBER
AND ACTIVATION OF CD 8 POSITIVE
CYTOLYTIC TUMOR CELLS TO IMPROVE
OVERALL TUMOR RESPONSE TO
RADIATION.
WE HAVE ALSO LOOKED AT CD
80-TREATED MICE IN THIS SAME
MODEL.
CD 40, WE'LL INITIATE A CYTOKINE
FORM OF PROINFLAMMATORY
CYTOKINES AND WE SHOWED HERE
THAT IF WE DID CD 40 DAY BEFORE
RERADIATE THE TUMOR THAT WE CAN
INCREASE THE TUMOR GROWTH DELAY
WHEN COMPARED TO RADIATION
ALONE.
TR A AKIOLY HAS DEMONSTRATED
ANTIBIOTICS CAN LIMIT THE CHEMO
THERAPEUTIC EFFECTS OF
OXLOFATTEN A AND SO WE EXAMINED
WHETHER OR NOT ANTIBIOTICS HAD
AN EFFECT IN TUMOR GROWTH DELAY
AND SIMILARLY WE EXAMINED THAT
WHEN WE GAVE MICE ANTIBIOTICS IT
DID REDUCE.
THESE HAVE OPENED DOOR TO NEW
AREA WHERE WE CAN EXAMINE
TARGETING NOS OR, YOU KNOW,
TARGETING POLARIZATION OF THE
IMMUNE SYSTEM TO IMPROVE
THERAPEUTIC RESPONSE TO
RADIATION.
SIMILARLY, CHANG ALSO SHOWED
THAT L MAIN POE TENUATED BETWEEN
THERAPEUTIC EFFECT OF DOSAP A
AXEL IN MICE — DOSAPAXEL IN
MICE AND YOU CAN SEE THE
SURVIVAL OF THESE ANIMALS IS
EXTENDED HERE.
THESE DATA SHOW THAT I NOS
PROMOTED TRIPLE NEGATIVE DISEASE
PROGRESSION, POSTULATES THAT
IT'S MODULATED IN STEM CELLS
METASTATIC POTENTIAL, AND AGAIN,
THEY IDENTIFIED TWO NEW
BIOMARKER PROTEINS THAT WERE
HIGH IN THEIR NEGATIVE BREAST
TUMORS WITH HIGH NOS TWO AND
KNOCK DOWN THESE TEAMS REDUCED
TUMOR GROWTH AND ME IT'S A
SCHISM IN MICE ME IT'S A
SCHIMICE METATISI
SM — WE ARE ALSO
INTERESTED IN LOOKING AT OTHER
NOVEL COMPOUNDS THAT MAYBE CAN
TARGET CANCER STEM CELLS AND
TIPS, AND ONE OF OUR FELLOWS IN
OUR LAB HAS MADE A SERIES OF
ABSENT CONJUGATEED BREAST WHERE
SHE SUBS VE KNOW ON TO ASPIRIN
AND iPANEL WHICH RELEASES A
REDUCED FORM OF NITROOXIDE.
THESE COMPOUNDS REDUCE TENNISTY
OF ACT-RIN.
GIVE THEM TO [INDISCERNIBLE]
ANIMALS, REDUCE TUMOR GROWTH IN
THESE MICE.
INTERESTINGLY, THESE DRUGS CAN
INCREASE OXIDATED STRESS AND DNA
DAMAGE, BUT THEY ALSO CAN TARGET
STEM CELL BIOMARKERS AND THEY
CAN REDUCE ANGIOGENESIS.
ANOTHER COLLEAGUE OF OURS FROM
BRAZIL, THEY ARE MAKING SOME
DRUGS THAT WILL RELEASE HNL AS
WELL.
THESE DRUGS ARE ACTIVATED TO
RELEASE HNO BY FILES.
HERE WE SHOW THAT WHEN WE INDUCE
IF ONE STABILIZATION BY STER-NO.
TREAT CELLS WITH COMPOUNDS WE
CAN SUPPRESS NO-INDUCED
STABILIZATION OF IF TEMP ONE.
WE THINK THAT THESE COMPOUNDS
MAY BE SUITABLE FOR ER-NEGATIVE
PATIENTS THAT HAVE HIGH NOS TWO
BECAUSE THEN GOING BACK TO OUR
TABLE, THESE PATIENTS EXPRESSED
HIGH LEVELS OF GLUTE MAID SYSTEM
LIGATE — GLUTAMATE SYSTEM
LIGATE, AND ALSO IF THESE DRUGS
CAN TEMP AND MAYBE REDUCE
ANGIOGENESIS WE ALSO KNOW IN OUR
COHORTS THAT INCREASED
VASCULARIZATION HAS BEEN
IDENTIFIED IN TU UH MORES THAT
HAVE HIGH NOS TWO.
BAY SUCKLY, IN SHORT, USE
DISINIUM COMPOUNDS MAY BE A
SUITABLE DRUG FOR TREATING
PATIENTS WITH THIS SIGNATURE.
TO END THE TALK, I THINK THESE
DATA HAVE SHOWN THAT WE CAN USE
READ-OUTS INFLAMMATION TO FOLLOW
CANCER PROGRESSION AND TREATMENT
AND BASICALLY THESE STUDIES HAVE
KIND OF STARTED FROM BED-SIDE TO
BENCH AND BACK TO BEDSIDE
BECAUSE CHAN SGSHGS, THEY'RE
GOING TO BEGIN A CLINICAL TRIAL
USING NOS INHIBITORS IN
COMBINATION WITH CHEMOTHERAPY
INCLUDING BOTH PAXIL AND IN
PART, WE THINK THAT IT'S
TARGETING CANCER STEM CELLS AND
IT'S PROMOTING METASTISES OF
CANCER CELLS AND NITRATION AND
INCREASING MNP 9; RATIO MAY BE
IMPORTANT METHOD IN THIS
PROCESS.
A LOT OF PEOPLE HELPED WITH ALL
OF THIS WORK.
STEFAN'S GROUP HERE AT NCI.
CHANG COHORT.
THEY HAVE EXAMINED TONS AND TONS
OF PROTEIN EXPRESSIONS IN THESE
TUMORS THAT WE CAN GO BACK AND
LOOK P MECHANISTICALLY AT
RELATIONSHIP WITH NOS TWO.
WE HAVE ACTIVE COLLABORATIONS
WITH DR. WELLCHILD AND TRANKIAR
DWROSHGS EXAMINE RULES AS IMMUNE
POLARIZATION IN RADIATION
THERAPY.
THANK ERNIE WHO DID ALL OF THE
MASS SPECK I SHOWED YOU BECAUSE
THAT WAS IMPORTANT.
GROUP AT DUKE, SHE HAD THE A
ALZHEIMER'S MODELING THAT WE
USED.
EVERYBODY IN DAVE'S LAB.
WE HAD A LOT OF HIGH SCHOOL KIPS
COME THROUGH THE LAB AND DID A
LOT OF THE WORK I E SHOWED YOU
TODAY.
THANKFUL FOR THEM AND WISH THEM
WELL IN THEIR FUTURES.
THANK YOU AND I'LL TRY TO ANSWER
ANY OF YOUR QUESTIONS.
[APPLAUSE]
>> [LOW AUDIO].
>> WELL, AGAIN, BENNY SHOWED
THAT A LOT OF DMC MARKERS, THOSE
MARKERS ARE UP IN HER MOUSE
MODEL AND I THINK SHE SHOWED
THAT THEY WERE ALSO — I DON'T
KNOW IF SHE SHOWED THEY WERE UP
IN THE PATIENTS BUT I DO KNOW
SHE SHOWED THEY WERE UP IN MOUSE
MODEL AND SHE COULD SUPPRESS
THEM WITH NOS INHIBITORS.
TEMP ONE IS ALSO NT MARKER, SO
THE IF TEMP IS HIGH AND CAN BE
MODIFIED IN PRESENCE OF HIGH NO,
HIGH NOS TWO OR DERIVED NO, THEN
THAT MAY ALSO WITH PROMOTING EMC
AS WELL.
[APPLAUSE]
>> DR. PACHER HAS ARRIVED.
HE GOT HIS MEDICAL DEGREE IN
EUROPE AND CAME TO U.S.
HE'S ONE OF THE WORLD'S EXPERTS
IN PHYSIOLOGY AND HE'S IN THE
LABORATORY OF CARDIOVASCULAR.
HE'S SECTION CHIEF HERE AT NIH.
AT NIH TRIPLE A AT BEN BROOK,
OFF CAMPUS.
INTERPLAY OF OXIDATED STRESS,
INFLAMMATION, LIPID AND CELL
DEATH SIGNALING PATHWAYS DURING
TISSUE — IMPLICATION F F FOR
PHYSIOLOGY AND PATHOLOGY.
PAUL.
>> THANK YOU VERY MUCH.
THANK YOUER VERY MUCH FOR COMING
TO THIS SEMINAR.
[LOW AUDIO].
OKAY.
SORRY.
SO TODAY I WOULD LIKE TO TALK TO
YOU ABOUT OXIDATIVE STRESS OF IN
VITRO SYSTEM HOW IMPORTANT TO
UNDERSTAND HOW OXIDATIVE STRESS
IS LINKED WITH INFLAMMATION
[INDISCERNIBLE] PHOSPHATES.
SO FIRST, THIS IS VARIOUS
[INDISCERNIBLE] SHOULD BE IN THE
CENTER OF MY PRESENTATION AND
DIFFERENT PROJECTS
[INDISCERNIBLE].
DURING ANY KIND OF TISSUE NIR —
INJURY, YOU HAVE [INDISCERNIBLE]
DIFFERENT SOURCES CONTRIBUTE
LIKEMITOCHONDRIA
[INDISCERNIBLE] — OTHERS.
SOME EXAMPLES GENERATED
[INDISCERNIBLE] INTERACT AS WITH
NITRIC OXIDE [INDISCERNIBLE]
INCLUDING [INDISCERNIBLE]
NITROGEN SPECIES AS WELL.
FINALLY, THIS OXYGEN NITROGEN
GENERATION SPECIES
[INDISCERNIBLE] OXIDATED DNA
INJURY WHICH [INDISCERNIBLE] —
MOST ABUNDANT NUCLEAR ENZYME.
[INDISCERNIBLE] DNA CONSUMPTION,
LOOK AT CONSUMPTION AND
[INDISCERNIBLE].
WALKING NEXT EACH OTHER AND
THEREFORE IT IS ALSO IMPORTANT
[INDISCERNIBLE] TRANSCRIPTION
PROCESS LIKE NUCLEAR
[INDISCERNIBLE] INVOLVED IN
INFLAMMATION AND IT CAN ALSO
INTERACT WITH MITOCHONDRIA AS
WELL AS [INDISCERNIBLE] EITHER
GO TO MITOCHONDRIA AND HELP WITH
[INDISCERNIBLE] AND FINALLY,
[INDISCERNIBLE] — ARE REACTION
AND ATTRACTION OF INFLAMMATORY
CELL [INDISCERNIBLE] OXYGEN AND
NITROGEN [INDISCERNIBLE].
SO TODAY I WOULD LIKE TO SHOW US
AN EXAMPLE OF [INDISCERNIBLE]
INJURY AND WE'LL GO TO SOME OF
THIS INTERACTION SO
[INDISCERNIBLE] OXYGEN AND
NITROGEN SPECIES.
SOURCES ON THAT AS WELL
[INDISCERNIBLE] NOT SURE WHAT IS
HAPPENING AND WHY
[INDISCERNIBLE] SO IMPORTANT
[INDISCERNIBLE].
MIE TO CON DRI Y'ALL
INFARCTIONS — MITOCHONDRIAL
INFARCTIONS [INDISCERNIBLE].
FOR EXAMPLE IF YOU HAVE
MITOCHONDRIAL INFARCTION
DECISION INJURY [INDISCERNIBLE].
ACTIVATION INFLAMMATORY
[INDISCERNIBLE] TRACK
INFLAMMATORY PRODUCED BY OXYGEN
AND NITROGEN SPECIES LEADS TO
FURTHER INJURY.
VERY IMPORTANT [INDISCERNIBLE]
THEY DIE FROM MASSIVE TISSUE
INJURY AS WELL AS DAMAGE JUST
[INDISCERNIBLE] HAVE YOU HAVE
NEXT GO HERE WHICH CAN BE DNA
FRAGMENT, CAN BE LIGATIONS, MOST
KNOWN OR EVEN CAN BE OXIDATIVE
STRESS BY PRODUCTIVE LIPID SHOWN
[INDISCERNIBLE].
ALSO USED FOR MARKER SO IN SOUTH
AND MEASURE IT.
THIS HAPPENS THROUGH SECONDARY
COMING FROM REACTION BECAUSE
THIS [INDISCERNIBLE] BIND TO
CERTAIN RECEPTORS INFLAMMATORY
RESPONSE.
IT GOES BACK UP PATHWAY.
ARE RELEASE OF THIS
[INDISCERNIBLE] USUALLY
[INDISCERNIBLE] BY OTHER
[INDISCERNIBLE] WHICH DO NOT
LEAVE SECONDARY INFLAMMATION.
THIS IS AN EXAMPLE OF DAMAGE
[INDISCERNIBLE] WHICH ACT ON
DIFFERENT AREA RECEPTORS LIKE
ONE OF THE MOST KNOWN IS PROTEIN
ONE IT'S ACTIVATED THE SAME AS
[INDISCERNIBLE] CR RECEPTORS
ANTITOXIN BUT ATT CAN ALSO
[INDISCERNIBLE] CYTOKINES ONE
ALPHA AND DNA FRAGMENT CAST
BEFORE US FOR EXAMPLE DURING
[INDISCERNIBLE] RELATED MORE
JOINTS BUT AFTER MUSCLE
CONSUMPTION [INDISCERNIBLE]
JOINTS WAS VERY BAD
INFLAMMATION.
FOR EXAMPLE, THIS CAN ALSO
TRIGGER ACTIVATION INFLAMMATORY
CELLS.
GOING BACK TO ANOTHER, I WOULD
LIKE TO TALK E ABOUT IMAGE TODAY
AND JUST OUTLINE THE
[INDISCERNIBLE] PROCESSES
INTERACT.
[INDISCERNIBLE].
WHAT'S HAPPENS FOR ONE HOUR
CELLS [INDISCERNIBLE] — THIS
PROCESS THERE'S MITOCHONDRIAL
FUNCTION AND DYSFUNCTION AND
HEPATOCYTE [INDISCERNIBLE].
IT STARTS TO RELIEVE VARIOUS
[INDISCERNIBLE] SHOWS VARIOUS
[INDISCERNIBLE] THEY ACTIVATE
THE CELLS MODIFIED MICROPHAGES
THAT SIT [INDISCERNIBLE] LEVER
OR NORMAL AND ONCE NORMAL CELLS
ACTIVATED, THEY CAN
[INDISCERNIBLE] OXIDATIVE WHICH
SHOW TO PRODUCE HYDROGEN
PEROXIDE AS WELL AS NITRIC OXIDE
AS WELL AS [INDISCERNIBLE]
REACTION TO [INDISCERNIBLE].
ATTRACT NEUTROPHIL TO THE SITE
OF THE INJURY.
FIRST TWO HOURS, THERE ARE NO
NEW TRI — NEUTROPHILS YET.
BUT THERE IS ACTIVATION OF CELL.
ATTRACTION IN THIS EDITION
OCCURS AFTER SIX HOURS AND PICKS
UP 24 HOURS.
YOU SEE VERY NICE DEMARCATION I
UH WILL SHOW YOU AND ALSO
IMPORTANT BECAUSE YOU SEE
INFLAMMATION WAS UP UH BUT IT
WAS BOUND LIKE HE E — HE
HEPATOCYTE.
[INDISCERNIBLE].
AT THE BEGINNING YOU HAVE
[INDISCERNIBLE] LATER YOU HAVE
MOST DIFFERENT FAST LIKE MICRO
STAGES COMING LIKE TISSUE
REPAIR.
[INDISCERNIBLE] THIS IS EXPOSED
TO ONE HOUR SKIN AND TWOER OR
TWO HOUR AND SIX AND 4-HOUR
RETROFUSION — 24-HOUR
RETROFUSION.
[INDISCERNIBLE] MACROPHAGES ARE
RELEASED ALSO CLINICALLY AND
LIVER DISEASES SO YOU SEE BOTH
[INDISCERNIBLE] PEAK SIX HOURS
AND THEN 24 HOURS.
THIS IS WHERE IT WAS BOUND
BECAUSE [INDISCERNIBLE] MADE
PROBLEM AROUND [INDISCERNIBLE].
WHERE ALSO THIS IS NUCLEAR
ENZYME [INDISCERNIBLE] WHICH I
SHOWED YOU ON THAT FIRST SLIDE
OXIDATIVE DNA INJURY, THIS IS
INCREASE [INDISCERNIBLE] DNA
FRAGMENTATION, MARKER OF UPWARD
[INDISCERNIBLE], YOU SEE TWO
HOURS YOU DON'T SAY UPWARD TWO
[INDISCERNIBLE] AND YOU'VE GOT
TO REALLY MORE SIGNIFICANT 24
HOURS.
[INDISCERNIBLE] IT'S SHIFTED.
YOU SEE MICROSCOPE, FIVE THIS IS
A NORMAL [INDISCERNIBLE]
MITOCHONDRIAL, AND TWO HOURS
AFTER [INDISCERNIBLE] IS THIS
ONE MIE TOE CON DRI ARE Y'ALL
DECREASED STRUCTURE, AND YOU
ALSO SEE AT TWO HOURS DECREASE
OF MITOCHONDRIAL COMPLEX ONE
ACTIVITY AND YOU ALSO SEE
INCREASE OF [INDISCERNIBLE]
OXIDATION SO THIS FAMILY SHOWN
HERE EACH IS A MARKER OF
[INDISCERNIBLE] EDITION BUT THIS
IS MORE STABLE MORE RELIABLE
MARKER WHICH CAN BE EFFECTIVE
[INDISCERNIBLE].
RELIABLE.
ALSO INCREASE IN CARBON
[INDISCERNIBLE] AT TWO HOURS
FROM MITOCHONDRIA AND ALSO
[INDISCERNIBLE] WHICH IS A
MARKER OF NITRATION IN THERE
ALSO IN PART [INDISCERNIBLE]
GENERATION.
SO THIS MARKER GO UP AND YOU SEE
MITOCHONDRIA DYSFUNCTION, BUT
THEREFORE ACTUALLY BY SIX, 24
HOURS MITOCHONDRIA DYSFUNCTION
24 HOURS AND IF YOU SEE LIPID
OXIDATION THEY START TO GO UP
VERY SIGNIFICANTLY AND THEREFORE
GP 91 [INDISCERNIBLE] THIS IS
ISOFORM, THIS IS NEXT TWO
[INDISCERNIBLE] YOU FEEL TWO
HOURS ACTIVE [INDISCERNIBLE]
MITOCHONDRIA PART AND THEN LIPID
GO UP.
WHY SO IMPORTANT TO SEPARATE
FROM IN VIVO EXPERIMENTS FROM IN
VIVO?
BECAUSE FOR EXAMPLE IF YOU TAKE
TISSUE AND MOST OF THE PREVIOUS
STUDIES FROM WHICH DRUG
DEVELOPMENT AND PRACTICAL FIELD
THIS FUSION ISOACTIVITY SHOE
PREPARATION, ISOHEART, THIS
SUBJECT HIGH [INDISCERNIBLE]
JUST TOOK NITROGEN SOLUTION AND
PROFUSED AND THEREFORE USED HIGH
OXYGEN CONTENT WITH SOLUTION
WHICH [INDISCERNIBLE] OXYGEN AND
PART OF CO 2.
THEN THEY INDUCED FOR AND BUT
THEN THERE'S MORE
[INDISCERNIBLE] OXYGEN/NITROGEN
SPECIES HAPPENED RIGHT AFTER THE
INTRODUCTION OF THIS OXYGEN
SOLUTION AND IT LASTED FOR
VARIABLE IF FOR SECONDS, BRIEF
PERIOD.
AS YOU SEE HERE IN VIVO, THE
SITUATION WAS TOTALLY DIFFERENT
AND THEY INDUCED [INDISCERNIBLE]
INFINITELY AND THOSE ARE ARE
EXTREMELY IMPORTANT IN INJURY OR
IN REPAIR.
ONE MORE REVEES STEM CELL HYPE S
SO YOU SEE MARKED INCREASE AS
BEEN IN THE EXPRESSION 24 HOURS
[INDISCERNIBLE] SO THIS IS HIGH
MODIFICATION YOU SEE IN
HEPATOCYTES AND YOU SEE
INFLAMMATORY CELLS AND THEY ARE
ATTACHED TO [INDISCERNIBLE].
AND THIS H IS MARKER FOR
[INDISCERNIBLE] FOR DNA INJURY,
DG.
YOU SEE HERE THIS IS HIGH
MODIFICATION MARK IN THE CUP
SPINNING IN NUCLEAR
[INDISCERNIBLE] NO INJURY
MARKERS SO THIS DNA DEP DEP E
HEPATOCYTES.
GO BACK TO TIME COURSE OF TWO
HOURS WHERE NITRO GOING UP BUT
THIS IS COMING TO
OXYGEN/NITROGEN SPECIES IN
MITOCHONDRIA, YOU SEE
[INDISCERNIBLE] LARGER, THIS IS
MORE MODIFICATION SO YOU SEE
PART OF MODIFICATION YOU SEE
THIS IS HEPATOCYTE, THIS IS
[INDISCERNIBL
[INDISCERNIBLE] — THEN INJURED
MY WORKING TO TISSUES.
HERE YOU CAN DAMAGED
[INDISCERNIBLE] IN BLACK.
DAMAGE IN TISSUE TO HELP US
DECIDE INJURY.
INFLAMMATION AND AGAIN THIS IS
VERY IMPORTANT TO DISTINGUISH
COLOR INFORMATION AND
INFLAMMATORY REACTION WHICH WE
CAN MEASURE CYTOKINES OR
[INDISCERNIBLE].
FOR EXAMPLE YOU HAVE
INFLAMMATION YOU CAN HAVE JUST
MICROOXIDATION AND INCREASE IN
[INDISCERNIBLE] INFLAMMATORY
MARKERS.
YOU BUY SINGLE HUMAN CELLS.
DIFFERENT CELL NEEDS TO PASS BAD
BRAIN BARRIER.
IN THIS CASE, YOU SEE THAT
THERE'S LOVELY INCREASE OF
[INDISCERNIBLE], TWO HOURS.
THIS IS COMING MOSTLY FROM
ACTIVATED [INDISCERNIBLE]
MICROSTAGES AND VERY IMPORTANT
WORK, BUT LATER, IT HAS BEEN
GOING BACK AND [INDISCERNIBLE]
ALPHA AND THIS IS APPLICATION
EXPRERGS PRESSED IN TISSUE.
— EXPRESSED IN TISSUE.
[INDISCERNIBLE] AGAIN, TWO
HOURS, THEN THREE, INFLAMMATORY
[INDISCERNIBLE]; SIX HOURS
[INDISCERNIBLE], AND THEN 24
HOURS YOU HAVE HUGE NUMBER, BUT
THIS PART ON NEUTROPHIL
[INDISCERNIBLE].
SUMMARIZING AS TO WHAT HAPPENS
DURING THIS PROCESS
[INDISCERNIBLE].
SO YOU HAVE INJURY WHICH IS FOR
EXAMPLE [INDISCERNIBLE] LIVER
SURGERY OR LIVER TRANSPLANTATION
AND THEN PUT BACK THIS LIVER
[INDISCERNIBLE].
OXYGEN TO THE BLOOD WAS COMING
AND YOU HAVE TISSUE INJURY AND
WHERE THIS DAMAGE
[INDISCERNIBLE] — ACTIVATED
SICKLE CELLS EXPRESSED
[INDISCERNIBLE] — NITROGEN —
N
NEUTROPHIL — AND FINALLY
[INDISCERNIBLE].
ATTACHED TO DAMAGED
[INDISCERNIBLE] AND THEN
[INDISCERNIBLE] TISSUE OCTOBER

— LATER SECONDARY REACTION AND
MIE TO CON DRI Y'ALL REACTION
TOCHONDRIAL
REACTION —
MITOCHONDRIAL [INDISCERNIBLE].
WHAT'S HATCHED IF UH YOU STOP TO
PAUSE [INDISCERNIBLE] WHERE FOR
EXAMPLE [INDISCERNIBLE] NEXT TO
THIS OR [INDISCERNIBLE]
MITOCHONDRIA — I'VE CHANGED
COUPLE AND UPDATED BUT I CAN
SEND YOU ALL THIS PRESENTATION
OR SEND YOU MOST OF THE SLIDES
FROM THE PRESENTATION BUT THERE
ARE A COUPLE NUANCE AND THERE IS
A STAFF ORGANIZATION.
SOME OF THE FIRST
[INDISCERNIBLE] HAPPENS OXYGEN
DOWN WHICH ARE POSSIBLE TO
TARGET TO MITOCHONDRIAL AND
ACTUALLY NOW THIS IS VERY
SPECIAL [INDISCERNIBLE] TO WHERE
YOU BASICALLY ALMOST
[INDISCERNIBLE] EVERYTHING IN
[INDISCERNIBLE] ORGANIZED.
FOR EXAMPLE [INDISCERNIBLE] —
FOR EXAMPLE USE COUPLE COMPOUNDS
AND TRY TO DETERMINE WHAT IS
[INDISCERNIBLE] THIS PROCESS AND
BASICALLY IF YOU DID MIE TO CON
DRI ARE YEAH TARGET AROUND THIS
CORE — MITOCHONDRIA TARGET
AROUND THIS CORE, THEY ARE VERY
PROTECTIVE AND THEY CAN STOP
ALMOST ALL THIS PROCESS BECAUSE
THEY CAN STOP THE INITIAL HE
HEPATOCYTE; HOWEVER, IF YOU
START TO LEAD THEM UP TO SIGS
THEY EXTREMELY LOSE
EFFECTIVENESS.
THEY ARE NOT VERY USEFUL BECAUSE
USUALLY WHEN YOU HAVE
[INDISCERNIBLE] MITOCHONDRIAL
INFARCTION WILL STOP FOR CERTAIN
PERIOD OF TIME SO YOU CANNOT
[INDISCERNIBLE] THIS PATIENT.
THIS IS VERY IMPORTANT BECAUSE
MITOCHONDRIA ARE IMPORTANT
[INDISCERNIBLE] INFLAMMATION AND
TISSUE INJURIES [INDISCERNIBLE]
BY INFLAMMATORY CELLS.
THAT IS WORST THAN OTHERS
[INDISCERNIBLE] DISTINCTION
BETWEEN EXTINCTION AND
[INDISCERNIBLE] — MOBILE SPIKE
LONG-TIME PREPARATION OF THE
HEART IN CLINICAL TRIALS BECAUSE
THEY HAVE NO EFFECT IN THE
SECONDARY PHASE.
COUPLE OTHER EXAMPLES.
WHAT HAPPENS IF YOU
[INDISCERNIBLE] INDUCE
[INDISCERNIBLE] YOU ACTUALLY
INDUCE RESTRICTION AND
[INDISCERNIBLE] AND MORE INJURY.
INDUCE
INDUCE LIPCYTE [INDISCERNIBLE].
SIMILAR TO MITOCHONDRIA, IT IS
BECAUSE THEY ARE MOSTLY
EFFECTIVE IN STAGES.
[INDISCERNIBLE] — INJURIES
BECAUSE ACTIVE OXYGEN PUSHES SUB
SUBDIVISION [INDISCERNIBLE].
PROBLEM IS PRODUCTION OF LIPID
BENEFITS THAN [INDISCERNIBLE] —
INFLAMMATORY PROCESS BY
THEMSELVES [INDISCERNIBLE] LIPID
ARE AVAILABLE.
AN EXAMPLE OF ACTIVITY, THERE
ARE LOTS OF DIFFERENT
[INDISCERNIBLE] THAT SOME PEOPLE
FIND THEM.
NITROGEN SPECIES, OXI NITRATES
[INDISCERNIBLE] MORE PROTECTIVE
THAN [INDISCERNIBLE] PERFUSION
INJURY, BUT EASILY OTHER
PROBLEMS THAT THEY ARE
[INDISCERNIBLE] VERY DIFFICULT
TO SEFRP THESE THIS COMPOUND —
SYMPATHIZE THIS COMPOUND
[INDISCERNIBLE] USUALLY BLACK OR
GREEN [INDISCERNIBLE] SOME IN
CLINICAL DEVELOPMENT.
VERY DIFFERENT DRUGS AND
PRECISION INJURY, AGAIN, THE
SOONER YOU GIVE, MORE EFFECTIVE
THEY ARE.
I'M SURE YOU HAVE HEARD ABOUT
OXYGEN DURING THE COURSE OF THIS
PRESENTATIONS EARLIER AND OXYGEN
[INDISCERNIBLE] VERY IMPORTANT
ROLE IN ACTIVE OXYGEN NITROGEN
SPECIES AND THE REASON WHY I'M
ALSO MENTIONING BECAUSE WHEN E
TALK ABOUT [INDISCERNIBLE] VERY
STRONG INTERACTIONS WITH TYPE
OXYGEN LIKE THE.
OXYGEN LIKE THIS IS PERFECTED
BUT HERE AGAIN THINK ABOUT
GENERATION WITH WHAT'S COST
AROUND HIM [INDISCERNIBLE] — IS
VERY BAD IN THIS BUT TOSSED
AROUND IN HERE TOO FOR EXAMPLE
WE WERE A GENERATION AND
[INDISCERNIBLE], SO
[INDISCERNIBLE] ACCORDING TO
THIS IT CAN ADVISORY AFFECT THE
WHOLE SYSTEM.
NOW WE TALK ABOUT
[INDISCERNIBLE] SIGNALING AND
THE REST OF HOW INTERACT WITH
OXIDATIVE STRESS AND
[INDISCERNIBLE] LIPID
[INDISCERNIBLE].
INTRODUCTION I'M SURE YOU
ALREADY KNOW OR HEARD ABOUT MARK
WARNER WHICH HAS [INDISCERNIBLE]
BUT ALSO [INDISCERNIBLE].
[INDISCERNIBLE] AFFECT MOSTLY
THIS COMPOUND THC AS POSSIBLE.
THIS HAS TWO RECEPTORS; ONE CD 1
MADE IN THE BRAIN SO IT INDUCES
[INDISCERNIBLE] EFFECT BUT ALSO
INCREASES [INDISCERNIBLE].
THIS WAS LEFT FOR THE
DEVELOPMENT OF [INDISCERNIBLE].
WHICH MARKUP HAS BEEN LARGE
NUMBER OF COUNTRIES EUROPE MORE
THAN 40 COUNTRIES, BUT THEY
INTRODUCE [INDISCERNIBLE] BUT
THEY RAN IT BACK THROUGH ENTIRE
[INDISCERNIBLE] COMPLICATION AND
WERE EFFECTIVE IN
[INDISCERNIBLE].
CD 1 RECEPTOR WAS MOST ABUNDANT
GENE COUPLE RECEPTOR IN THE
BRAIN SO IT IS IN EVERY SINGLE
SYNOPSIS.
[INDISCERNIBLE] IS THIS
CONDITION HAVE THIS EFFECT.
OTHER COMPOUND [INDISCERNIBLE]
WAS THOUGHT FOR MANY YEARS THAT
IT IS COMPLETELY AS
[INDISCERNIBLE] EFFECT.
[INDISCERNIBLE].
MIXTURE OF COMPOUND
[INDISCERNIBLE] HAS PROVED IN
MANY COUNTRIES CERTAIN
CONDITIONS AND CERTAIN
BENEFICIAL EFFECTS.
MORE INTEREST IN THIS
[INDISCERNIBLE] NEITHER CD 1,
NOO
DMOOETER IN — NEITHER IN THE
OTHER ONE WHICH IS
ANTI-INFLAMMATORY.
NEITHER SHOWN BENEFICIAL EFFECTS
OF INFLAMMATION AND USUALLY
[INDISCERNIBLE] THIS IS ALSO
VERY POWERFUL ANTI-INFLAMMATORY
[INDISCERNIBLE] MIGRATION
[INDISCERNIBLE] VERY PROTECTIVE
IN PROFUSION INJURY AND RECENTLY
IT IS APPROVED BY FDA IN
CHILDREN WITH EPILEPSY AND ALSO
FOR SVRL SEVERAL INDICATIONS.
[INDISCERNIBLE] MIXTURE OF
[INDISCERNIBLE] WITH THC.
AGAIN THE MOST INTERESTING
THOUGHT HERE IS NOT THAT YOU
HAVE LIGAND BUT YOU HAVE ANTIGEN
IN THE SYSTEM [INDISCERNIBLE]
VERY THE TISSUE YOU HAVE
[INDISCERNIBLE] DEGREE OF CB 1
AND CB 2 RECEPTORS AND THIS PLAY
IMPORTANT WORK AND THIS ALSO
VERY IMPORTANT [INDISCERNIBLE]
ACTIVE OXYGEN SPECIES GENERATION
AND REST OF [INDISCERNIBLE]
OXYGENS.
SO [INDISCERNIBLE] AND ALSO
SECOND IS [INDISCERNIBLE].
CD 1 AND CD 2 RECEPTORS.
MORE ALIVE THAN SUPPOSED TO BE
TWO RECEPTORS AND ALSO MORE
IMPORTANTLY [INDISCERNIBLE]
PROXIMITY [INDISCERNIBLE] ARE
HIGHER SO CAN BE VERY
SIGNIFICANT SOURCE OF
[INDISCERNIBLE].
[INDISCERNIBLE] EXHIBIT BY FDH
AND TWO AG BY MAGL
[INDISCERNIBLE].
SO I WILL TALK BRIEFLY ABOUT
THESE TWO [INDISCERNIBLE].
BASICALLY NOW THEY ARE TWOS, TWO
[INDISCERNIBLE] ENZYME
[INDISCERNIBLE] 2 AG 11.
I WANT TO TALK PRIMARILY ABOUT
THIS ONE BECAUSE THIS IS
[INDISCERNIBLE] TIE IN TISSUES
CAN BE SIGNIFICANT SOURCE OF
[INDISCERNIBLE].
CD 1 RECEPTORS IN
[INDISCERNIBLE] CARDIOVASCULAR
EFFECT OF [INDISCERNIBLE]
MYOCARDIAL INFARCTIONS
[INDISCERNIBLE] YOU KNOW WHY I
CALL IT THE SPLICE AND K 2 ARE
DIFFERENT NAMES FOR
[INDISCERNIBLE] USUALLY MIXTURE
OF FIVE, SIX [INDISCERNIBLE] BUT
THEY ARE ABOUT ROUGHLY ON THE
BLACK MARKET AND FOR AS YOU CAN
BUY [INDISCERNIBLE] AND USE
POUND TAKING [INDISCERNIBLE]
VERY PROFOUND [INDISCERNIBLE].
ALSO STUDY INFLAMMATORY CELLS CD
1 RECEPTOR MICROPHAGES FOR
EXAMPLE CANNOT [INDISCERNIBLE]
DIABETES AND DIFFERENT OTHER
COMPLICATION.
SO OTHER RECEPTOR IS CB 2
RECEPTOR WHICH HAS NO
DETRIMENTAL EFFECT IN CELL AND
USUALLY CB 2 RECEPTOR ACTIVATION
LEADS TO DECREASE OF
[INDISCERNIBLE] SINGLE CELL,
LOCATION AND MIGRATION DECREASE
[INDISCERNIBLE] BENEFICIAL
[INDISCERNIBLE] INJURY
[INDISCERNIBLE] INJURY.
NOW GOING BACK TO THIS
[INDISCERNIBLE] TALK LITTLE BIT
WHAT IS THE ROLE OF HOW
[INDISCERNIBLE] ALSO INTERACTS
WITH [INDISCERNIBLE] BENEFITS OF
CD 9 AND CORPS TWO.
[INDISCERNIBLE] — DURING THE
[INDISCERNIBLE] BY DURING THE
HEPATOCYTES FIRST OF ALL AND
[INDISCERNIBLE] ITSELF.
[INDISCERNIBLE] INJURY, FROM
THIS ONE CONFUSION CAN BE
ANTIGEN GENERATED BUT TO PUT
TISSUES ALL [INDISCERNIBLE]
RECEPTORS FROM FURTHER INJURY OR
[INDISCERNIBLE] INJURY.
ALSO THIS QUESTION, VARIOUS MICE
AS I MENTIONED ONE JUST GOING
BACK SO ONE [INDISCERNIBLE] MAGL
[INDISCERNIBLE].
SO [INDISCERNIBLE] RECEPTORS IN
[INDISCERNIBLE] CELLS FOR WHICH
I DESCRIBE MICROPHAGES AND HE
PA
— HEPATOCYTES [INDISCERNIBLE].
THIS KIND OF PRECISION MAKES
[INDISCERNIBLE] LARGELY
DECREASED BY IT [INDISCERNIBLE].
YOU ALSO INCREASE AT THREE HOURS
[INDISCERNIBLE] MARKERS AS I
MENTIONED OXIDATE, THEN LOOKS
TWO AND GOES UP [INDISCERNIBLE]
24 HOURS DECREASE.
ALSO I DON'T WANT TO GO IN THIS
[INDISCERNIBLE] IMPORTANT
CONCLUSION OF THESE DIFFERENT
[INDISCERNIBLE] CB TWO
RECEPTORS.
CONCLUSION WAS RECEPTOR WAS FOR
[INDISCERNIBLE] RECEPTORS
[INDISCERNIBLE].
YOU SEE THAT EXAMPLE
[INDISCERNIBLE] FUSIONS
[INDISCERNIBLE] WHICH IS
DECREASED BY [INDISCERNIBLE]
BECAUSE LEVER IT IS VERY
IMPORTANT [INDISCERNIBLE]
PROCESS.
TWO AG GOES TO [INDISCERNIBLE]
AGAINST INFLAMMATION BUT YOU
ALSO GET [INDISCERNIBLE] —
[INDISCERNIBLE] WHICH IS A
[INDISCERNIBLE] PROFUSION.
[INDISCERNIBL
[INDISCERNIBLE] DOING THE
[INDISCERNIBLE] DECREASE.
AGAIN [INDISCERNIBLE] LIVER
INJURY OR THIS IS INDUCED BY
ANTITOXIN [INDISCERNIBLE]
INFLAMMATION [INDISCERNIBLE]
DECREASE OF THE INJURY, LIVER
ENZYME [INDISCERNIBLE].
THIS H IS ANOTHER
[INDISCERNIBLE].
HERE COMES TO WHETHER YOU HAVE
ENOUGH LIVER INJURY OR INDUCE
[INDISCERNIBLE] MARKING
HEPATOCYTE AND YOU HAVE
[INDISCERNIBLE] YOU ALSO HAVE
[INDISCERNIBLE] POSITION
[INDISCERNIBLE], YOU ALSO LOOK
AT [INDISCERNIBLE] HAVELESS
HAVE LESS [INDISCERNIBLE] TAG
CAN CREATE ACTIVATION OF
[INDISCERNIBLE] CELLS AND
[INDISCERNIBLE] AND ATTACH TO —
[INDISCERNIBLE].
AS I MENTIONED YOU, THIS IS
UPDATE OF ANOTHER.
FOR EXAMPLE, [INDISCERNIBLE] ET
2 IS PROTECTIVE [INDISCERNIBLE]
GENERATION SO TAKING FOR EXAMPLE
COX TWO [INDISCERNIBLE] FOR
WHICH YOU CAN BUY OVER THE
COUNTER AND USE FOR
[INDISCERNIBLE] IS NO GOOD
BECAUSE THIS IS [INDISCERNIBLE]
GENERATION.
COX TWO WOULD BE SHOWN TO ANY
KIDNEY FUNCTION.
FOR EXAMPLE, BECAUSE
[INDISCERNIBLE] COX
[INDISCERNIBLE] KEEP INJURY AND
[INDISCERNIBLE] MAINTAINED BY
NITRIC OXIDE BUT IF YOU HAVE
KIDNEY [INDISCERNIBLE] NITRIC
OXIDE SUSTAINS IN PART
[INDISCERNIBLE].
SO IF YOU TAKE ALL OF TOXIN HIB
TORS [INDISCERNIBLE] —
INHIBITORS [INDISCERNIBLE] — TO
KEEP NORMAL PERSON.
IT IS KNOWN ONE OF FIVE EFFECT
OF THIS [INDISCERNIBLE]
INFLAMMATORY DRUG INDUCED
[INDISCERNIBLE] AGAIN GOING BACK
TO HEARTS AND [INDISCERNIBLE],
THE REASON WHY I MENTION BECAUSE
NOW INHIBITORS OF OTHER ENZYME
[INDISCERNIBLE] WHICH I MENTION
THIS WAS VERY [INDISCERNIBLE]
AND FOR CERTAIN [INDISCERNIBLE]
BECAUSE IF YOU GIVE
[INDISCERNIBLE] GET IT.
BUT BY THIS [INDISCERNIBLE]
WHICH WOULD [INDISCERNIBLE] HAVE
MUCH E EFFECT AND MAYBE YOU CAN
ADD DEN — BENEFICIAL
[INDISCERNIBLE] — ARE
PERFECTED.
IT HAPPENS WITH THIS CLINICAL
TRIAL THAT LAST YEAR BY FRENCH
COMPANY [INDISCERNIBLE] SO
[INDISCERNIBLE] SOME OF THEM HAD
DIVISIONS, INFLAMMATION, EVEN
[INDISCERNIBLE] DIET AND THEN
THEY BACK TO TRY TO MAKE
[INDISCERNIBLE] INFLAMMATION BY
LOOKS OF DIFFERENT
[INDISCERNIBLE] AND SO GOING
ENDOCRINE IN THE HEART
[INDISCERNIBLE] INFLAMMATORY
EFFECT, [INDISCERNIBLE] ANTI
ANTI-INFLAMMATORY
[INDISCERNIBLE] — EXPRESSED IN
CELL.
IF YOU HAVE MYOCARDIAL
INFARCTION [INDISCERNIBLE] FROM
INCREASED DEFINITION BUT IF YOU
[INDISCERNIBLE] ANYTHING
BENEFICIAL.
[INDISCERNIBLE] IS BAD
[INDISCERNIBLE] IN ADDITION TO
THAT AS I MENTIONED, CAN EXERT
METHOD ACTS AND FOLLOWING
[INDISCERNIBLE] MUSCLE SPASM
TURN INTO MYOCARDIAL INFARCTION.
VERY COMPLICATED AND THIS IS
[INDISCERNIBLE].
[INDISCERNIBLE] KNOCKOUT MICE
[INDISCERNIBLE] SIGNIFICANTLY
HIGHER SO DIFFERENT TISSUES
[INDISCERNIBLE] SEVERAL IN THE
HEART [INDISCERNIBLE].
INITIALLY [INDISCERNIBLE] EXPECT
IT WOULD BE [INDISCERNIBLE].
USE [INDISCERNIBLE] DRUG AND
WHAT WE FOUND IN THIS KNOCKOUT
MICE [INDISCERNIBLE] INCREASE,
[INDISCERNIBLE] TO THE BLOOD,
AND [INDISCERNIBLE] RICH LIPID
OXIDATION [INDISCERNIBLE]
MYOCARDIAL AND SURPRISINGLY IN
THE [INDISCERNIBLE] NOT
ASSOCIATE WITH INFLAMMATION
[INDISCERNIBLE] INFILTRATION.
AGAIN, THIS IS LAST THING THAT
WHEN YOU TARGET SOMETHING YOU
HAVE TO TRY TO THINK ABOUT THE
[INDISCERNIBLE] YOU TARGET
SOMETHING IN THE BRAIN YOU HAVE
TO THINK ABOUT HEART AND OTHER
ORGANS.
FOR EXAMPLE, LIKE LESSONS
LEARNED FROM THIS CLINICAL
TRIALS [INDISCERNIBLE].
FOR EXAMPLE, CELEBREX WHICH WAS
THE MOST WIDELY-USED
[INDISCERNIBLE] STARTED TO COME
CAUSING BLOCKS AND LATER
[INDISCERNIBLE] EVERYTHING YOU
CAN BUY OVERCOUNTER
[INDISCERNIBLE] PATIENT WITH
HEART [INDISCERNIBLE] — AT RISK
FOR MYOCARDIAL INFARCTION IN
FAMILY.
SUMMARIZING [INDISCERNIBLE] THAT
OXIDATIVE STRESS INDUCES
SYMPTOMS OF [INDISCERNIBLE]
WHICH IS LIPIDS SIFTER WHICH CAN
PROFOUNDLY AFFECT INFLAMMATION
TO [INDISCERNIBLE] RECEPTORS
WHICH IS [INDISCERNIBLE] AND
USUALLY [INDISCERNIBLE] IT CAN
ALSO LEAD TO BLIND AND
[INDISCERNIBL
[INDISCERNIBLE] MARKEDLY
INCREASED [INDISCERNIBLE] TISSUE
AND IMPORTANT CONTACT DEPENDENT
E EFFECT.
FINALLY, I WOULD LIKE TO JUST
SHOW US AN EXAMPLE BRIEFLY THAT
[INDISCERNIBLE] STRESS CAN BE
BENEFICIAL AND ACTUALLY MIMIC
COMPACT [INDISCERNIBLE] WHICH IS
JUST AN EFFECT REACTION TO AN
INJURY AND [INDISCERNIBLE]
EMOTION WITH COX TWO
[INDISCERNIBLE] SO IF YOU HAVE
INJURY YOU CAN'T TELL
[INDISCERNIBLE] BUT
[INDISCERNIBLE] CONDITION
[INDISCERNIBLE].
SO THIS IS RELATIVELY SIMPLE
[INDISCERNIBLE] — JUST
[INDISCERNIBLE] YOU SEE
[INDISCERNIBLE] GENERATING BY IN
THE MOUSE THREE.
[INDISCERNIBLE] THERE IS MARKED
INCREASE GENERATION AND IF THE
INJURY [INDISCERNIBLE]
GENERATION [INDISCERNIBLE].
THIS IS JUST AN EXAMPLE THINGS
DIFFERENT [INDISCERNIBLE], AND
YOU SEE HERE [INDISCERNIBLE] —
SO THIS IS THE THING ACTUALLY
[INDISCERNIBLE] NORMALIZE
EVERYTHING LIKE BLOOD PRESSURE
AND HIGH BLOOD GLUCOSE COMPOUND.
THIS PATIENT STARTED TO DIE.
WE LOOK AT CONFUSION WAS THAT
PHOSPHATE NORMALLIZATION
[INDISCERNIBLE] IS NEVER GOOD.
[INDISCERNIBLE] AND YOU MAY
INTERFERE WITH THIS TWO AND
INDUCE MORE DAMAGE THAN BENEFIT.
FINALLY, IS JUST IT IS VERY
IMPORTANT TO US TO THINK ABOUT
THAT COMPLEX.
SO YOU MAY HAVE [INDISCERNIBLE]
TRY TO WHAT'S HAPPENED
[INDISCERNIBLE] OTHER SYSTEMS
AND THIS IS VERY IMPORTANT
BECAUSE LIKE MOST OF THE DRUGS
ACTUALLY MEASURE [INDISCERNIBLE]
BECAUSE IT TURNS OUT THAT THEY
HAVE TO FIGHT EFFECT IN OTHER
SYSTEMS [INDISCERNIBLE] LIKE
CARDIOVASCULAR.
[INDISCERNIBLE] FINALLY I WOULD
LIKE TO THANK YOU FOR LISTENING
AND COMING TO THIS PRESENTATION
AND OUR SCIENTIFIC DIRECTOR, MY
MENTOR [INDISCERNIBLE]
CONTRIBUTED TO SOME OF THIS.
THANK YOU VERY MUCH.
[APPLAUSE]
>> ANY QUESTIONS?
>> TERMINAL CANCER PATIENT [LOW
AUDIO].
>> [INDISCERNIBLE] BENEFITS OF
[INDISCERNIBLE] — THERE WERE
SOME STUDIES [INDISCERNIBLE] AND
IN THE FIRST STUDIES
[INDISCERNIBLE] WHICH IS ONE OF
THE [INDISCERNIBLE] IN BRAIN
TUMORS WHICH IS VERY MALIGNANT
AND ALMOST IMPOSSIBLE TO CURE
AND THE PROBLEM IS
[INDISCERNIBLE] BE SURE THEY
INJECT THOSE [INDISCERNIBLE] IN
THESE TUMORS AND THEY SHRUNK BUT
THIS WAS MANY, MANY YEARS AGO
[INDISCERNIBLE].
FOR EXAMPLE TUMOR WHICH IS BAY
SUCKLY NOTHING BUT IN CASE OF
[INDISCERNIBLE] WHICH I
MENTIONED [INDISCERNIBLE] WHICH
HAS NO EFFECT ON [INDISCERNIBLE]
RECEPTORS.
BUT IN THAT CASE [INDISCERNIBLE]
STUDIES THEY ARE SHORING
[INDISCERNIBLE] BUT THIS IS
OBVIOUSLY MORE PROMISING AND
THIS WAS [INDISCERNIBLE] — IN
CERTAIN PATIENTS WHO
[INDISCERNIBLE] AND DISEASE AND
Ph.D. VERY LOW [INDISCERNIBLE]
LEVELS INDUCED TO
[INDISCERNIBLE].
IF THEY ARE RESPONDING TO THIS
[INDISCERNIBLE] RESPONDING
[INDISCERNIBLE] — AGAIN, IT'S
COMPETITION EVEN IN CANCER
PATIENTS WHO [INDISCERNIBLE]
THEY ARE REACTING
[INDISCERNIBLE] BUT I MEAN I
THINK MOST STUDIES GOES ON AND
MAJOR PROGRAM [INDISCERNIBLE]
THAT YOU CAN BUY MOST ANYTHING
BUT YOU HAVE NO IDEA WHAT EFFECT
[INDISCERNIBLE] AND THIS MAKES
DIFFERENCE BECAUSE NOW CHECK THE
TRAM LIKE [INDISCERNIBLE] AND
ALSO THE OTHER THING THAT — AND
AGAIN I'M JUST [INDISCERNIBLE]
MOUSE THAT CAUSES
[INDISCERNIBLE] IMPOSSIBLE TO DO
CLINICAL TRIALS BECAUSE
EVERYBODY THAT GOES THROUGH
[INDISCERNIBLE] YOU CAN BUY
[INDISCERNIBLE] YOU HAVE NO IDEA
WHAT IS THERE.
THERE ARE FIVE HUNDRED
[INDISCERNIBLE] WAS BECAUSE OF
THE DISEASE [INDISCERNIBLE]
THERE WAS JUST Ph.D. ON THE
[INDISCERNIBLE] BECAUSE OF THE
HIVE BUT THERE WAS NO REAL
IMPROVEMENT.
[INDISCERNIBLE] TEMPERATURE YOU
WILL GET THE [INDISCERNIBLE] BUT
LOOK AT DIFFERENT
[INDISCERNIBLE] BUT YOU CAN GET
[INDISCERNIBLE] CARCINOGEN,
EVERYTHING, [INDISCERNIBLE]
HEAVY METALS AND SO GOING THERE
UH YOU CAN GO [INDISCERNIBLE].
SO THIS IS VERY COMPLICATED AND
THINK DEFINITELY HAS TO BE
[INDISCERNIBLE] BECAUSE
OTHERWISE IT'S JUST A HUGE MESS
AND EVENTUALLY JUST EXPLORE THEM
REALLY DO NOTHING.
>> [LOW AUDIO].
>> YEAH, EXACTLY.
>> [LOW AUDIO].
[APPLAUSE]
>> THANK YOU VERY MUCH.

Leave A Comment

Your email address will not be published
*