Discuss the effects of FGF23 and PTH on phosphate and calcitriol.
52 Comments
Muhammad Soobadar
There is increased FGF23 in early CKD . FGF 23 works by increase phosphate excretion in kidney by working on renal tubules by binding klotho co-receptor and activating its FGFR-1 and FGFR-3 and leads to decrease in concentration of sodium co transporters NAPI2a NAPI2c through Protein Kinase and A /C dependent pathways. It also inhibits 1 alpha hydroxylase decreasing 1 25 hidroxyvitamin d and decreasing intestinal phosphate absorption. PTH is phosphaturic too by binding its own receptor and then leading as FGF23 to decrease in concentration of sodium co-tranporters NAPI2a and NAPI2C through protein kinase A/C dependent pathways.
FGF23 and PTH interestingly have different effect on 1a -hydroxlyase. fgf 23 decrease 1a hydroxylase and decrease 1 25 OH therefore decreased calcium absorption from gut.
PTH increases 1 a hydroxlase and low a hydroxlase stimulate PTH too. there increasing calcium via intestinal absorption. PTH acts on bones by stimulating osteoblast which increase expression of RANKL allowing for differentiation into osteoblast and osteocyte. it leads bone resorption and release of calcium into blood from bone.
Phosphate tends to accumulate in the very early stages of CKD FGF23 increases first followed by PTH, both of them are phosphaturic. This phosphaturic effect is achieved by decreasing NaPi2 transporter PTH increases 1a-Hydroxylase thereby tending to increase active vitamin D and consequently tending to restore serum calcium. FGF23 has the opposite effect on 1a-Hydroxylase (inhibition), and hence tending to lower serum calcium
* FGF23 inhibit 1alpha hydroxylase hence vitamin D activation decreasing intestinal absorption of phosphorus (on the other hand vitamin D inhibit FGF23) * FGF23 inhibit NaPi2a,c in PCT, decreasing phosph reabsorption, promoting its excretion (phosphaturic effect) * FGF23 inhibit NaPi2b decreasing intestinal absorption of phosphorus
The effects of FGF23 and PTH on phosphate and calcitorial.
The increase of PTH and FGF23 decrease in serum calcitorial in later stages of CKD.
FGF23 and PTH have collaborating effects on renal phosphate excretion and they have opposite effects on calcitorial synthesis , FGF23 inhibits the alpha 1 hydroxylase decreasing the synthesis of calcitorial and PTH stimulates the production of alpha 1 hydroxylase and increases the calcitorial synthesis and both increase phosphate excretion by decreasing the concentration of Napi2
(PHOSPHORUS)
Both FGF 23 and PTH have a phosphaturic effect via action on tubular Napi2a and NaPi2c cotransporters in the renal tubules.
(Calcitriol)
FGF 23 decreases alpha-hydroxylase activity by binding to Klotho co-receptors on FGFR-1 and 3
while PTH increases 1 alpha-hydroxylase activity increasing calcitriol level synthesis
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis. FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis .FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor. Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways.
The increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Both FGF-23 and PTH are a phosphaturic effect. They have an opposite effect on alpha-hydroxylase. PTH increases the effect trying to incase the calcitriol synthesis while FGF-23 shows an inhibitory effect
· FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol.
· PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
· FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors. While PTH does so by binding to its specific receptor.
The effect of fgf23 on po4 is a phosphaturic effect via increase its excretion and prevent reabsorption in proximal tubules and after the progression of ckd decrease koltho and more increase in fgf23 with decrease po4 excretion due to damage kideny tissue with decrease level of calciterol
The effect of pth early in disease have senirgistic effect with fgf23 in it’s phosphaturic effect and increase level of alpha hydroxylase to increase level of calciterol
Up to (GFR) of around 30–40 ml/min, serum calcium and phosphate values usually remain within the normal range, changes usually manifested with GFR below 20–30 ml/min. In contrast, calcitriol begins to decrease early in the course of CKD (GFR between 70 and 80 ml/min), calcidiol and PTH increase abit later, from GFR of 60–70 ml/min
FGF23 inhebits 1-alfa hydroxylase in the kidney decreasing calcitriol while PTH increases 1-alfa hydroxylase in the kidney FGF23 and PTH in early CKD both increase serum phosphate excretion then with progression of Ckd and nephron loss and decrease klotho expression serum phosphate starts to increase and serum calcitriol decrease.
FGF -23 role on phosphate and calcitriol
has role in inhibition of na/ pi cotransporter in the proximal tubule so decrease reabsorption of phosphate and stimulation of renal po4 excretion required klotho for its action as phosphaturic action
–suppression of intestinal phosphate absorption
BUT its effect on calcitriol
–inhibit of renal 1-alfa hydroxylase
PTH hormone synergistic effect for urinary phosphate excretion
and increase production of 1-alfa hydroxylase and increase level of calcitriol
EFFECT OF FGF23 ON PTH AND PHOSPHATE AND CALCITRIOL
===================
FGF23 AND PTH HAVE SYNERGISTIC EFFECTS IN RELATION TO THE RENAL EXECRETION OF PHOSPHATE BUT HAVE OPPOSITE EFFECT ON CALCITRIOL
1-EFFECT OF FGF23 ON PHOSPHATE
act as phosphaturic hormone >increase phosphate execrtion by inhibition of Na/pi cotransporter at PCT
==========
2-EFFECT OF FGF23 ON CALCITRIOL
reduce calcitriol by inhibition of 1 alfa hydroxylation
=================
PTH increase calcitiriol by activation of 1 alfa hydroxylation from kidney
FGF23 and PTH have stimulatory effects on phosphate excretion in the kidney. They have opposing effects on the production of calcitriol. FGF23 inhibits 1–hydroxylase through lowering calcitriol production. PTH increases calcitriol synthesis by stimulating the formation of 1–hydroxylase.
During the early stage of CKD, “normal” phosphorus levels are maintained by continual increases in FGF-23 and PTH levels.
Eventually, this compensatory mechanism is overwhelmed with a further decline in kidney function.
FGF23 and PTH are both phosphaturic hormones, reducing renal phosphate reabsorption downregulation of the luminal membrane NaPi2a and NaPi2c through protein kinase A and C- dependent pathways.
Feedback loops for both PTH and FGF-23 are dependent on calcitriol:
PTH increases 1-alpha-hydroxylase and, therefore, the production of calcitriol, which in turn inhibits further PTH release.
Whereas, FGF-23 inhibits 1-alpha-hydroxylase and decreases calcitriol production, which will inhibit FGF-23 secretion.
Discuss the effects of FGF23 and PTH on phosphate?
FGF23 and PTH have stimulatory effects on phosphate excretion in the kidney. They have opposing effects on the production of calcitriol.
Discuss the effects of FGF23 and PTH on calcitriol?
FGF23 inhibits 1–hydroxylase through lowering calcitriol production.
PTH increases calcitriol synthesis by stimulating the formation of 1–hydroxylase.
One of the crucial points in CKD-MBD, despite the synergistic effect of FGF23 and PTH in decreasing the phosphate level through the kidney, they have opposite effects on calcitriol synthesis, FGF23 inhibits1alpha hydroxylation, while PTH increases it.
Discuss the effects of FGF23 and PTH on phosphate?
FGF23 and PTH both are phosphaturic ( increase po4 excretion ) by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, in proximal tubule.
Discuss the effects of FGF23 and PTH on calcitriol?
FGF23 inhibit 1 alpha hydroxylase leading to calcitriol synthesis
As regard phosphate they are the same. both of them increase po4 excretion from the kidney but this is different in calcitriol. PTH stimulate calcitriol action but FGF-23 inhibit calcitriol action in contrary .
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis.
FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
FGF23 exerts its tubular e ect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor.
Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways
Effects of FGF23 and PTH on phosphate and calcitriol Synergistic effect of FGF23 and PTH:
FGF23 binds to its Klotho co-receptor and activates FGFR-1 FGFR-3 receptors while PTH does so by binding to its specific receptor Both of them increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C dependent pathways.
The opposite effect of FGF23 and PTH:
FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, while PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
FGF23 and PTH are both phosphaturic hormone.
FGF23 act with it cofactor klotho on renal tubules (fgf receptor 1and3).
PTH act on it receptors on kidney.
Both receptor will decrease the natrium phosphate cotransport 2a& 2c on renal tubules what lead to more phosphat loss.
Together have synergetic effect.
But on 1alpha hydroxylase they have antagonistic effects.
– fgf23 will inhibit this enzyme what lead to decreased 1,25OH Vitamin D level.
– PTH will activate 1alpha hydroxylase what lead to increased 1,25 OH level .
Calcitriol will exercise his negative feedback on Parathyroid gland throw VDR receptors and decreasing his transcription.
The production of calcitriol is decreased when 1–hydroxylase is inhibited by FGF23, but PTH promotes the production of 1-hydroxylase, which results in an increase in the amount of calcitriol that is produced.
The tubular impact that FGF23 has is caused by its binding to its Klotho co-receptor and the activation of its FGFR-1 and FGFR-3 receptors, while the tubular effect that PTH has is caused by its binding to its particular receptor.
By decreasing the concentration of the sodium cotransporters NaPi2a and NaPi2c, both of these things contribute to an increase in the excretion of phosphate through pathways that are reliant on protein kinases A and C.
The FGF23 will causes decrease activity of 1 alfa hydrxylase which lead to decrease in calcitriol synthesis while PTH increase synthesis and activity of 1 alfa hydrxylase so increasing the synthesis of calcitriol.
Both FGF23 and PTH causes phosphoturia, FGF23 exert it’s effect through tubular Receptor klotho co transporter FGFR1 and FGFR3 while PTH will bind to its Receptor, both of them causes decrease in sodium phosphate cotransporter NaPi2a and NaPi2c through protein kinase A and C
So increase phosphote excretion to normalize s. Phosphate level
There is increased FGF23 in early CKD . FGF 23 works by increase phosphate excretion in kidney by working on renal tubules by binding klotho co-receptor and activating its FGFR-1 and FGFR-3 and leads to decrease in concentration of sodium co transporters NAPI2a NAPI2c through Protein Kinase and A /C dependent pathways. It also inhibits 1 alpha hydroxylase decreasing 1 25 hidroxyvitamin d and decreasing intestinal phosphate absorption. PTH is phosphaturic too by binding its own receptor and then leading as FGF23 to decrease in concentration of sodium co-tranporters NAPI2a and NAPI2C through protein kinase A/C dependent pathways.
FGF23 and PTH interestingly have different effect on 1a -hydroxlyase. fgf 23 decrease 1a hydroxylase and decrease 1 25 OH therefore decreased calcium absorption from gut.
PTH increases 1 a hydroxlase and low a hydroxlase stimulate PTH too. there increasing calcium via intestinal absorption. PTH acts on bones by stimulating osteoblast which increase expression of RANKL allowing for differentiation into osteoblast and osteocyte. it leads bone resorption and release of calcium into blood from bone.
Phosphate tends to accumulate in the very early stages of CKD
FGF23 increases first followed by PTH, both of them are phosphaturic.
This phosphaturic effect is achieved by decreasing NaPi2 transporter
PTH increases 1a-Hydroxylase thereby tending to increase active vitamin D and consequently tending to restore serum calcium.
FGF23 has the opposite effect on 1a-Hydroxylase (inhibition), and hence tending to lower serum calcium
* FGF23 inhibit 1alpha hydroxylase hence vitamin D activation decreasing intestinal absorption of phosphorus (on the other hand vitamin D inhibit FGF23)
* FGF23 inhibit NaPi2a,c in PCT, decreasing phosph reabsorption, promoting its excretion (phosphaturic effect)
* FGF23 inhibit NaPi2b decreasing intestinal absorption of phosphorus
* PTH stimulate 1alpha hydroxylase, promoting calcitriol activation
* PTH decreases phosphorus reabsorption (phosphaturic hormone)
Excellent Dr. Marwa
The effects of FGF23 and PTH on phosphate and calcitorial.
The increase of PTH and FGF23 decrease in serum calcitorial in later stages of CKD.
FGF23 and PTH have collaborating effects on renal phosphate excretion and they have opposite effects on calcitorial synthesis , FGF23 inhibits the alpha 1 hydroxylase decreasing the synthesis of calcitorial and PTH stimulates the production of alpha 1 hydroxylase and increases the calcitorial synthesis and both increase phosphate excretion by decreasing the concentration of Napi2
Good answer. Thanks Dr. Mohamed
(PHOSPHORUS)
Both FGF 23 and PTH have a phosphaturic effect via action on tubular Napi2a and NaPi2c cotransporters in the renal tubules.
(Calcitriol)
FGF 23 decreases alpha-hydroxylase activity by binding to Klotho co-receptors on FGFR-1 and 3
while PTH increases 1 alpha-hydroxylase activity increasing calcitriol level synthesis
Great Dr. Radwa
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis. FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis .FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor. Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways.
The increase in FGF23 and PTH favor urinary phosphate excretion, maintaining normal serum phosphate levels until stages 3–4 of CKD .Despite the compensatory increases in PTH, it is well known that in CKD there is currently a hyporesponsiveness to PTH which limits its action .
Excellent clarification. Thanks Dr. Asmaa
Both FGF-23 and PTH are a phosphaturic effect. They have an opposite effect on alpha-hydroxylase. PTH increases the effect trying to incase the calcitriol synthesis while FGF-23 shows an inhibitory effect
Thanks Dr. Mahmud.
In addition:
· FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol.
· PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
· FGF23 exerts its tubular effect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors. While PTH does so by binding to its specific receptor.
The effect of fgf23 on po4 is a phosphaturic effect via increase its excretion and prevent reabsorption in proximal tubules and after the progression of ckd decrease koltho and more increase in fgf23 with decrease po4 excretion due to damage kideny tissue with decrease level of calciterol
The effect of pth early in disease have senirgistic effect with fgf23 in it’s phosphaturic effect and increase level of alpha hydroxylase to increase level of calciterol
Great Dr. Rabab.
I want to add some points:
Both FGF23 and PTH have opposite effects on calcitriol synthesis
· FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol.
· PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
Up to (GFR) of around 30–40 ml/min, serum calcium and phosphate values usually remain within the normal range, changes usually manifested with GFR below 20–30 ml/min.
In contrast, calcitriol begins to decrease early in the course of CKD (GFR between 70 and 80 ml/min), calcidiol and PTH increase abit later, from GFR of 60–70 ml/min
FGF23 inhebits 1-alfa hydroxylase in the kidney decreasing calcitriol while PTH increases 1-alfa hydroxylase in the kidney
FGF23 and PTH in early CKD both increase serum phosphate excretion then with progression of Ckd and nephron loss and decrease klotho expression serum phosphate starts to increase and serum calcitriol decrease.
Great answer Thanks Dr. Rola
FGF -23 role on phosphate and calcitriol
has role in inhibition of na/ pi cotransporter in the proximal tubule so decrease reabsorption of phosphate and stimulation of renal po4 excretion required klotho for its action as phosphaturic action
–suppression of intestinal phosphate absorption
BUT its effect on calcitriol
–inhibit of renal 1-alfa hydroxylase
PTH hormone synergistic effect for urinary phosphate excretion
and increase production of 1-alfa hydroxylase and increase level of calcitriol
Good answer. Thanks Dr. Elsayed.
EFFECT OF FGF23 ON PTH AND PHOSPHATE AND CALCITRIOL
===================
FGF23 AND PTH HAVE SYNERGISTIC EFFECTS IN RELATION TO THE RENAL EXECRETION OF PHOSPHATE BUT HAVE OPPOSITE EFFECT ON CALCITRIOL
1-EFFECT OF FGF23 ON PHOSPHATE
act as phosphaturic hormone >increase phosphate execrtion by inhibition of Na/pi cotransporter at PCT
==========
2-EFFECT OF FGF23 ON CALCITRIOL
reduce calcitriol by inhibition of 1 alfa hydroxylation
=================
PTH increase calcitiriol by activation of 1 alfa hydroxylation from kidney
Great Dr. Emad
FGF23 and PTH have stimulatory effects on phosphate excretion in the kidney. They have opposing effects on the production of calcitriol.
FGF23 inhibits 1–hydroxylase through lowering calcitriol production.
PTH increases calcitriol synthesis by stimulating the formation of 1–hydroxylase.
Good answer Dr. Ahmed
During the early stage of CKD, “normal” phosphorus levels are maintained by continual increases in FGF-23 and PTH levels.
Eventually, this compensatory mechanism is overwhelmed with a further decline in kidney function.
FGF23 and PTH are both phosphaturic hormones, reducing renal phosphate reabsorption downregulation of the luminal membrane NaPi2a and NaPi2c through protein kinase A and C- dependent pathways.
Feedback loops for both PTH and FGF-23 are dependent on calcitriol:
Great answer. Thanks Dr. Amna
FGF23 and PTH both are phosphaturic by affecting sodium cotransporters NaPi2a and NaPi2c, in proximal tubule.
FGF23 inhibit 1 alpha hydroxylase leading to calcitriol synthesis
PTH stimulates calcitriol production
Good answer Dr. Mahmoud
effects of FGF23 and PTH on phosphate :
effects of FGF23 and PTH on calcitriol :
Great answer. Thanks Dr. Ibrahim
Discuss the effects of FGF23 and PTH on phosphate?
FGF23 and PTH have stimulatory effects on phosphate excretion in the kidney. They have opposing effects on the production of calcitriol.
Discuss the effects of FGF23 and PTH on calcitriol?
FGF23 inhibits 1–hydroxylase through lowering calcitriol production.
PTH increases calcitriol synthesis by stimulating the formation of 1–hydroxylase.
Great Dr. Rania
One of the crucial points in CKD-MBD, despite the synergistic effect of FGF23 and PTH in decreasing the phosphate level through the kidney, they have opposite effects on calcitriol synthesis, FGF23 inhibits1alpha hydroxylation, while PTH increases it.
Good job Dr. Rihab
Discuss the effects of FGF23 and PTH on phosphate?
FGF23 and PTH both are phosphaturic ( increase po4 excretion ) by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, in proximal tubule.
Discuss the effects of FGF23 and PTH on calcitriol?
Great Dr. Ashraf
As regard phosphate they are the same. both of them increase po4 excretion from the kidney but this is different in calcitriol. PTH stimulate calcitriol action but FGF-23 inhibit calcitriol action in contrary .
Good answer Dr. Mark
-Discuss the effects of FGF23 and PTH on phosphate?
-Discuss the effects of FGF23 and PTH on calcitriol?
Excellent Dr. Ben
Thnxs prof
Despite the fact that FGF23 and PTH have synergistic effects in relation to the renal excretion of phosphate, they have opposite effects on calcitriol synthesis.
FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, whereas PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
FGF23 exerts its tubular e ect by binding to its Klotho co-receptor and activating its FGFR-1 FGFR-3 receptors, while PTH does so by binding to its specific receptor.
Both increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C -dependent pathways
Good job Dr. Alaa
Effects of FGF23 and PTH on phosphate and calcitriol
Synergistic effect of FGF23 and PTH:
FGF23 binds to its Klotho co-receptor and activates FGFR-1 FGFR-3 receptors while PTH does so by binding to its specific receptor Both of them increase the phosphate excretion by reducing the concentration of the sodium cotransporters NaPi2a and NaPi2c, through Protein Kinase A and C dependent pathways.
The opposite effect of FGF23 and PTH:
FGF23 inhibits 1-α-hydroxylase by decreasing the synthesis of calcitriol, while PTH stimulates the production of 1-α-hydroxylase, increasing calcitriol synthesis.
Great Dr. Mohammed
FGF23 and PTH are both phosphaturic hormone.
FGF23 act with it cofactor klotho on renal tubules (fgf receptor 1and3).
PTH act on it receptors on kidney.
Both receptor will decrease the natrium phosphate cotransport 2a& 2c on renal tubules what lead to more phosphat loss.
Together have synergetic effect.
But on 1alpha hydroxylase they have antagonistic effects.
– fgf23 will inhibit this enzyme what lead to decreased 1,25OH Vitamin D level.
– PTH will activate 1alpha hydroxylase what lead to increased 1,25 OH level .
Calcitriol will exercise his negative feedback on Parathyroid gland throw VDR receptors and decreasing his transcription.
Excellent Dr. Nour
The production of calcitriol is decreased when 1–hydroxylase is inhibited by FGF23, but PTH promotes the production of 1-hydroxylase, which results in an increase in the amount of calcitriol that is produced.
The tubular impact that FGF23 has is caused by its binding to its Klotho co-receptor and the activation of its FGFR-1 and FGFR-3 receptors, while the tubular effect that PTH has is caused by its binding to its particular receptor.
By decreasing the concentration of the sodium cotransporters NaPi2a and NaPi2c, both of these things contribute to an increase in the excretion of phosphate through pathways that are reliant on protein kinases A and C.
Good answer Dr. Weam
The FGF23 will causes decrease activity of 1 alfa hydrxylase which lead to decrease in calcitriol synthesis while PTH increase synthesis and activity of 1 alfa hydrxylase so increasing the synthesis of calcitriol.
Both FGF23 and PTH causes phosphoturia, FGF23 exert it’s effect through tubular Receptor klotho co transporter FGFR1 and FGFR3 while PTH will bind to its Receptor, both of them causes decrease in sodium phosphate cotransporter NaPi2a and NaPi2c through protein kinase A and C
So increase phosphote excretion to normalize s. Phosphate level
Great Dr. Israa
The effects of FGF23 and PTH on phosphate and calcitriol:
Parallel effects:
Increases renal phosphate excreesion== phosphaturia, by reducing;
Co-transporter, through protein kinase A and C -dependant pathways.
Opposite effects:
Great answer. Thanks Dr. Kamal