Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

@792e31d6

Could you tell us your regimen?

 

[Valentijn]

I know from reading this thread that you feel Mario's protocol is BS, I can also see from this post that you think methylation disorders are BS.

So I'm wondering if you think that freddd's protocol is worthless? or is your objection more that there is no scientific explanation to support the idea of methylation disorders?

It's not so much that I think the entire treatments are necessarily BS. In fact, I personally find folate beneficial (taken as needed for avoiding migraines), and high doses of injected hydroxoB12 to be beneficial (for pain). There's probably things on the other protocols which I have taken in isolation and found some benefit from.

But the theories underlying those protocols have little or no substance. So while I have no problem with someone saying "Hey, B12 helped me", it's misleading to say "B12 will help you because you have these (actually meaningless) Yasko SNPs." It's incorrect and even dishonest to suggest that there is a scientific basis for most of the treatments proposed, and I object to that use of pseudoscience to "sell" the treatment protocol.

 

[792e31d6]

@792e31d6

Could you tell us your regimen?

Tudca 250mg AM and PM
MethylB12 injections 5mg twice per week
Dibencozide 10mg QD - I just ran out of this so am discontinuing for now
5-MTHF 5mg QD
AlphaGPC 300mg QD
TMG 750mg QD
FMN 25mg QD
P-5-P 50mg QD
L-Tyrosine 500mg QD
Pycogenol 50mg AM and PM
Pantothenic Acid 500mg QD
Vit B-1 100mg QD
Biotin 10mg QD
Iodine 1.1mg QD
Selenium 100mcg QD
Ferrochel 27mg - I have chronically low ferritin if I don't supplement
Zinc Chelate 20mg QD
Magnesium Threonate 2000mr PM - helps me sleep
NAC Sustain 600mg PM
Melatonin 1mg PM
Levothyroxine 50mcg QD - been on this for several years
I'm also on TRT, tried to stop, but my insomnia got worse.

 

[mariovitali]

Tudca 250mg AM and PM
MethylB12 injections 5mg twice per week
Dibencozide 10mg QD - I just ran out of this so am discontinuing for now
5-MTHF 5mg QD
AlphaGPC 300mg QD
TMG 750mg QD
FMN 25mg QD
P-5-P 50mg QD
L-Tyrosine 500mg QD
Pycogenol 50mg AM and PM
Pantothenic Acid 500mg QD
Vit B-1 100mg QD
Biotin 10mg QD
Iodine 1.1mg QD
Selenium 100mcg QD
Ferrochel 27mg - I have chronically low ferritin if I don't supplement
Zinc Chelate 20mg QD
Magnesium Threonate 2000mr PM - helps me sleep
NAC Sustain 600mg PM
Melatonin 1mg PM
Levothyroxine 50mcg QD - been on this for several years
I'm also on TRT, tried to stop, but my insomnia got worse.

OK, Thanks (Please go to the first page and notice that i was too Hypothyroid and had Hypogonadism. Do you have Subclinical Hypothyroidism?).

Some more questions :

-How did you get CFS? Did you -by any chance- took any Medication such as Cirpo/Finasteride/Accutane etc? Did you get it after an Epstein-Barr virus infection?

-How long do you have this condition?

-Do you have DNA Data available?

-Have you ever had Liver tests?

-Have you checked your Manganese Levels?

 

[792e31d6]

It's not so much that I think the entire treatments are necessarily BS. In fact, I personally find folate beneficial (taken as needed for avoiding migraines), and high doses of injected hydroxoB12 to be beneficial (for pain). There's probably things on the other protocols which I have taken in isolation and found some benefit from.

But the theories underlying those protocols have little or no substance. So while I have no problem with someone saying "Hey, B12 helped me", it's misleading to say "B12 will help you because you have these (actually meaningless) Yasko SNPs." It's incorrect and even dishonest to suggest that there is a scientific basis for most of the treatments proposed, and I object to that use of pseudoscience to "sell" the treatment protocol.

OK, thank you. That's what I thought.

I spend a lot of time on men's health forums, which deal mostly with hormone replacement, and I'm sometimes amazed to watch people spin elaborate theories about how fluctuations in certain hormones or neurotransmitters can cause various symptoms when, at the end of the day, all you can do is try various types and dosages of hormones and see if they make you feel better or worse or do nothing.
On the other hand, I do understand how theorizing about some mechanism of action can provide hope that what they are doing will actually help their symptoms.

 

[792e31d6]

OK, Thanks (Please go to the first page and notice that i was too Hypothyroid and had Hypogonadism. Do you have Subclinical Hypothyroidism?).

Some more questions :

-How did you get CFS? Did you -by any chance- took any Medication such as Cirpo/Finasteride/Accutane etc? Did you get it after an Epstein-Barr virus infection?

I don't want to say I have CFS, seems people on this forum get pretty upset when someone new comes on and claims to have CFS.
What precipitated my health decline was a health crisis for a family member. This meant I needed to provide 24 hour care for that family member and as a result I did not get more than 3-4 hours of sleep per night for 3-4 years. Once this improved to the point where I actually had the time to get more sleep I found that I no longer could. This was 12 years ago. This eventually lead to a whole series of doctors and a whole series of treatments from anti-depressants to IV chelation therapy. But through all that time I was still able to work, although not at my best. Things really came to a head last summer when I developed really severe PEM (or rather my existing PEM got much worse). It was to the point where a 3 hour bus ride would leave me barely able to get out of bed for 2 days.
At this point I saw a doctor who treats CFS (he's listed in the ME/CFS doctors thread on this forum) and he said my symptoms were consistent with a diagnoses of CFS.

-How long do you have this condition?

See above. About 12 years.

-Do you have DNA Data available?

No, haven't got the money to do that right now.

-Have you ever had Liver tests?

Other than AST/ALT, no. Those were normal.

-Have you checked your Manganese Levels?

No. Curious, how is that related?

 

[mariovitali]

@792e31d6

Sorry, what is PEM exactly?

Regarding Manganese : It is a very important cofactor, why i am mentioning it is a rather big story.

It is unfortunate that you do not have your DNA Data...


FYI My regimen is as follows.


08:00 Dibencozide,FMN, Metafolin
10:00 Alpha GPC, Biotin,Pantothenic Acid
12:00 TUDCA, Selenium, P5P
16:00 TMG (1 gram)
23:00 Alpha GPC

NO Vitamin A / Gluten / Glutamate
NO P450 Inhibitors
EDIT : No Alcohol is allowed while taking TUDCA

-Eating oats for Manganese (100 grams about 300% RDA if i am not mistaken). Manganese levels should be checked : Too low or too High is not good.

Since you will start eliminating Supplements, perhaps you could try slowly moving to this subset and evaluate how you feel.

I was hypothyroid for years and was receiving HCG shots for many months since -my hypothesis- the HPTA Axis was affected. I also began having signs of Insulin Resistance.


All is gone now, my endo was amazed..i also think she got a bit upset because i remember her saying to me "Let's see if this lasts, i highly doubt it".

That was 6 months ago. Poor doc...

 

[792e31d6]

@792e31d6

Sorry, what is PEM exactly?

Regarding Manganese : It is a very important cofactor, why i am mentioning it is a rather big story.

It is unfortunate that you do not have your DNA Data...


FYI My regimen is as follows.


08:00 Dibencozide,FMN, Metafolin
10:00 Alpha GPC, Biotin,Pantothenic Acid
12:00 TUDCA, Selenium, P5P
16:00 TMG (1 gram)
23:00 Alpha GPC

NO Vitamin A / Gluten / Glutamate
NO P450 Inhibitors
-Eating oats for Manganese (100 grams about 300% RDA if i am not mistaken). Manganese levels should be checked : Too low or too High is not good.

Since you will start eliminating Supplements, perhaps you could try slowly moving to this subset and evaluate how you feel.

I was hypothyroid for years and was receiving HCG shots for many months since -my hypothesis- the HPTA Axis was affected. I also began having signs of Insulin Resistance.


All is gone now, my endo was amazed..i also think she got a bit upset because i remember her saying to me "Let's see if this lasts, i highly doubt it".

That was 6 months ago. Poor doc...

PEM = Post Exertional Malaise

At least for me this meant that after any physical activity outside the norm that I would suffer from extreme fatigue, brain fog, and sometimes headache. I would have to retreat back to bed and wait to recover enough energy to perform basic daily tasks.

For HRT I'm doing DHEA, pregnenolone, testosterone and HCG.

I don't feel great, but I'm able to work full time again, which was really what I needed to happen.

As I taper down my supplements I'l evaluate which seem to help and which don't. It will be interesting to see if I end up with the same list as you.

 

[mariovitali]

@792e31d6

I forgot to write : No alcohol should be taken with TUDCA.


Good Luck with your regimen.

 

[Bdeep86]

@mariovitali what form of selenium are you taking?

 

[mariovitali]

@mariovitali what form of selenium are you taking?

It's L-Selenomethionine

 

[mariovitali]

I wanted to give a minor update.


I am still working on my Predictive Models so that i may increase their accuracy. See the following example :

Essentially the algorithm picks the most important aspects of Symptoms associated with CFS/PFS etc.

So my goal is to find the best subset of Topics that "characterize" the symptoms in the most efficient way. The run takes 2-3 days unfortunately...


FYI @Bdeep86 : Numerous times "iron_deficiency" was chosen on the top places by the Machine Learning Algorithm. As i said to you in the PM, i think that one more problem lies to Heme Biosynthesis (?) but i would be very interested to hear what you think.


Factors of importance are :


-The role of Biotin and Pantothenic Acid
-Krebs Cycle
-Oxidative Phosphorylation (OXPHOS)


I will post as soon as i have new results..

 

[Bdeep86]

@mariovitali I am not surprised that this came up several times.

 

[Bdeep86]

@mariovitali high levels of lipid peroxidation (due to excess levels of unbound iron) greatly stimulates the unfolded protein response.

 

[mariovitali]

@Bdeep86

I see, where do you attribute the fact that iron is unbound?


@all

See below some new output from the analysis that i am doing.


First of all, look at the following chart, paying attention to the Left list of Topics :

Notice how Liver_disease, iron_deficiency, Cannabis are on the top levels. Oxidative phosphorylation, PDHC (Pyruvate Dehydrogenase Complex) and notice the entries related to CoA (Coenzyme A)


Note : I am NOT suggesting that you should supplement with Iron or take any form of Cannabis!!

Next we have the times that each Topic has been matched (Notice Glutamate, ROS, Glycine, Phosphorylation, Mitochondria, Hypoxia etc). This number is the one shown on the right :


file y
144 glutamate 481
341 ros 479
150 glycine 471
238 mitochondria_human 470
232 methionine 469
306 phosphorylation 467
187 hypoxia 465
164 hepatocytes 464
305 phospholipid_human 460
128 flavoprotein 459
159 gut 458
58 catalase 457
195 immune_response 457
222 liver_disease 457
101 dexamethasone 456
162 heat_shock_protein 456
252 nadph 456
108 dopamine 455
100 detoxification 452
239 mitochondrial_dysfunction 450
71 cofactor 449
145 glutamine 449
197 inflammatory_response 448
156 gsh 447
152 glycoproteins 445
374 sulfur 445
283 p450 443
319 protein_kinase_c 443
24 amyloid 442
163 heme 439
278 oxidation 438
286 p53 438
377 tau 438
39 b_cell 437
64 choline 437
202 insulin_resistance 436
192 igg 435
78 creatine 434
9 acetylation 433
53 calcium_homeostasis 433
147 glutathione_stransferase 433
57 caspase_human 432
223 liver_injury 432
248 nac 432
281 oxidative_stress_markers 432
153 glycosylation 431
32 astrocytes 428
160 h2o2 428
199 inositol 428
69 ckd 427
366 steatohepatitis 427
48 bilirubin 426
26 angiotensin_human 425
72 conjugation 425
250 nad 424
61 chaperones 423
227 manganese 423
347 selenium 423
168 histamine 422
211 l_arginine 420
284 p450oxidoreductase 419
302 phosphatidylcholine 419
115 er_stress 414
346 schizophrenia 414
378 taurine 413
75 cortisol 412
274 omega3 411
176 hsp70 410
310 porphyrins 410
10 acetylcholine 408
77 cox_2 408
231 melatonin 408
282 oxidative_stress_protection 408
165 hepatotoxicity 406
291 parasitic 405
151 glycolysis 403
196 inducible_nos 403
259 ngf 402
99 dermatitis 400
350 serotonin_levels 400
12 acyl_coa 399
63 cholestasis 399
214 l_carnitine 399
279 oxidative_phosphorylation 398
52 butyrate 397
76 cortisol_levels 397
194 il_10 394
264 nmda 394
135 gaba_human 393
244 mtor 393
191 igf_1 391
230 mcp_1 389
170 histone_deacetylase 388
193 igm 387
400 uric_acid 387
337 resveratrol 385
407 xanthine_oxidase 385
233 methotrexate 384
387 tlr 384
46 bile_acid 383
140 glucocorticoid_receptor 383
188 iga 383
318 protease_inhibitor 382
44 beta_glucuronidase 381
66 chop 380
190 ige 380
236 microglia 380
7 acetyl_coa 379
28 anorexia 379
81 curcumin 379
265 norepinephrine 379
405 vitamin_d3 378
385 thioredoxin 377
212 l_cysteine 376
307 polyamines 375
406 vitamin_k 375
11 acetylcholinesterase 373
102 dhea 371
269 nrf2 371
79 crohns_disease 368
393 ubiquitination 368
181 hydroxysteroid_dehydrogenase 366
16 adrenergic_receptor 365
41 bdnf 365
293 pbmc 365
241 monoamine_oxidase 364
399 urea_cycle 363
113 endothelial_nos 361
172 hmgcoa 361
299 peroxynitrite 361
303 phosphatidylserine 360
379 tbars 360
49 biotin 359
177 human_proteinuria 358
37 autism 357
390 triiodothyronine_levels 354
180 hydrolysis 353
220 lipoic_acid 353
54 caloric_restriction 350
213 l_dopa 349
361 solute_carrier 349
384 thiamine 349
218 lactobacillus 348
242 monosodium_glutamate 347
257 neuroinflammation 344
136 ggt 343
253 nafld 342
343 sam_e 341
161 hba1c 340
111 ebv 338
328 quinone_reductase 338
266 notch 337
324 pulmonary_fibrosis 336
351 sialic_acid 336
224 liver_regeneration 335
25 amyloidosis 334
205 iron_deficiency 334
262 nk_cell 334
273 odc 334
358 sod1 334
398 upr 334
403 vcam_1 334
179 hydrogen_sulfide 333
198 inosine 333
155 gpr78 330
298 peroxiredoxin 330
167 hgh 329
380 testosterone_production 329
17 advanced_glycation_end 328
89 cyp3a4 327
178 human_semen 327
45 betaine 326
125 fas_ligand 325
246 n_acetylglucosamine 325
251 nadh_dehydrogenase 325
88 cyp2e1 324
38 avidin 323
106 disulfide_bonds 323
260 niacin 323
338 riboflavin 323
74 constipation 322
256 neurite_outgrowth 322
36 atrial_fibrillation 321
247 n_acetyltransferase 320
316 probiotics 320
30 arginase 318
353 sirt1 317
142 glucuronic_acid 316
184 hyperhomocysteinemia 316
365 stat1 316
50 bradycardia 315
261 nitration 315
23 ampa 314
47 biliary_cirrhosis 314
83 cyp1a1 314
207 isoprostane 314
356 sleep_apnea 314
15 adrenal_insufficiency 313
67 cimetidine 312
141 glucose_6_phosphatase 311
332 redox_cofactor 310
373 sulfotransferase 310
148 gluten 309
258 neuronal_nos 309
395 udpgluc 309
334 redox_potential 308
119 excitotoxicity 307
103 dht 306
297 perk 306
335 redox_regulation 305
112 ed 304
314 pregnenolone 303
323 pulmonary_edema 303
237 misfolded_proteins 302
370 sulfation 302
200 insomnia 301
410 zinc_supplementation 300
139 ginkgo 299
277 oxalates 299
359 sod2 299
84 cyp1a2 297
65 choline_deficiency 296
133 freet3 296
215 l_tryptophan 296
333 redox_homeostasis 296
174 hpa_axis 294
268 nqo1 294
87 cyp2d6 292
209 kainate 292
217 lactic_acidosis 292
235 microbiome_humans 291
234 metronidazole 290
240 molybdenum 290
357 social_anxiety 290
183 hypercortisolism 289
254 naltrexone 288
363 sshl 288
43 beta_alanine 287
381 tetrahydrobiopterin 287
404 vitamin_b6 286
8 acetyl_coa_carboxylase 285
21 aminoglycoside 285
143 glucuronidation 285
13 adhd 284
312 ppp 282
55 cannabis 281
60 cfs 281
294 pdhc 281
348 selenium_deficiency 281
110 dysautonomia 280
70 coenzymeq10 279
409 zinc_deficiency 277
342 rxr 275
68 ciprofloxacin 274
219 limbic_system 274
206 irritable_bowel 273
367 steroidogenesis_human 273
210 krebs 272
382 th1th2 272
1 three_betahsd 271
186 hypokalemia 271
287 p5p 270
402 uti 269
121 fad 268
126 fibromyalgia 268
182 hyperammonemia 268
308 pomc 268
391 trpv 268
171 hmgb1 266
295 pdi 266
349 serca 264
352 sinusitis 264
62 cholangitis 262
329 rar 262
14 adrenal_hyperplasia 260
73 conjunctivitis 258
330 reactive_intermediates 258
166 hexosamine 257
344 sarcosine 257
331 reactive_metabolites 256
408 xbp1 256
243 mthfr 255
33 asymmetric_dimethylarginine 254
309 porphyria 253
372 sulforaphane 253
5 five_alphareductase 252
216 l_tyrosine 252
267 nox4 252
249 nachr 249
226 magnesium_deficiency 246
383 thermoregulation 246
339 rituximab 245
263 nlinkedglycosylation 244
3 five_ht2 243
34 atf4 243
124 fas 243
203 intestinal_motility 241
229 mastocytosis 240
4 five_htp 237
134 fxr 237
169 histolytica 235
29 are 234
321 psc 233
114 enterohepatic_circulation 231
301 phenylketonuria 230
85 cyp1b1 226
296 peristalsis 225
290 pantothenic_acid 224
386 tinnitus 222
35 atf6 221
325 pxr 221
208 isotretinoin 220
146 glutaredoxin 218
364 star 217
396 ugt1a1 217
401 urolithiasis 216
131 fmn 215
137 ghd 215
175 hsc 215
221 lithium_treatment 213
97 d_serine 212
311 potassium_levels 211
118 esr1 210
276 osmolytes 210
228 mast_cell_activation 209
20 allopregnanolone 208
40 baroreceptor 208
157 gtp_cyclohydrolase 208
326 pyrogen 208
225 lpa 202
322 ptp1b 202
96 d_aminolevulinic_acid 201
288 panic_disorder 201
389 tocotrienol 198
327 pyruvate_carboxylase 197
376 systemic_amyloidosis 197
392 tudca 197
90 cyp7a1 195
127 finasteride 195
130 fluoroquinolone 195
56 car 193
275 orthostatic_intolerance 191
388 tmao 191
95 d_aminoacid_oxidase 190
204 ire1 190
120 exercise_intolerance 186
189 igd 186
345 scfa 185
27 anhedonia 184
304 phospholamban 183
355 sirt3 183
107 dolichol 182
201 insp3 181
300 pgc1 181
320 prpc 181
369 succinyl_coa 180
271 o_glcnac 179
285 p450scc 179
270 ntcp 177
368 subclinicalhypo 176
340 rls 173
132 fmo3 172
51 bsep 171
315 primary_immunodeficiency 171
360 sod3 160
149 glycerylphosphorylcholine 159
371 sulfite_oxidase 159
116 erad 158
394 udpglcnac 158
313 pqq 153
82 cvid 152
86 cyp27a1 152
272 o_glcnacylation 150
158 gulfwar_syndrome 149
80 csad 147
185 hypogammaglobulynemia 144
154 gnmt 143
354 sirt2 140
105 dim 137
31 artichoke 132
104 dihydroprogesterone 131
397 ugt1a9 127
336 resistant_starch 126
292 paromomycin 125
375 sult2a1 119
94 d_limonene 118
18 ae2 117
91 cyp7b1 117
317 propionyl_coa_carboxylase 117
22 amoebic_liver 114
138 gilberts 114
289 pantethine 113
92 cyp8b1 111
117 ero1 105
173 hnmt 103
42 benfotiamine 93
123 fads2 92
280 oxidative_protein_folding 92
59 cerebrovascular_amyloidosis 91
122 fads1 82
245 mucuna 82
93 cysteine_desulfurase 79
6 five_mthf 78
2 three_methylcrotonyl_coa_carboxylase 65
129 floaters 60
19 akr1d1 50
98 daoa 46
362 srd5a3 26
255 ndufs7 24
109 dpagt1 22

 

[792e31d6]

Notice how Liver_disease, iron_deficiency, Cannabis are on the top levels. Oxidative phosphorylation, PDHC (Pyruvate Dehydrogenase Complex) and notice the entries related to CoA (Coenzyme A)

I certainly find this interesting, because I have to supplement iron in order to keep my ferritin above 50 mcg/L.

I suffer from restless legs syndrome and if my ferritin gets too low my RLS gets worse.

 

[mariovitali]

@Bdeep86

Well, that wasn't that difficult after all ;-)



We should look more into ABC Transporters i think.

ABCB2/TAP1 and ABCB3/TAP2 are half-transporters, and form heterodimers in order to function as peptide transporters involved in the MHC-I-dependent antigen presentation. They are localized in the membrane of endoplasmic reticulum, and pump degraded cytoplasmic peptides into the ER lumen where the MHC class I molecular complexes assemble (21).ABCB4/MDR3 and ABCB11/BSEP are involved in the transport of phosphatidylcholine (ABCB4) and bile salts (ABCB11), respectively, across the hepatocyte canalicular membrane into bile.Their mutations are responsible for various forms of progressive familial intrahepatic cholestasis (PFIC); mutations in ABCB4 were found in patients with PFIC3, resulting from a defective transport of phosphatidylcholine across the canalicular membrane (22-24). Mutations in ABCB11 cause PFIC2, in this case the biliary bile salt secretion is very low (25).ABCB6-8 are not well characterized as yet. These are ABC half-transporters, most probably localized in the mitochondrial inner membrane. They likely play a role in the mitochondrial metal homeostasis; ABCB6 probably mediates the transport of an iron complex, ABCB7 and ABCB8 are thought to be involved in the heme transport from mitochondria to the cytosol. They are also candidate genes for inherited metabolic disorders, ABCB6 for the lethal metabolic syndrome, ABCB7 for X-linked sideroblastic anemia with ataxia. ABCB9 is expressed in the lysosomes with unknown function as yet (26).

http://www.solvobiotech.com/scienti...rs-in-drug-resistance-metabolism-and-toxicity


and of course we have mentions of CFS and MDR3!!! :


https://books.google.com/books?id=amvdOprZZpEC&pg=PA89&lpg=PA89&dq=cfs mdr3&source=bl&ots=nKlME7EXBk&sig=nUC_lwYpxoEjKvsvTjRQ_WXAw2U&hl=en&sa=X&ved=0ahUKEwihvoC-8v_KAhXiIJoKHeo5BckQ6AEIHTAA#v=onepage&q=cfs mdr3&f=false

and also mentions of MDR3 being associated with Liver injury


Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Disease

MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.

 

[Bdeep86]

@mariovitali I will look at this I can't say i'm well versed in ABC transporters.

 

[mariovitali]

I just tried to find something to connect Bile Acids and Heme Levels. It was great that PhosphatidylCholine appears too

 

[Bdeep86]

@mariovitali in my own research its seems that there is quite a substantial link. Going to look at this today.