New Therapeutic Strategies for Brain Edema and Cell Injury 2 Bradykinin is a mediator of edema formation Bradykinin is a well-known mediator of the brain edema formation and BBB disruption (Gröger et al., 2005; Plesnila et al., 2001; Schulz et al., 2000). However, its role in BSCB permeability is still not clear (Bannister et al., 2014; Ma et al., 2019; Mandadi et al., 2016; Pan, Kastin, Gera, & Stewart, 2001; Sharma, 2000; Wahl, Görlach, Hortobágyi, & Benyó, 1999; Xu et al., 2008; Yan-Feng, Gang, & Yan-Ting, 2008). Increased bradykinin content following brain injury has been demonstrated. Bradykinin has 2 receptors such B1 and B2. The detail mechanisms of B1 and B2 receptors in mediating the BBB permeability however, is still not well known (Görlach et al., 2001; Görlach, Benyó, & Wahl, 1998; Görlach & Wahl, 1996; Gröger et al., 2005; Plesnila et al., 2001; Schulz et al., 2000; Schürer, Temesvari, Wahl, Unterberg, & Baethmann, 1989; Unterberg, Wahl, & Baethmann, 1984; Wahl et al., 1996; Wahl, Young, Edvinsson, & Wagner, 1983; Whalley & Wahl, 1983). Both bradykinin and its receptors are present in healthy human brain and altered in disease processes such as ischemic brain injury (Bannister et al., 2014; Xu et al., 2008; Yan-Feng et al., 2008). Increased bradykinin concentration in the cerebrospinal fluid (CSF) is well documented for traumat6ic brain injury, ischemic stroke and intracerebral hemorrhages (Gröger et al., 2005; Kunz et al., 2013; Ma et al., 2019; Plesnila et al., 2001; Schulz et al., 2000; Schürer et al., 1989;Unterberg et al., 1984; Wahl et al., 1983; Whalley & Wahl, 1983). Increased bradykinin concentration correlates well with the severity of brain edema (Kunz et al., 2013; Unterberg et al., 1984; Unterberg, Polk, Ellis, & Marmarou, 1990; Wahl et al., 1983; Whalley & Wahl, 1983). Brain edema following increased bradykinin concentrations in the brain is largely due to bradykinin-induced vasodilatation together with venous constriction (Unterberg et al., 1984; Wahl et al., 1983; Whalley & Wahl, 1983). Bradykinin also increases microvascular permeability to plasma proteins causing fluid retention and development of cerebral edema (Pan et al., 2001; Sharma, 2000; Xu et al., 2008; Yan-Feng et al., 2008). Several in vitro studies suggest that blockade of B2 receptors decreases the permeability of isolated cerebral endothelial cells and increased the electrical resistance. (Liu, Xue, Liu, & Wang, 2008; Raslan et al., 2010; Schöller, Feiler, Anetsberger, Kim, & Plesnila, 2011; Trabold et al., 2010). This suggest that blockade of B2 receptors somehow strengthen the endothelial cell permeability (Baethmann et al., 1983, 1988; Wahl et al., 1993, 1988, 1990). There are reports that activation of bradykinin B2 receptors increases the size of the lesion in stroke and enhances BBB breakdown resulting in local neuroinflammation (Görlach et al., 1998, 2001; Görlach & Wahl, 1996; Kunz et al., 2013; Pan et al., 2001; Schürer et al., 1989; Sharma, 2000; Unterberg et al., 1984; Wahl et al., 1999, 1996, 1983; Whalley & Wahl, 1983). Upregulation of bradykinin B2 receptors is seen as early as 2 h after the onset of ischemic stroke that continue to be elevated up to 24 h after the primary insult (Dobrivojević, Špiranec, & Sinđić, 2015; Gauberti, Potzeha, Vivien, & Martinez de Lizarrondo, 2018; Smeda & Daneshtalab, 2017). Interestingly, role of bradykinin and its receptors in SCI are still unclear and require further investigation (see Pan et al., 2001; Sharma, 2000). 2.1 Bradykinin stimulates nitric oxide production Bradykinin induced vasodilatation is largely caused by endothelial production of nitric oxide (NO) (Genaro, Stranieri, & Borda, 2000; Landmesser & Drexler, 2006). Nitric oxide (NO) is a free radical gas and when produced in vivo could also affect microvascular permeability disturbances and cell injury (Sharma, 1998, 1999; Sharma, Alm, & Westman, 1998; Sharma, Drieu, Alm, & Westman, 2000). Our previous studies show that SCI leads to upregulation of neuronal nitric oxide synthase (nNOS) in the traumatized cord and the adjacent rostral and caudal segments (Sharma et al., 1998; Sharma, Westman, Olsson, & Alm, 1996). Upregulation of nNOS is well known to induce NO production that is responsible for cell injury and microvascular permeability disturbances (Sharma, 1998; Sharma & Alm, 2004; Sharma, Alm, & Westman, 1998; Sharma, Nyberg, Westman, et al., 1998; Sharma et al., 1996). This is further substantiated by our findings that when nNOS antibodies were applied topically over the injured spinal cord, cell changes, edema formation and nNOS upregulation in the spinal cord were absent (Sharma et al., 1996; Sharma, Nyberg, Westman, et al., 1998). In cell culture studies, bradykinin stimulated nitric oxide production by twofold within 30 min after its application. This NO stimulation by bradykinin is blocked by bradykinin B2 receptor antagonist HOE-140 (Sesti, Martino, Mazzulla, & Chimenti, 2005; Zhang, Nasjletti, Xu, & Hintze, 1998). This observation clearly suggests that bradykinin induced endothelial NO production is mediated by bradykinin B2 receptors. 2.2 Bradykinin B2 receptors in spinal cord injury Bradykinin is implicated in spinal network, neuropathic pain, rhizotomy, inflammatory hyperalgesia and neuroinflammation in the spinal cord (Bannister et al., 2014; Ma et al., 2019; Mandadi et al., 2016; Pan et al., 2001; Sharma, 2000; Xu et al., 2008; Yan-Feng et al., 2008). Very few report deal with bradykinin in spinal cord injury (Pan et al., 2001; Sharma, 2000). There are reports of significant elevation of bradykinin after experimental spinal cord injury (see Pan et al., 2001). Also interaction of bradykinin with aquaporin4 in spinal cord ischemic injury to the cord was described. (Xu et al., 2008) We reported reduction in BSCB breakdown by B2 receptor antagonist HPE-140 in cord injury indicating involvement of bradykinin in SCI (see Sharma, 2000). However, detailed investigations on bradykinin involvement in SCI require further investigations. With view of bradykinin interacting with dynorphin and nitric oxide in the CNS it is important to understand the modulating roles of bradykinin in SCI that upregulated both nitric oxide and dynorphin after trauma (see Bannister et al., 2014; Sharma, Nyberg, Gordh, et al., 1998; Sharma, Nyberg, & Olsson, 1992; Sharma, Olsson, & Nyberg, 1995; Sharma et al., 1996; Stålberg et al., 1998; Winkler, Sharma, Stålberg, & Westman, 1998). Peat on Bradykinin Direct mentions are sparse: "Bacterial endotoxin increases serotonin release from the intestine, and increases its synthesis in the brain (Nolan, et al., 2000) and liver (Bado, 1983). It also stimulates its release from platelets, and reduces the lungs' ability to destroy it. The formation of serotonin in the intestine is also stimulated by the lactate, propionate and butyrate that are formed by bacteria fermenting fiber and starch, but these bacteria also produce endotoxin. The inflammation-producing effects of lactate, serotonin, and endotoxin are overlapping, additive, and sometimes synergistic, along with histamine, nitric oxide, bradykinin, and the cytokines." "Y. Kuraishi (2015) said that noradrenaline inhibits pain by inhibiting the release of substance P and glutamate (the excitatory amino acid), and that the suppression of cancer pain results in the inhibition of tumor growth and lung metastasis..., apparently by inhibiting the release of substances from cancer cells (e.g., ATP, endothelin-1, and bradykinin). Things that activate and enliven the patient, and that at the same time decrease pain, seem to be therapeutically appropriate." A role for bradykinin signaling in chronic vulvar pain​ Chronic vulvar pain is alarmingly common in women of reproductive age and is often accompanied by psychological distress, sexual dysfunction, and a significant reduction in quality of life. Localized provoked vulvodynia (LPV) is associated with intense vulvar pain concentrated in the vulvar vestibule (area surrounding vaginal opening). To date, the origins of vulvodynia are poorly understood, and treatment for LPV manages pain symptoms, but does not resolve the root causes of disease. Until recently, no definitive disease mechanisms had been identified; our work indicates LPV has inflammatory origins, although additional studies are needed to understand LPV pain. Bradykinin signaling is one of the most potent inducers of inflammatory pain and is a candidate contributor to LPV. We report that bradykinin receptors are expressed at elevated levels in LPV patient versus healthy control vestibular fibroblasts, and patient vestibular fibroblasts produce elevated levels of proinflammatory mediators with bradykinin stimulation. Inhibiting expression of one or both bradykinin receptors significantly reduces proinflammatory mediator production. Finally, we determined that bradykinin activates NFκB signaling (a major inflammatory pathway), while inhibition of NFκB successfully ablates this response. These data suggest that therapeutic agents targeting bradykinin sensing and/or NFκB may represent new, more specific options for LPV therapy. Bradykinin in Pain & Inflammation + How to Decrease It Positive Effects of Bradykinin Although bradykinin may cause problems, it also serves an important purpose in the body. Bradykinin protects your heart and your nerves from damage. In the heart, it widens vessels and lowers blood pressure, which prevents heart failure and damage caused by high blood pressure. When the spinal cord or other nerves are injured, bradykinin protects nerve cells and prevents them from dying [15, 16]. 1) Heart Health and Blood Pressure High blood pressure can lead to heart failure. Bradykinin widens blood vessels and decreases blood pressure, which can protect the heart and keep it functioning after congestive heart failure [17, 18]. Doctors often take advantage of the protective effects of bradykinin to help patients with heart conditions. Angiotensin-converting-enzyme inhibitors, or ACEIs, are often prescribed to prevent heart failure in people with high blood pressure. ACEIs stop bradykinin from being broken down, and the increased concentration of bradykinin decreases blood pressure [15, 19]. 2) Insulin Sensitivity Bradykinin makes fat and muscle cells more sensitive to insulin, possibly by increasing the activity of insulin receptors on these cells [20]. Insulin resistance, the condition in which cells are not sensitive enough to insulin, develops before and often predicts type 2 diabetes. Because bradykinin increases the insulin sensitivity of certain cells, it may reduce the risk of developing type 2 diabetes. In turn, drugs which increase bradykinin, such as ACEIs, may prevent type 2 diabetes from developing [21, 20].

@T-3, he objected to coconut milk and cream for the same reason he objected to unrefined coconut oil—it’s potentially allergenic. Unfortunately, I’m unable to search the old RPF for a direct quote, but the exchange below is from an interview with Patrick Timpone: Patrick: What about refined bleach coconut oil or expeller pressed? Any issues there? Ray: That's the only thing I've used. Because I used to occasionally get some homemade coconut oil that was just delicious for making ice cream, coconut ice cream. With fresh coconut, it's just a fantastic taste. But it happens to be allergenic. If you have any stress problems or digestive problems, it's better to use the refined deodorized coconut oil. https://bioenergetic.life/?q=coconut+cream And below are some of Ray’s email exchanges regarding coconut and coconut oil: COCONUT [Coconut meat] "It often causes gas and irritation symptoms." [Coconut water] "If it is fresh from the coconut, it's good, also if it has been bottled without additives." [Coconut fiber: If it lowers cholesterol (study), does it also lower estrogen?] "Do you know how the fiber is manufactured, and from what? Fibrous foods can lower both absorbed cholesterol and estrogen, but some fibers are broken down by bacteria to produce estrogenic materials. The husk fiber, coir, is being sold as a food additive. I don't know whether coir has been tested for the release of lignans, which could be carcinogenic. If it's just dried coconut meat, the problem would probably just be gas from the starches." [follow-up: I have cooked finely shredded coconut meat with some sugar and I have used it occasionally and it works a lot like carrot salad for me but there was some mild gas problem. ] "I think gas is the only problem from the mature meat." COCONUT OIL "If you are using coconut oil regularly, that's a possible source of allergens, if it isn't well refined and deodorized." "Most cities have wholesale grocers that either stock it (in five gallon buckets) or can get it, and they usually charge about $50 per bucket. GloryBee in Eugene is one place I have bought it, and Tropical Traditions has a good one, called expeller expressed, non-certified, and I think it's shipped from Nevada." "It's just filtered, usually through diatomaceous earth, to remove materials other than the fat; the main problem with the unfiltered oil is that it's allergenic for many people. It also degrades quicker." [MCT OIL] "The problem lots of people have is diarrhea or other bowel reaction when they take more than a very small amount at a time. The first times I used it I smelled like a goat for several days, and even a small amount is enough for me to notice on my skin the next day." https://expulsia.com/health/emailexchanges#Coconut And for anyone who may be interested, below is a link to Ray’s article on coconut oil, along with two experiences he shares in it that match my own with coconut—better blood sugar control and leaning out. In hopes of overcoming my reliance on thyroid supplementation, I’ve been experimenting heavily with my diet since last year and in its current iteration, my caloric intake is up by 300 calories from coconut (mostly milk and young meat) and I’m down two grains of thyroid, I'm leaner/my body is tighter and I now feel hunger without symptoms of hypoglycemia. “The ability of some of the medium chain saturated fatty acids to inhibit the liver's formation of fat very likely synergizes with the pro-thyroid effect, in allowing energy to be used, rather than stored. When fat isn't formed from carbohydrate, the sugar is available for use, or for storage as glycogen. Therefore, shifting from unsaturated fats in foods to coconut oil involves several anti-stress processes, reducing our need for the adrenal hormones. Decreased blood sugar is a basic signal for the release of adrenal hormones. Unsaturated oil tends to lower the blood sugar in at least three basic ways. It damages mitochondria, causing respiration to be uncoupled from energy production, meaning that fuel is burned without useful effect. It suppresses the activity of the respiratory enzyme (directly, and through its anti-thyroid actions), decreasing the respiratory production of energy. And it tends to direct carbohydrate into fat production, making both stress and obesity more probable. For those of us who use coconut oil consistently, one of the most noticeable changes is the ability to go for several hours without eating, and to feel hungry without having symptoms of hypoglycemia. Although I had stopped using the unsaturated seed oils years ago, and supposed that I wasn't heavily saturated with toxic unsaturated fat, when I first used coconut oil I saw an immediate response, that convinced me my metabolism was chronically inhibited by something that was easily alleviated by "dilution" or molecular competition. I had put a tablespoonful of coconut oil on some rice I had for supper, and half an hour later while I was reading, I noticed I was breathing more deeply than normal. I saw that my skin was pink, and I found that my pulse was faster than normal--about 98, I think. After an hour or two, my pulse and breathing returned to normal. Every day for a couple of weeks I noticed the same response while I was digesting a small amount of coconut oil, but gradually it didn't happen any more, and I increased my daily consumption of the oil to about an ounce. I kept eating the same foods as before (including a quart of ice cream every day), except that I added about 200 or 250 calories per day as coconut oil. Apparently the metabolic surges that happened at first were an indication that my body was compensating for an anti-thyroid substance by producing more thyroid hormone; when the coconut oil relieved the inhibition, I experienced a moment of slight hyperthyroidism, but after a time the inhibitor became less effective, and my body adjusted by producing slightly less thyroid hormone. But over the next few months, I saw that my weight was slowly and consistently decreasing. It had been steady at 185 pounds for 25 years, but over a period of six months it dropped to about 175 pounds. I found that eating more coconut oil lowered my weight another few pounds, and eating less caused it to increase.” https://raypeat.com/articles/articles/coconut-oil.shtml

@LucH I take the position that JAMA frames the supposed salutary effect of omega-3s as solely based on how it is anti-inflammatory and supposedly beneficial from the standpoint that all inflammation is bad. But inflammation is part of the healing process. When there is trauma or infection, inflammation is needed to allow white blood cells inside tissues to effect repair. We see this when we get injured and we see this when there in infection. To simply say that omega-3s are good because it is anti-inflammatory is like saying all oxidative processes are bad because antioxidants are good, which isn't the case as the simplistic association is just misleading. I also don't take much stock in meta-analysis. It's like 10 dogs outnumbering humans in an election and dogs getting their candidate to win. If there are 10 flawed studies with conclusion A and only 2 good studies with a conclusion B, hands down conclusion A wins.

@AlphaCog simply its a mindset link text

@DavidPS Let's reveal what the linked article claims. "The following foods contain compounds that have been shown to increase aromatase activity, thereby increasing the production of estrogen." Beef Lamb Your argument is that beef and lamb will increase the synthesis of testosterone because of their cholesterol content, thereby increasing the amount of estrogen that will be synthesized. That's not the claim that the article makes. It claims that lamb and beef increase aromatase activity. That is a different claim than your claim that eating beef or lamb will increase the amount of estrogen synthesized. You could have a given level of aromatase activity but because there are more substrates for aromatase, you produce more estrogen. The article's claim is far more radical, though I think your claim and the article's claims are both wrong. For one, lamb and beef are high in SFA. Aromatase is most highly expressed in adipose tissue. High PUFA adipose tissue expresses more aromatase than does low PUFA adipose tissue. Insofar as lamb and beef resaturate adipose tissue, they should decrease aromatase expression. Testosterone is also a mild aromatase inhibitor, as is its metabolite DHT.

@Rah1woot @Rah1woot said in Since when decreasing brain blood flow is good?: If blood flow was truly reduced, it would not also increase oxygen consumption in the way that it does (so it goes). This is helpful, because when reading about oxygen deprivation, that's tied to pain and stress instead of vasoconstriction, though the two are similar.

@DavidPS I've thought along the same lines but struggled to fit those concepts coherently together. expression of Hmgcs2, the gene encoding rate-limiting enzyme of ketogenesis, decreases significantly in Leydig cells from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid and acetoacetic acid in young testes are substantially higher than that in serum, but significantly diminish in aged testes. Silencing of Hmgcs2 in young Leydig cells drives cell senescence and accelerated testicular aging. So what I'll do is shower you and the others with my open questions: First in line for me is the question: Why is (testicular) Hmgcs2 being downregulated in aging? Obviously feeding BHB as the end product of ketogenesis increased testosterone. Therefore the underlying mechanism can't be about sex hormone substrate availability (cholesterol). Rather, it's about a decline in ketogenesis, i.e. a tissue energy depletion: "suppression of ketogenesis impairs steroidogenic function of LCs" Is it locally or systemically/predominantly hepatically? --> The study tells us it's locally, because testicular tissue concentrations are higher than serum and "BHB andAcAc concentrations in serum were comparable between the young and the aged group (Fig. 2k, l)." "Remarkably, the concentration of ketone bodies in the testes were more than tenfold higher than that in serum (Fig. 2i–l), implying ketone bodies might have testis-specific functions" Is there a decline in peripheral fatty acid circulation as a reason for declining tissue ketogenesis? In contrast to ketone bodies, free fatty acids don't really cross the blood--brain-barrier. Do they significantly cross the blood-testis-barrier? If it's not about fatty acids as a ketogenesis substrate, is it about peripheral protein circulation levels? If it's about neither upstream substrates, is there perhaps a tissue-specific decrease of utilization to Acetyl-CoA? Is the HMGGCS2-decreasing cause founded in a lack of carnitine or a lack of CoA? Will supplementation of carnitine or stimulation of CoA then attain similar results to exogenously supplying BHB for that matter? --> The authors have followed this strain of thought and injected AAV vectors to deliver and overexpress the Hmgcs2 gene, demonstrating "that Hmgcs2 overexpression increased the levels of H3K9ac and FOXO3a in aged testicular tissue, similar to the levels in young testes" --> So it's not immediately about any substrate levels but HMGCS2 activity itself. Does this lead back to epigenetic downregulation of bodily functions, in this case HMGCS2, and the concepts of DNMTi and HDACi? --> Clearly there's a positive association between acetylation of H3K9 and HMGSC2 expression in rats in that HMGSC2 induced higher H3K9ac. Is this reciprocal, i.e. would H3K9ac also induce HMGCS2? Or does H3K9ac come about by increased concentrations of the products of HMGCS2, like BHB, and the cellular energy abundance provided by it? --> The authors followed this and found: "Consistent with in vitro results, Western blot analysis revealed that BHB increased the levels of H3K9ac and FOXO3a in aged testicular tissue, similar to the levels observed in young testes (Fig. 7d, e)." Is this then a course of gradual decline, wherein a decrease of testicular ketone energy in turn decreases its own synthesis? Just as the observation that more BHB increases its own synthesis? I.e. a positive / negative feedback loop? Would, therefore, a one time course of exogenous BHB or induced Hmgcs2 overexpression "reset" testicular ketogenesis back to a youthful level, wherefrom it may once again gradually decline? --> Well, the authors fed exogenous BHB in addition to the control diet to 18-months old rats for a duration of 2 months. Those were then 20-months old rats. Unfortunately, no subgroup to follow up on wrt to their physical activity and testicular findings has been kept and reported on beyond that. "Last, we validated the changes in FOXO3a-related inflammation genes through quantitative RT-PCR analysis, revealing that inflammation-related genes were significantly upregulated in aged mice, and Hmgcs2 overexpression reduced the expression of these genes (Supplementary Fig. 9b–e). Overall, these data suggest that enhancing ketogenesis is sufficient to alleviate LCs senescence and testicular aging in aged mice."

@yerrag Wow. Those are some additional challenges. Coincidentally, my brother just survived a 4 day hospital stay for congestive heart failure. I think your perspective of leaning on Peat and alternative counterculture, as a defense against status quo medical pathology, is the general perspective of most of us. But, just as you say, it's challenging, and can be daunting, because we are limited. I hope more alternative and naturopathic doctors adopt bioenergetic and similar principles to help those like us to bridge the gap, so we don't have to play doctor. There does seem to be a trend of some going that way. My thought is that it really won't be at its best until it's local, so we can have real-doctor support.

This is the fatty acid composition of the three fats. Margarine actually only has slightly higher PUFA content than olive oil and less MUFA than it. So overall margarine contains less unsaturated fats than olive oil does. One reason olive oil performs so well despite its high UFA content, might be its polyphenol content, containing oleocanthal, hydroxytyrosol or even small amounts of policosanol. I've talked about their pro-metabolic, testosterone enhancing effects here: https://bioenergetic.forum/topic/3624/olive-leaf-extract-increases-t3-t4-lowers-tsh?_=1748111089619 [image: 1748110991784-1000015133.png]

Canadian rancher Maggie is laughing at this study [image: 479882288_122215646534203038_8548433945113970019_n.jpg?_nc_cat=110&ccb=1-7&_nc_sid=aa7b47&_nc_eui2=AeEONy5dG5Kx5-34XHtxhRQBt5ClT8lPVV63kKVPyU9VXjMr1mkTi5uagTB2CxAehkeMCdDBREO5RBO6pNTE93Mh&_nc_ohc=46Rx1dxfwK4Q7kNvwHmX991&_nc_oc=AdmQT2HphoIoZDS5BY83m388IDQ46DPQi6doYYGDnPlUdOM_9e35SSXFjPrvkAF8swp6HaOwxtxUB8czLyOGK_S4&_nc_zt=23&_nc_ht=scontent.faep14-2.fna&_nc_gid=WOU-dhxC1Pp9RB-E-Ol0oA&oh=00_AfLaHX6bWJHfDaQa_ouMnc4b-wYLn9Thp0GkPwaUIA7U-Q&oe=68368F06]

Maybe something to do with tonicity, vascular tone and everything thereafter. Onset in reverse, I wonder what causes that. https://pmc.ncbi.nlm.nih.gov/articles/PMC11293686/ (Only a sample.) If "the next pandemic" had an energy mandate as or opposed to a vaccine mandate. I wonder what would happen.

the study in women athletes had them taking ridiculously high doses, something like 1g a day of TTFD iirc. it is dopamingeric, the first time i took a 25mg alinamin f tablet i got pronounced euphoria. it’s popular in japan.