Joint problems have never been much of an issue for me, but given some consideration, I really do have some arthritic symptoms as well. The most evident and persistent of these is the knee crackling. Whenever I try to do squats the knees always creak terribly. It is strange though that most of the time it is not even painful. When I have muscle pain it tends to be more painful though. Actually the association is very strong between these two. On one hand the joints may have to compensate for the insufficient muscle power and this puts a burden on them resulting in more wear and tear. However on the other hand I can practically feel the propagation of inflammation that starts around the prostate then extends towards the leg muscles then the joints. The knee joint is the most involved being closest to the epicenter, however whenever I work the inflammation expands due to exercise intolerance. I have often noticed whenever I had a longer work day and stronger muscle pain as a consequence the joint issues would be also worse as well. The feet joints normally don’t crackle that much, however on these occasions practically every step would involve perceptible and worrisome crackling. Fortunately the arms are less involved in muscle pain and these joints creak less as well. There were also a few times when I had managed to significantly reduce muscle pain and at these times the joints felt incredibly flexible as well. I guess this is how it should be normally if I was not under the influence of POIS constantly. This is also an age related issue as 10 or 20 years ago I was more flexible and I could more easily overcome the pain, however the intensity of POIS is clearly the most determinant factor.
Methylene blue regulates inflammatory response in osteoarthritis by noncoding long chain RNA CILinc02
The results showed that CILinc02 was overexpressed in osteoarthritic cartilage tissues and in OA primary cells, but methylene blue can inhibit the expression of CILinc02. In addition, overexpression of CILinc02 induced the inflammation and apoptosis in primary OA cells, however, the effect of methylene blue was reversed compared to CILinc02. Meanwhile, methylene blue can regulate the expression of TIMP-1, MMP-1, and MMP-13 proteins, thereby suppressing the degradation of chondrocyte in OA. This evidence indicates that methylene blue can act as an inflammatory inhibitor by targeting CILinc02 to regulate the inflammatory response.
I suspect involvement of MMPs in POIS induced joint pain/damage:
I once needed crutches for a period of two weeks because sexual arousal flares fiercly attacked my knee joints. I couldn't withstand pressure from my weight and turning corners was difficult.
https://www.reddit.com/r/POIS/comments/1bthzfv/osteoarthritis_due_to_pois/
Three weeks ago i had second mri and xray of my hip, knee and shoulde joints. According to my doc, I lost significant amount of cartilage in these joints. Every time i orgasm or get aroused, i get burning feeling in my joints along with all other symptoms.
Pois is damaging my joints and i have no choice but to see my body rotting away with time. All the time my joints make clicking sounds and pain is unbearable in hip joint# especially.
The earlier post caught my attention and so I did some research on the matter. I think the following nicely complements earlier research on the nature of the POIS inflammation, which is not so unique after all. Most of the supplements mentioned also helped other POIS symptoms as well. Unfortunately I can’t claim they had helped with joint issues that much though. Nevertheless the approach is clearly right and taking supplements marketed to be good for joint health is a necessity to slow the deterioration process. Even so the greatest hurdles are drug resistance and the power of POIS especially when induced by exercise intolerance in a daily manner. Drug resistance builds up no matter what I take be it a supplement, drug, vitamin or mineral.
Considering the research the most interesting finding is that estrogen receptor beta once again has a key role in the reduction of inflammation and thus joint health generally, thus no wonder that many of these supplements are ER beta agonists as well. It is also evident that in my case the arthritic process is due to inflammation expansion by propagating 4-hydroxynonenal and other LPOs produced by excessive lipid peroxidation following sexual activity or intense exercise. Actually this is the cause of the burning pain mentioned.
I can also share some specific experiences regarding the cited supplements. First I would really recommend Rumalaya Forte (Boswellia, Guggul, greater galangal, licorice, Tribulus, Guduchi/giloy), which contains several of these and is actually recommended for joint health. The ingredients are also testosterone boosters and Rumalaya Forte certainly boosted my libido and erection on several occasions. In the beginning it also had an anti-depressive effect, but drug resistance resulted in diminishing returns. I tried the constituents separately as well and in my opinion Guggul is the most effective generally followed by licorice, giloy, Tribulus and Boswellia in order. I believe Ecdysterone is even more powerful than Guggul and I had some nice experience in POIS reduction when combining the two. Burdock may have a similar strength as licorice and it had an anti-depressive effect on several occasions. NAC and Quercetin have a similar strength as Boswellia meaning they have a noticeable benefit, but to a lesser extent. Carnosine had a little anti-oxidant effect, however the one I took was too small in dose. I have been taking a good amount of collagen on a daily basis, but I couldn’t note it making much of a difference so far. Similarly the hyaluronic acid pills weren’t of much use. MSM works a little on POIS, while I didn’t notice anything particularly with glucosamine, however both had some benefit on my joint issues. Specifically I have some accident related chronic pain in one of my elbows and daily glucosamine sulphate was the only supplement that had managed to reduce it to a lesser extent. Nevertheless it did not solve the knee creaking and pain after work. The first time I used shark cartilage the knee joints certainly felt more flexible, however when continuously taking daily 2-3 caps the benefit was inperceptible. Maybe trying a more concentrated form of chondroitin could be worthwhile. I haven’t tested calcium d-glucarate extensively, however I could often note a general increase in crackling, though this may be a misperception as I was more aware. It did not have any other adverse effects at least, though this is strange if I consider that it should actually help with arthritis. I also found a concentrated form of curcumin to be moderately useful, however when taken in a daily manner it lost its power and I couldn’t note it being specifically useful for joint issues. I have been taking 6 mg of boron daily for more than two months. In the beginning it was certainly quite good for gut issues, but as the days passed there came a time when I was not able to tell if it made much of a difference. I have been taking daily 2-3000 IU vitamin D for several month without it making any particular difference, which was until I upped the dose to daily 10000 IU, which made me feel much better for about 2-3 days after which it was once again mostly same old POIS even tough I kept taking the increased dose. I am not sure about acteoside as Cistanche did not prove especially useful, but I could not test it extensively due to its price. However I had some positive experience with acteoside containing herbs here and there, though acteoside’s contribution is also not clear. Chinese skullcap may be slightly better than Boswellia, however it is possibly slightly toxic as well. This may be true for licorice too, but at least when taking a small daily amount (1 capsule) it was not harmful in any way. I am not really sure about papaverine, but poppy seeds are one of the worst POIS mimetics for me. At least poppy seed is known to be crazy good for bone health, though I couldn’t care less when I have a massive chest inflammation due to it.
Of course drug resistance would kill everything in a few days, afterwards which everything only provides a small benefit making it feel like a vain effort generally, but no matter how one searches they won’t find better alternatives in the treatment of their arthritic problems, so I recommend taking them in a daily manner if only to slow down the deterioration process.
Research and supplements:
Lipoxin A4 (LXA4) ameliorates knee osteoarthritis (KOA) progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes (FLSs).
Knee osteoarthritis (KOA) is a degenerative disease of the joints primarily characterized by articular cartilage degeneration, synovial inflammation, and subchondral bone remodeling. Multiple risk factors, including aging, obesity, trauma, and mechanical loading, play important roles in the pathogenesis of KOA.
Lipoxin A4 (LXA4) is a potent anti-inflammatory lipid mediator that promotes the reduction of inflammation and is considered a novel "inflammation turn-off signal".
Lysophosphatidic acid receptor-3 (LPAR3), the most widely studied receptor for LPA signaling, is regarded as the gatekeeper of mitochondrial health and protects cells from oxidative stress. LPAR3 attenuates oxidative stress by improving mitochondrial homeostasis and modulating the expression of the downstream antioxidant factor Nrf2.
Estrogen Receptor Beta (ESR2) is a classical nuclear receptor located in the nucleus that exerts "genotypic" regulatory effects by controlling the transcription of specific target genes. Currently, ESR2 has been validated to inhibit oxidative damage induced by high-glycemic conditions and promote intracellular matrix synthesis by activating the p38MAPK pathway.
Ferroptosis is an iron-dependent form of cell death that is regulated by excessive lipid peroxidation. Several studies have indicated the occurrence of ferroptosis in damaged areas of the synovium in patients with KOA with lipid peroxidation levels higher in these patients than in healthy individuals.
After IL-1B treatment, the levels of synovial inflammation-related destructive markers MMP3 and MMP13, as well as the ferroptosis marker COX2, were significantly increased; the levels of HO-1 and Nrf2 were upregulated, while the levels of SOD1 and GPX4 were downregulated.
FLSs treated with IL-1B exhibited decreased mitochondrial membrane potential, increased mitochondrial and intracellular ROS levels, and aggregation of intracellular Fe2+.
We found that ESR2 can act as a transcription factor (TF) of LPAR3, and co-expression analysis showed they were strongly associated. We observed that after ESR2 overexpression, the expression of LPAR3 was also significantly increased. Among the destructive markers, the expressions of COX2, MMP13, and MMP3 were downregulated, while the levels of the antioxidant factors Nrf2, HO-1, and GPX4 were upregulated; the level of SOD1 did not significantly change.
The results showed that LXA4 treatment elevated ESR2 and LPAR3 levels to attenuate ferroptosis in FLSs, ultimately alleviating chondrocyte ECM degeneration and inflammatory responses.
In the co-culture system, LXA4 upregulated both ESR2 and LPAR3 levels in FLSs. In vitro experiments, knockdown of the LPAR3 gene reversed the inhibition of ferroptosis by ESR2 gene overexpression in FLSs. This reinforces our conclusion that ESR2 exerts anti-inflammatory and antioxidant effects in FLSs after IL-1B intervention, and that these effects depend on the normal function of its downstream target, LPAR3.
These findings reveal that exercise can alleviate KOA lesions by inhibiting synovial ferroptosis by elevating LXA4 levels and that this therapeutic effect is partially dependent on the function of ESR2, a novel intracellular receptor for LXA4.https://www.sciencedirect.com/science/article/pii/S2213231724001198Studies have shown that antioxidant agents, such as N-acetyl-cysteine or nuclear GSTA4-4, can suppress 4-Hydroxynonenal (HNE) production, and inhibit apoptosis in cell lines. In a recent study, we observed that there are significantly more HNE-protein adducts in osteoarthritic (OA) synovial fluid compared to normal subjects. HNE binds to the matrix metalloproteinase 13 (MMP-13) in vitro. It also induces a post-translational modification (PTM) of type II collagen (COLII), both of which resulting in the degradation of the articular cartilage in OA. During cartilage degeneration, HNE is produced in OA synovial cells. In vitro HNE binding to MMP-13 activated the enzyme, and HNE modification of COL2 accelerated its degradation by MMP-13. Increased levels of HNE in OA cartilage and the ability of HNE to induce transcriptional modifications and PTMs of COL2 and MMP-13 suggest HNE is involved in OA. In addition, in vitro formation of HNE-COL2 resulted in multiple phenotypic abnormalities of OA chondrocytes. However, the dipeptide carnosine, an efficient HNE-trapping agent, was able to counteract these effects.https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S1874391920303924The hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by Epas1) is the catabolic transcription factor in the osteoarthritic process. Ecdysteroids (Ecd) can reduce the IL-1B-induced inflammatory effect of the cartilage. Ecd may suppress IL-1B- induced cartilage catabolism via HIF-2a pathway.
HIF-2a directly induces chondrocytes expression of genes encoding catabolic factors, such as matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS-2) and prostaglandin-endoperoxide synthase-2. According to this paradigm, a stress-induced increase in the activity of HIF-2a will overshadow the beneficial effects of the closely related HIF-1a, then push the chondrocytes in the joint toward a more differentiated state known as hypertrophy, which then drives osteoarthritis changes.https://link.springer.com/article/10.1186/s12906-015-0520-zTissue damage and destruction are the key mechanisms of progressive arthritis and is attributed to the combined actions of matrix metalloproteinases (MMPs), hyaluronidases (HAase), aggrecanases and exoglycosidases. Furthermore, reactive oxygen species (ROS) and pro-inflammatory mediators like tumor necrosis factor-a (TNF-a), interleukin (IL)-1B, IL-6, cyclooxygenase-2 (COX-2) and other cytokines significantly contribute by stimulating inflammatory signaling cascades.
Hematological analysis revealed substantial elevation of WBC count and reduced RBC and platelet counts, and Hb levels in arthritis-induced animals. However, oral administration of guggulipid (GL) (100 mg/kg) significantly mitigated the altered hematological parameters.
Immunoblots of serum MMPs further confirmed elevated levels of MMP-1, -3, -9 and -13 in arthritic rats. Interestingly, oral administration of GL significantly inhibited the elevated levels of HAase and MMPs in both serum and ankle joint bone homogenates. Results were more pronounced in arthritic rats treated with GL (100 mg/kg) in comparison with standard NSAID control ibuprofen.
Immunoblots of the serum and liver homogenate showed significant elevation in the levels of TNF-a, IL-1B, IL-6, IL-23 and COX-2 in arthritis-induced group. In contrast, the anti-inflammatory cytokine IL-10 was significantly reduced in both serum and liver homogenate of arthritis-induced group.
Elevated levels of articular cartilage and subchondral bone degrading enzymes such as MMPs, HAase, exoglycosidases, TRAP, cathepsins, ACP and ALP are confirmed by several studies and are considered as most serious concern in progressive arthritis.https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0944711319300935In the group of rats treated with 5-Loxin, a standardized Boswellia serrata extract, the suppression of inflammatory enzymes such as cyclooxygenase (COX)-2 and 5-lipoxygenase (LOX) resulted in a significant reduction in the prostaglandin (PG) E2 and leukotriene (LT) B4 levels. Moreover, 5-Loxin ameliorated the deterioration of the main components of the articular extracellular matrix (ECM), such as glycosaminoglycans (GAGs) and aggrecan, through the downregulation of matrix metalloproteinases (MMPs). These findings suggest that 5-Loxin may be a potential therapeutic agent for the treatment of osteoarthritis (OA). The loss of aggrecan, a cartilage-specific proteoglycan core protein, and an increase in matrix metalloproteinases (MMPs), which degrade collagen, are closely associated with OA.
A previous in vitro study indicated that 5-Loxin could potentially inhibit TNF-a-induced expression and activity of MMPs such as MMP-3, MMP-10, and MMP-12 in human microvascular endothelial cells. In another study, which examined the effects of 5-Loxin on OA of the knee joint, 5-Loxin was well tolerated and exerted its therapeutic effect by reducing levels of synovial MMP-3. 5-Loxin (200?mg/kg) treatment significantly suppressed the MIA-mediated increases in MMP-2, MMP-3, and MMP-13 gene expression in the cartilage tissue.
High levels of MMP-13 and gelatinase can cause degradation of the basement membrane. In this study, we demonstrated that 5-Loxin-mediated suppression of COX-2 and 5-LOX led to a significant decrease in PGE2 and LTB4. Moreover, the inhibition of inflammatory cytokines, including TNF-a, IL-1B, and IL-6, by 5-Loxin treatment resulted in a reduction in levels of cartilage-degrading enzymes, MMP-2 and 13, within both the serum and cartilage tissue.https://www.hindawi.com/journals/ecam/2022/3067526/Oral administration of Boswellia serrata gum resin (FJH-UBS) (80 mg/kg BW/day) reduced monosodium iodoacetate (MIA)-induced knee swelling and cartilage degradation and increased the expression of type II collagen and aggrecan in articular cartilage. Furthermore, FJH-UBS administration reduced MIA-induced increases in the serum levels of prostaglandin E2, leukotriene B4, interleukin (IL)-1B, IL-6, and MMP-13, and MIA-induced increases in the mRNA expressions of inducible nitric oxide synthase, cyclooxygenase-2, 5-lipoxygenase, IL-1B, IL-6, TNF-a, MMP-2, MMP-9, and MMP-13 in the synovia of knee joints.https://koreascience.kr/article/JAKO202322047091847.pageHypertrophic differentiation of chondrocytes is characterized by the increased expression of RUNX2, Collagen X, VEGFA, and MMP-13 and the decreased expression of cartilage-specific markers, such as Collagen II and SOX9.
Kaempferol, glabridin, and isoliquiritigenin have the potential to interact with important proteins in the pathogenesis of OA such as MMP-13, SOX9, COL2A1, and COL10A1.
Although there are adverse effects, non-steroidal anti-inflammatory drugs (NSAIDs) have been important treatments for OA. However, these drugs only provide temporary relief from clinical symptoms and fail to prevent the progression of OA.
RUNX2 is a key regulator of chondrocyte hypertrophy, which plays a role in OA development and is involved in the increase of Collagen X, VEGFA, and MMP-13 expression. Collagen X is produced by hypertrophic chondrocytes. MMP-13 is a matrix metalloproteinase that degrades Collagen II. VEGFA, a well-known angiogenic factor expressed by hypertrophic chondrocytes, is required for chondrocytes survival, cartilage angiogenesis, and endochondral bone development. In the current study, hypertrophy markers including the RUNX2, Collagen X, VEGFA, and MMP-13 levels which were significantly elevated following IL-1B stimulation were downregulated by Licorice (WG) treatment. Whereas, WG induced Collagen II expression inhibited by IL-1B. Hence, according to the results, WG exhibited protective effects against IL-1B-induced chondrocytes by alleviating the hypertrophic transition.
Quercetin increased tissue inhibitors of metalloproteinases-1 and superoxide dismutase and decreased MMP-13 expression which attenuated the progression of OA through inhibiting oxidative stress and cartilage degradation. Glabridin prevented the apoptosis of human chondrocytes from oxidative stress by inducing autophagy in an mTOR-dependent manner. Isoliquiritigenin is a flavonoid compound that exerts anti-cancer, anti-inflammatory, anti-diabetic, hepatoprotective, and cardioprotective effects. Isoliquiritigenin attenuated cartilage destruction in ACLT-induce OA mice by downregulating the Collagen X and MMP-13 levels.https://www.mdpi.com/1424-8247/14/12/1337After treatment with Alpinia galanga extracts, MMP-2 activity in the culture medium was significantly reduced. In addition, MMP-1, MMP-3, MMP-13, and Cox-2 expression were downregulated. Therefore, A. galanga extracts might be a promising therapeutic agent for arthritis.https://link.springer.com/article/10.1007/s11626-010-9375-2Arctigenin (burdock) significantly inhibited proliferation, invasion, and the stemness of cancer cells via decreasing the tumor-promoting cytokines GM-CSF, MMP-3, MMP-9, and TSLP both in murine mammary cancer cell line and in human breast cancer cell tumor-bearing BALB/c female mice.https://www.researchgate.net/profile/Shalini-Singh-96/publication/366524547_Arctigenin_A_Potential_Component_with_Multifaceted_Therapeutic_Properties/links/63a962f9c3c99660eba7041a/Arctigenin-A-Potential-Component-with-Multifaceted-Therapeutic-Properties.pdfAvocado/soybean unsaponifiables showed some promise for OA. It was demonstrated that treatment with avocado/soybean unsaponifiables could reduce the development of early structural changes in an experimental OA dog model. This effect appears to be mediated through the inhibition of inducible nitric oxide synthase (iNOS) and MMP-13, which are key mediators of the structural changes that take place in OA.
It could be concluded that the combination of methylsulfonylmethane (MSM) with glucosamine provided better and more rapid improvement in patients with OA. Glucosamine, chondroitin and hyaluronic acid are basic components of the cartilage extracellular matrix, and viscous synovial fluid. Although glucosamine, chondroitin, and hyaluronic acid can be synthesized by chondrocytes and synoviocytes, they may also be consumed via diet.
Although some of the literature has failed to show significant benefits of glucosamine supplementation over placebo or NSAIDs, the totality of the available preclinical and clinical evidence suggests that glucosamine can improve joint pain and function, reduce risk of total joint replacement, and encourage regeneration by decreasing and stabilizing cartilage degradation consistent with reversing the pathology of OA.https://sci-hub.st/https://www.sciencedirect.com/science/article/abs/pii/S0968089615004095In human research, IL-1 is the main cytokine instigator of cartilage degeneration in cases of arthritis. IL-1 induces MMP-3 and MMP-13 RNA and protein in chondrocytes through the activation of mitogen-activated protein kinase (MAPK), AP-1 and NF-kB transcription factors. Based on human studies, curcumin resulted in 48-99% suppression of MMP-3, 45-97% of MMP-13 in human and 8-100% MMP-3 and 32-100% MMP-13 in bovine chondrocytes. Evidently, inhibition of IL-1 signal transduction could be useful for reducing cartilage resorption by MMP’s in cases of arthritis.https://www.jstage.jst.go.jp/article/jat/14/2/14_2_51/_pdfBoric Acid (BA) shows potential efficacy in reducing inflammation in experimental knee osteoarthritis (KOA) model in rats. Random assignment was performed for the experimental groups as follows: group-1(control), group-2(KOA control), group-3 (BA:4 mg/kg, orally), group-4(BA:10 mg/kg, orally), group-5(BA:4 mg/kg, intra-articularly), and group-6(BA:10 mg/kg, intra-articularly). Group-2 exhibited higher serum IL-1B and TNF-a levels and MMP-13 activity than group-1. However, IL-1B and TNF-a levels and MMP-13 activity were lower in all treatment groups than in group-2, with statistically significant reductions observed in groups-4, 5, and 6.https://link.springer.com/article/10.1007/s12011-023-03872-0Vitamin D Inhibits Activities of Metalloproteinase-9/-13 in Articular Cartilage In Vivo and In Vitro. Low levels of serum vitamin D have been shown to accelerate progression of osteoarthritis.
The in vivo study showed vitamin D deficiency increased the expressions of MMP-9 and MMP-13 in rat articular cartilage, and the increase was inhibited by 1a,25(OH)2D3 supplementation.https://www.jstage.jst.go.jp/article/jnsv/65/2/65_107/_articleKhan et al. demonstrated that wogonin (Chinese skullcap) was able to protect chondrocytes through the amelioration of oxidative stress, inflammation, and matrix degradation at the molecular level. Furthermore, Park et al. reported that wogonin would target the MMP-3 on articular chondrocytes to play a protective role. Here, it was suggested that wogonin would regulate NGF signaling pathway and anti-inflammation effect may be the primary mechanism underlying its therapeutic effects.https://www.hindawi.com/journals/mi/2023/4436587/Osteoarthritis is characterized by low chronic inflammatory joint diseases. Acteoside (AC) has been shown to ameliorate IL-1B-induced MMP-13, MMP-3, and MMP-1 expression by decreasing the activity of MAPK/NF-kB signaling pathway in the primary rat chondrocytes. Consistently, AC inhibits IL-1B-induced IL-6, IL-12, TNFa, and IFNg expression, enhances chondrocyte proliferation, and attenuates cell apoptosis by down regulating the activity of JAK/STAT pathway. In addition, AC also ameliorates synovial inflammation in osteoarthritic rats. The expression of P2X7R, MMP-13, substance P, and PGE2 are higher in rat OA chondrocytes, and these alterations can be reversed by treatment with AC through inactivation of NF-kB signaling pathway. In collagen-induced arthritis mice, the cartilage destruction, synovial hyperplasia, and the expression of MMP-9, MMP-13, and ADAMTS-4/-5 can be significantly alleviated by Fufang Shatai Heji, which includes AC as one of the major active compounds.https://www.sciencedirect.com/science/article/pii/S0753332222006850In the subacute MPTP/P animal model of Parkinson’s disease, the data revealed that papaverine reduces neuroinflammation and MMP-3 production, which prevents dopaminergic neuronal cell death and alpha-synuclein aggregation.https://www.mdpi.com/1420-3049/28/7/3149Among numerous natural food substances tested in experimental studies, D-glucaric acid and its derivatives indicate B-glucuronidase (B-G) inhibitor activity in humans and are suggested to reduce cancer risk.
Serum levels of proinflammatory cytokines such as interleukin-1 and C-reactive protein correlate well with B-G activity in the serum from patients with inflammatory disorders.
D-glucaric acid is converted into D-glucaro-1,4-lactone, the substance which competitively inhibits B-G and reveals the capacity to reduce mammary, skin, liver, colon, lung and oral cancers in animals. Interestingly, these natural, nontoxic agents have been also used with several therapeutic approaches including cholesterol reduction, diabetes treatment, rheumatoid arthritis and protective activity against oxidative/nitrative damage of plasma protein.
Activity of calcium D glucarate (CG) is believed to drive from gradual conversion of about one-third of this agent to the B-glucuronidase inhibitor, D-glucaro-1,4-lactone, at the low pH of the stomach. D-glucaro-1,4-lactone, competitively inhibits B-G and has been indicated to reduce chemically induced mammary, liver, skin, oral carcinogenesis in animals.
The obtained data revealed that dietary CG diminished gradually serum level of TNFa, IL-6 and IL-12p70. Dietary CG markedly inhibited COX-2 activity.https://www.researchgate.net/profile/Zofia-Kilianska/publication/313403382_Pleiotropic_effects_of_calcium-glucarate_on_chemically-induced_lung_carcinogenesis_in_AJ_mice/links/5899d091a6fdcc32dbdea1c2/Pleiotropic-effects-of-calcium-glucarate-on-chemically-induced-lung-carcinogenesis-in-A-J-mice.pdfPatients with rheumatoid arthritis (RA) were characterized by significantly elevated activities of B-D-glucuronidase and B-D-N-acetyl-glucosaminidase in SF compared with patients with osteoarthritis, seronegative spondylarthritis, or acute sports injury.
In joint diseases, the major clinical symptoms and disability of patients are caused by an irreversible destruction of hyaline cartilage. Enzymes capable of degrading extracellular matrix components (collagen and aggrecan) and concomitantly exposing chondrocytes to a variety of cytotoxic and apoptosis-inducing factors are considered to be the major effector molecules in cartilage degradation. Active proteases are currently implicated in the destructive processes and include matrix metalloproteinases (MMPs), the ADAM family, the ADAM-TS family, and serine proteases (elastase, cathepsins, and granzymes). Of the 4 groups of MMPs, collagenase (MMP-1 in particular) appears to be responsible for the degradation of interstitial collagens. The gelatinases (including MMP-2 and MMP-9) degrade the denatured form of collagens, thus acting in synergy with MMP-1. The stromelysins (including MMP-3) have a broader substrate specificity for non–connective tissue components.https://acrjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/art.11093MMP families can be divided into 6 groups: collagenases (MMP-1, MMP-8, MMP-13 and MMP18), stromalysines (MMP-3, MMP-10 and MMP-11)…https://scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Orientin+inhibits+invasion+by+suppressing+MMP-9+and+IL-8+expression&btnG=During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.
Moreover, several cytokines and growth factors have been demonstrated to affect Mmp13 gene expression, including parathyroid hormone, IGF-1, TGF-B, hepatocyte growth factor and many inflammatory cytokines such as IL-1a and IL-1B.https://en.wikipedia.org/wiki/Matrix_metallopeptidase_13Oxidative injury to the outermost layers of the skin can initiate localized inflammatory responses, resulting in the recruitment of phagocytes and their tightly regulated, cellspecific NAD(P)H-oxidase systems for generating oxidants, further amplifying the oxidative stress damage.
Cigarette smoke (CS) is able to affect skin aging by activating MMPs in the connective tissues. For instance, MMP-1 induces the degradation of both collagen and elastic fibers. In addition, production of the procollagen types I and III is affected by CS, while MMP-1 and MMP-3 are strongly induced.https://www.researchgate.net/profile/Roxane-Prieux/publication/333096253_Involvement_of_4-hydroxy-2-nonenal_in_pollution-induced_skin_damage/links/5e1238fe92851c8364b26db7/Involvement-of-4-hydroxy-2-nonenal-in-pollution-induced-skin-damage.pdfSeveral SASP factors, including IL-6, IL-1B, TNF-a, MMP-1, MMP-3, and MMP-10, have also been found to be elevated in the cerebrospinal fluid (CSF) and serum of AD patients.https://www.frontiersin.org/articles/10.3389/fnagi.2020.00148/full
