Sports Recovery Program
Research & Studies

Molecular hydrogen in sports medicine: New therapeutic perspectives

“Roughly a dozen human clinical trials demonstrated promising therapeutic effects of hydrogen, with the application in sports medicine focusing on H2 as a novel ergogenic and alkalizing agent. Hydrogen delivered through H2-dissolved water seems to increase muscular performance, decrease fatigue and improve exercise induced acidosis in athletes, but its effects are probably not due to the antioxidant properties of H2. Promising results from clinical trials involving sports injury affirm the use of H2 as an antiinflammatory and recovery aid.

 

Ostojic, S. (2014). Molecular hydrogen in sports medicine: New therapeutic perspectives. International Journal of Sports Medicine, 36(4), 273-279. doi: 10.1055/s-0034-1395509

 

Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries


“Oral and topical hydrogen intervention was found to augment plasma viscosity decrease as compared with the control group (P = 0.04). Differences were found for range-of-motion recovery between the 3 groups; oral and topical hydrogen intervention resulted in a faster return to normal joint range of motion for both flexion and extension of the injured limb as compared with the control intervention (P < 0.05). These preliminary results support the hypothesis that the addition of hydrogen to traditional treatment protocols is potentially effective in the treatment of soft tissue injuries in male professional athletes.”

Ostojic, S. M., Vukomanovic, B., Calleja-Gonzalez, J., & Hoffman, J. R. (2014). Effectiveness of oral and topical hydrogen for sports-related soft tissue injuries. Postgraduate Medicine, 126(5), 188-196. doi: 10.3810/pgm.2014.09.2813

 

Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases


“Effects of molecular hydrogen have been observed essentially in all the tissues and disease states including the brain, spinal cord, eye, ear, lung, heart, liver, kidney, pancreas, intestine, blood vessel, muscle, cartilage, metabolism, perinatal disorders, and inflammation/allergy.”

Ohno, K., Ito, M., Ichihara, M., & Ito, M. (2012). Molecular hydrogen as an emerging therapeutic medical gas for neurodegenerative and other diseases. Oxidative Medicine and Cellular Longevity, 2012, 1-11. doi: 10.1155/2012/353152

 


Hydrogen supplementation of preservation solution improves viability of osteochondral grafts

 

“In the present study, hydrogen gas was evaluated as a potential material for improving osteochondral tissue quality during long-term storage due to its antiapoptotic and anti-inflammatory effects associated with its antioxidant properties. The continuous delivery of hydrogen to culture medium improved osteochondral grafts viability during cold preservation. The present findings suggest that osteochondral grafts preserved in hydrogen-rich culture media are a promising material for cartilage repair in the clinical setting.”

 

Yamada, T., Uchida, K., Onuma, K., Kuzuno, J., Ujihira, M., Inoue, G., … Takaso, M. (2014). Hydrogen supplementation of preservation solution improves viability of osteochondral grafts. The Scientific World Journal, 2014(109876), 1-7.doi: 10.1155/2014/109876

 


Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide

 

“These results imply that one of the functions of H2 exhibits cytoprotective effects and transcriptional alterations through reducing ONOO-. Novel pharmacological strategies aimed at selective removal of ONOO- may represent a powerful method for preventive and therapeutic use of H2 for joint diseases. Cartilage has no blood vessels and nutrients are supplied through fluid. Since H2 has a great advantage to rapidly diffuse into tissues even without blood flow, it may be useful to prevent joint diseases by reducing oxidative stress and by suppressing the decrease in matrix proteins and inhibiting degradation by proteinases.”

 

Hanaoka, T., Kamimura, N., Yokota, T., Takai, S., & Ohta, S. (2011). Molecular hydrogen protects chondrocytes from oxidative stress and indirectly alters gene expressions through reducing peroxynitrite derived from nitric oxide. Medical Gas Research, 1(18), 1-8. doi: 10.1186/2045-9912-1-18

 


Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells

 

“The bone protective effects of the hydrogen molecule (H2) have been demonstrated in several osteoporosis models. Hydrogen molecules prevented RANKL-induced osteoclast differentiation associated with inhibition of reactive oxygen species formation and inactivation of NF-κB, mitogen-activated protein kinase and AKT pathways.”

 

Li, D., Zhang, Q., Dong, X., Li, H., & Ma, X. (2013). Treatment with hydrogen molecules prevents RANKL-induced osteoclast differentiation associated with inhibition of ROS formation and inactivation of MAPK, AKT and NF-kappa B pathways in murine RAW264.7 cells. Journal of Bone and Mineral Metabolism, 32(5), 494-504. doi: 10.1007/s00774-013-0530-1

 


Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast

 

“Tumor necrosis factor-alpha (TNFα) plays a crucial role in inflammatory diseases such as rheumatoid arthritis and postmenopausal osteoporosis. Recently, it has been demonstrated that hydrogen gas, known as a novel antioxidant, can exert therapeutic anti-inflammatory effect in many diseases. Treatment with H(2) alleviates TNFα-induced cell injury in osteoblast through abating oxidative stress, preserving mitochondrial function, suppressing inflammation, and enhancing NO bioavailability.”

 

Cai, W., Zhang, M., Yu, Y., & Cai, J. (2012). Treatment with hydrogen molecule alleviates TNFα-induced cell injury in osteoblast. Molecular and Cellular Biochemistry, 373(1-2), 1-9. doi: 10.1007/s11010-012-1450-4
 


Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats

 

“Treatment with HW alleviated HLS-induced reduction of bone mineral density, ultimate load, stiffness, and energy in femur and lumbar vertebra. Treatment with HW alleviated HLS-induced augmentation of malondialdehyde content and peroxynitrite content and reduction of total sulfhydryl content in femur and lumbar vertebra. Treatment with molecular hydrogen alleviates microgravity-induced bone loss through abating oxidative stress, restoring osteoblastic differentiation, and suppressing osteoclast differentiation and osteoclastogenesis.”

 

Sun, Y., Shuang, F., Chen, D. M., & Zhou, R. B. (2012). Treatment of hydrogen molecule abates oxidative stress and alleviates bone loss induced by modeled microgravity in rats. Osteoporosis International, 24(3), 969-978. doi: 10.1007/s00198-012-2028-4

 


Impact of oxidative stress on exercising skeletal muscle


“It is well established that muscle contractions during exercise lead to elevated levels of reactive oxygen species (ROS) in skeletal muscle. These highly reactive molecules have many deleterious effects, such as a reduction of force generation and increased muscle atrophy. Chronic oxidative stress is associated with an increase in protein loss and muscle atrophy.”

Steinbacher, P., & Eckl, P. (2015). Impact of oxidative stress on exercising skeletal muscle. Biomolecules, 5(2), 356–377. doi: 10.3390/biom5020356

 


Exercise-induced oxidative stress: Cellular mechanisms and impact on muscle force production

 

“Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species promote contractile dysfunction resulting in muscle weakness and fatigue. Ongoing research continues to probe the mechanisms by which oxidants influence skeletal muscle contractile properties and to explore interventions capable of protecting muscle from oxidant-mediated dysfunction.”

 

Powers, S. K., & Jackson, M. J. (2008). Exercise-induced oxidative stress: Cellular mechanisms and impact on muscle force production. Physiological Reviews, 88(4), 1243-1276. doi: 10.1152/physrev.00031.2007

 


Optimal management of ulnar collateral ligament injury in baseball pitchers

 

“Nonsurgical interventions are typically split into two phases. During Phase I, the patient is treated symptomatically. The goal of this phase is to manage pain and inflammation and restore normal range of motion.”

Hibberd, E. E., Brown, J. R., & Hoffer, J. T. (2015). Optimal management of ulnar collateral ligament injury in baseball pitchers. Open Access Journal of Sports Medicine, 6, 343–352. doi: 10.2147/OAJSM.S71326

 


Modulation of inflammation by vitamin E and C supplementation prior to anterior cruciate ligament surgery

 

“Muscle atrophy commonly follows anterior cruciate ligament (ACL) injury and surgery. Proinflammatory cytokines can induce and exacerbate oxidative stress, potentiating muscle atrophy. In summary, our findings show that circulating inflammatory cytokines increase and antioxidant supplementation attenuated the increase in IL-10 in patients post-ACL surgery.”

 

Barker, T., Leonard, S. W., Trawick, R. H., Martins, T. B., Kjeldsberg, C. R., Hill, H. R., & Traber, M. G. (2009). Modulation of inflammation by vitamin E and C supplementation prior to anterior cruciate ligament surgery. Free Radical Biology and Medicine, 46(5), 599-606. doi: 10.1016/j.freeradbiomed.2008.11.006

 


Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine

 

“The numerous publications on its biological and medical benefits revealed that H2 reduces oxidative stress not only by direct reactions with strong oxidants, but also indirectly by regulating various gene expressions. Moreover, by regulating the gene expressions, H2 functions as an anti-inflammatory and anti-apoptotic, and stimulates energy metabolism.”

 

Ohta, S. (2014). Molecular hydrogen as a preventive and therapeutic medical gas: Initiation, development and potential of hydrogen medicine. Pharmacology & Therapeutics, 144(1), 1-11. doi: 10.1016/j.pharmthera.2014.04.006

 


The basic science of tendinopathy

“The cells in tendinopathic tendon are rounder, more numerous, and show evidence of oxidative damage and more apoptosis. These studies suggest prevention of tendinopathy should be directed at reducing the volume of repetitive loads to below that which induces oxidative-induced apoptosis and cartilage-like genes.”

Xu, Y., & Murrell, G. A. C. (2008). The basic science of tendinopathy. Clinical Orthopaedics and Related Research, 466(7), 1528–1538. doi: 10.1007/s11999-008-0286-4

 


Cytokines and apoptosis in supraspinatus tendinopathy


“Based on observations that increased cytokine expression has been demonstrated in cyclically-loaded tendon cells we hypothesised that because of their role in oxidative stress and apoptosis, pro-inflammatory cytokines may be present in rodent and human models of tendinopathy. We further confirmed significantly increased levels of cytokine and apoptotic genes in human supraspinatus and subscapularis tendon harvested from patients with rotator cuff tears (p = 0.0008). These findings suggest that pro-inflammatory cytokines may play a role in tendinopathy and may provide a target for preventing tendinopathies.”

Millar, N. L., Wei, A. Q., Molloy, T. J., Bonar, F., & Murrell, G. A. (2009). Cytokines and apoptosis in supraspinatus tendinopathy. Journal of Bone and Joint Surgery - British Volume, 91(3), 417-424. doi: 10.1302/0301-620x.91b3.21652

 

Molecular hydrogen as a novel antioxidant: Overview of the advantages of hydrogen for medical applications

 

“Moreover, by regulating gene expression, H2 functions as an anti-inflammatory, antiallergic, and antiapoptotic molecule, and stimulates energy metabolism. Since most drugs specifically act on their specific targets, H2 seems to differ from conventional pharmaceutical drugs. Owing to its great efficacy and lack of adverse effects, H2 has potential for clinical applications for many diseases.”


Ohta, S. (2015). Molecular hydrogen as a novel antioxidant: Overview of the advantages of hydrogen for medical applications. Methods in Enzymology, 555, 289-317. doi: 10.1016/bs.mie.2014.11.038

 


Oxidative stress in secondary osteoarthritis: From cartilage destruction to clinical presentation?

 

“The data from literature indicates a link between free radical burden and OA pathogenesis mediating local tissue reactions between the joint compartments. Hence, oxidative stress is likely not only to promote cartilage destruction but also to be involved in inflammative transformation, promoting the transition from clinically silent cartilage destruction to apparent OA. ROS induced by exogenous factors such as overload, trauma, local intraarticular lesion and consecutive synovial inflammation cause cartilage degradation.”

 

Ziskoven, C., Jäger, M., Zilkens, C., Bloch, W., Brixius, K., & Krauspe, R. (2010). Oxidative stress in secondary osteoarthritis: From cartilage destruction to clinical presentation? Orthopedic Reviews, 2(2), 95-101. doi: 10.4081/or.2010.e23

 

Vulnerability to ROS-induced cell death in ageing articular cartilage: The role of antioxidant enzyme activity

 

“Substantial loss of chondrocytes occurs in rat articular cartilage which may result from increased vulnerability to elevated intracellular ROS levels, consequent upon a decline in antioxidant defense.”

 

Jallali, N., Ridha, H., Thrasivoulou, C., Underwood, C., Butler, P., & Cowen, T. (2005). Vulnerability to ROS-induced cell death in ageing articular cartilage: The role of antioxidant enzyme activity. Osteoarthritis and Cartilage, 13(7), 614-622. doi: 10.1016/j.joca.2005.02.011
 


The role of reactive oxygen species in homeostasis and degradation of cartilage

 

“Some intracellular signaling pathways are redox sensitive and ROS are involved in the regulation of the production of some biochemical factors involved in cartilage degradation and joint inflammation. Further, ROS may cause damage to all matrix components, either by a direct attack or indirectly by reducing matrix components synthesis, by inducing apoptosis or by activating latent metalloproteinases. This review of the literature supports the concept that ROS are not only deleterious agents involved in cartilage degradation, but that they also act as integral factors of intracellular signaling mechanisms.”

 

Henrotin, Y., Bruckner, P., & Pujol, J. (2003). The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis and Cartilage, 11(10), 747-755. doi: 10.1016/s1063-4584(03)00150-x

 

A review of hydrogen as a new medical therapy

 

“In the past few years many initial and subsequent clinical studies have demonstrated that hydrogen can act as an important physiological regulatory factor to cells and organs on the antioxidant, anti-inflammatory, anti-apoptotic and other protective effects. So far several delivery methods applied in these studies have proved to be available and convenient, including inhalation, drinking hydrogen-dissolved water and injection with hydrogen-saturated saline.”

 

Zhang, J., Liu, C., Zhou, L., Qu, K., Wang, R., Tai, M., . . . Wang, Z. (2012). A Review of hydrogen as a new medical therapy. Hepatogastroenterology, 59(116), 1026-1032. doi: 10.5754/hge11883

 

Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: Oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function

 

“Our findings clearly show that the presence of oxidative stress induces telomere genomic instability, replicative senescence and dysfunction of chondrocytes in OA cartilage, suggesting that oxidative stress, leading to chondrocyte senescence and cartilage ageing, might be responsible for the development of OA. New efforts to prevent the development and progression of OA may include strategies and interventions aimed at reducing oxidative damage in articular cartilage.”

 

Yudoh, K., Nguyen, V. T., Nakamura, H., Hongo-Masuko, K., Kato, T., & Nishioka, K. (2005). Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: Oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. Arthritis research and therapy, 7(2), 380-391. doi: 10.1186/ar1499

 

Oxidative stress induces senescence in chondrocytes

 

“Taken together, oxidative stress considerably accelerated telomere shortening and cellular aging in chondrocytes. Senescent cells showed a reduced tolerance to oxidative stress.”

 

Brandl, A., Hartmann, A., Bechmann, V., Graf, B., Nerlich, M., & Angele, P. (2011). Oxidative stress induces senescence in chondrocytes. Journal of Orthopaedic Research, 29(7), 1114-1120. doi: 10.1002/jor.21348

 

Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals

“Hydrogen selectively reduces the hydroxyl radical, the most toxic free radical, and effectively protects cells. It does not react with free radicals that have physiological benefits, making it an incredibly effective therapy to neutralize acute oxidative stress.”

 

Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., . . . Ohta, S. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13(6), 688-694. doi: 10.1038/nm1577

 


Contribution of oxidative stress to the degeneration of rotator cuff entheses

 

“Sod1 deficiency-induced degeneration is associated with impaired elasticity in the supraspinatus tendon enthesis, recapitulating human rotator cuff degeneration. These results suggest that intracellular oxidative stress contributes to the degeneration of rotator cuff entheses.”

Morikawa, D., Itoigawa, Y., Nojiri, H., Sano, H., Itoi, E., Saijo, Y., . . . Shimizu, T. (2014). Contribution of oxidative stress to the degeneration of rotator cuff entheses. Journal of Shoulder and Elbow Surgery, 23(5), 628-635. doi: 10.1016/j.jse.2014.01.041

 


Rotator cuff degeneration etiology and pathogenesis

 

“Oxidative stress leads to tenocyte apoptosis via the JNK-MMP pathway and likely contributes to further tendon degeneration.”

 

Nho, S. J., Yadav, H., Shindle, M. K., & MacGillivray, J. D. (2008). Rotator cuff degeneration etiology and pathogenesis. The American Journal of Sports Medicine, 36(5), 987-993. doi: 10.1177/0363546508317344

 


Hydrogen treatment protects against cell death and senescence induced by oxidative damage

“Thus, this study showed the antioxidant and anti-senescence effects of hydrogen water. Nanoparticle hydrogen water is potentially a potent anti-aging agent.”

Han, A. L., Park, S., & Park, M. S. (2017). Hydrogen Treatment Protects against Cell Death and Senescence Induced by Oxidative Damage. Hydrogen treatment protects against cell death and senescence induced by oxidative damage, 27(2), 365-371. doi: 10.4014/jmb.1608.08011

 


Oxygen radicals and nitric oxide levels in chondral or meniscal lesions or both

“Although patients with chondral lesions had a significant increase in nitric oxide, the increase in patients with meniscal plus chondral lesions was more pronounced in peroxynitrite concentration. These reactive species will lead to tissue damage along with the mechanical damage caused by meniscal or chondral lesions or both.”

Haklar, U., Yüksel, M., Velioglu, A., Turkmen, M., Haklar, G., & Yalçin, A. S. (2002). Oxygen Radicals and Nitric Oxide Levels in Chondral or Meniscal Lesions or Both. Clinical Orthopaedics and Related Research, 403, 135-142. doi: 10.1097/00003086-200210000-00021

 


Molecular hydrogen: A therapeutic antioxidant and beyond

 

“Although the underlying mechanisms were initially proposed as selective extinctions of hydroxyl radical and peroxynitrite, the signaling pathway regulation effect of molecular hydrogen by modulating a various molecules expressions/activities, gene expression and microRNA may also account for the ultimate effects of anti-reperfusion injury, anti-infammation, anti-apoptosis, anti-metabolic disorders, anti-allergy, anti-radiation injury, anti-dementia as well as anti-aging.”

 

Huang, L. (2016). Molecular hydrogen: A therapeutic antioxidant and beyond. Medical Gas Research, 6(4), 219–222. doi: 10.4103/2045-9912.196904 
 


Oxidative stress reaction in the meniscus of Bach 1 deficient mice: Potential prevention of meniscal degeneration


“In the menisci of Bach 1 deficient mice, the anti-oxidative stress activity was considered to be increased by abrogating the suppression of HO-1 expression, resulting in a reduction of histological degeneration. This finding showed a potential new strategy for the prevention and treatment of meniscal degeneration.”

Ochiai, S., Mizuno, T., Deie, M., Igarashi, K., Hamada, Y., & Ochi, M. (2008). Oxidative stress reaction in the meniscus of Bach 1 deficient mice: Potential prevention of meniscal degeneration. Journal of Orthopaedic Research, 26(6), 894-898. doi: 10.1002/jor.20579

 


Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway

 

“H2 regulated endothelial injury and the inflammatory response via Nrf2-mediated HO-1 levels. These results suggest that H2 could suppress excessive inflammatory responses and endothelial injury via an Nrf2/HO-1 pathway.”

 

Chen, H., Xie, K., Han, H., Li, Y., Liu, L., Yang, T., & Yu, Y. (2015). Molecular hydrogen protects mice against polymicrobial sepsis by ameliorating endothelial dysfunction via an Nrf2/HO-1 signaling pathway. International Immunopharmacology, 28(1), 643-654. doi: 10.1016/j.intimp.2015.07.034

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