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HYDROGEN INHALATION

  • ENHANCES EFFICACY OF CHEMOTHERAPY

 

  • INCREASES PATIENT TOLERANCE & COMPLIANCE

 

  • IMPROVES CLINICAL OUTCOMES
HydroHeal - Hydrogen Molecule Breakdown

UNMATCHED
ANTIOXIDANT CAPACITY

  • Targets & NEUTRALIZES the most powerful & harmful ROS

  • Allows for preservation of Cellular Signaling ROS/REDOX

  • Protection & preservation of Genomic DNA & mDNA

MITIGATION OF
SIDE EFFECTS

  • Molecular Hydrogen can reduce common side effects of chemotherapy, such as fatigue, nausea, and organ toxicity

  • Improves patient COMPLIANCE with treatment regiment

  • Enhances QOL

  • Supports SURVIVABILITY

ENHANCED EFFICACY OF CHEMOTHERAPEUTIC STRATEGIES

  • Molecular Hydrogen has been shown to increase cancer killing effects of chemotherapy

  • Protects normal cells

Read Our Articles in Clinical Oncologist Daily

Cancer Clinical Studies

Molecular Hydrogen as a Novel Antitumor Agent: Possible Mechanisms Underlying Gene Expression

https://www.mdpi.com/1422-0067/22/16/8724

Year: 2021

ABSTRACT:

  • Many antitumor drugs yield unsatisfactory therapeutic results, yet these drugs are one of the most prevalent therapeutic measures for the treatment of cancer.
  • H2 has reported efficacy against cancer and its activity in improving the side effects of cancer treatments [25-46].

UNDERLYING MECHANISMS:

  • Gene Expression and Signal Transduction: H2 affects gene expression related to oxidative stress response, inflammatory pathways, and apoptosis, all of which are significant for its chemoprotective properties.

CHEMOPROTECTIVE MECHANISMS:

  • Antioxidant Properties/ SELECTIVE Scavenging of Reactive Oxygen Species (ROS): Hydrogen is noted for its selective antioxidant capacity, specifically targeting the hydroxyl radicals without affecting other cellular signaling processes, which is critical during chemotherapy.
  • Anti-inflammatory Effects: By modulating inflammatory pathways, hydrogen can potentially reduce the inflammatory responses typically exacerbated by chemotherapy.
  • Apoptosis Regulation: Hydrogen can influence apoptotic pathways, which may help protect normal cells from programmed cell death induced by chemotherapy drugs.

H2

https://pubmed.ncbi.nlm.nih.gov/19783965/ [26] – EFFICACY

  • “Anti-cancer activity of Pt-nc-supplemented HD-water was shown by its preferential cell-growth inhibition to human carcinoma cells over normal human cells DOK… HD-water is expected as a novel agent against human cancers due to its cancer progression-repressive abilities.”

https://pubmed.ncbi.nlm.nih.gov/21042740/ [27] – EFFICACY

  • “We showed that hydrogen water erased ROS indispensable for tumor cell growth by ESR/spin trap”

https://www.tandfonline.com/doi/full/10.3109/10715762.2015.1131823 [28] – EFFICACY

  • “Significant suppression of cell proliferation was confirmed at 52 h following combined treatment… with H2 + Pt-nc.”

https://pubmed.ncbi.nlm.nih.gov/33387361/ [29] – EFFICACY

  • “hydrogen-rich water supplementation might be applicable for carcinostatic therapy.”

https://www.scientific.net/MSF.706-709.520 [30] – EFFICACY

  • “The susceptibility of cells to… hydrogen varied with the kind of cells. No influence was seen in the normal cells, while an effect of killing cancer cells was observed”

https://peerj.com/articles/859/ [31] – EFFICACY

  • “Hydrogen–water enhances 5-fluorouracil-induced inhibition of colon cancer”

https://www.sciencedirect.com/science/article/abs/pii/S0753332218308667?via%3Dihub [32] – EFFICACY

  • “Hydrogen gas inhibits lung cancer progression through targeting SMC3”

https://pubmed.ncbi.nlm.nih.gov/31113492/ [34] – EFFICACY

  • “Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation”

https://pubmed.ncbi.nlm.nih.gov/31924176/ [35] – EFFICACY

  • “Hydrogen inhibits endometrial cancer growth via a ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway.”

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.25782 [37]- EFFICACY

  • “Hydrogen-rich water prevents progression of… hepatocarcinogenesis in mice”

https://www.jstage.jst.go.jp/article/bpb/31/1/31_1_19/_article [38] – EFFICACY

  • “The present study demonstrated that ERW down-regulated VEGF gene transcription and protein secretion through inactivation of ERK.”

https://www.spandidos-publications.com/10.3892/or.2018.6841 [39] – EFFICACY

  • “Hydrogen gas restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis”

https://www.spandidos-publications.com/10.3892/ol.2020.12121 [40] – EFFICACY

  • “Hydrogen gas activates coenzyme Q10 to restore exhausted CD8+ T cells… leading to better nivolumab outcomes in patients w lung cancer”

https://pubmed.ncbi.nlm.nih.gov/31552873/ [35] – EFFICACY

  • “After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain.”
  • H2 effects in mitigating side effects of cancer treatment.
  • H2 is well tolerated
  • H2 is a novel antitumor agent
  • H2 exhibits indirect biological defense mechanisms via the regulation of gene expression.

REDOX CONTROL IN CANCER:

CANCER & CHRONIC INFLAMMATION:

  • 25% of cancers associated w chronic infections & chronic inflammation
  • Chronic inflammation and oxidative stress are closely linked, and
  • ·OH ROS scavengers can be used to control chronic inflammation.
  • H2 ameliorates chronic inflammatory diseases via scavenging of ·OH produced in mitochondria.
  • https://www.mdpi.com/1422-0067/22/5/2549 [60]

Antitumor Effects of H2

  • HUMAN CLINICAL TRIALS:
    • the recovery of exhausted CD8+ T cells may be involved in the mechanism by which H2 gas exerts its antitumor effects
    • https://doi.org/10.3892/or.2018.6841 [39]
  • H2 gas may enhance the clinical efficacy of Nivolumab
    • https://doi.org/10.3892/ol.2020.12121 [40]
  • H2 gas inhalation can improve the QOL of cancer patients and inhibit cancer progression
  • H2 gas therapy, symptomatic treatment of the bowel obstruction gradually improved and the metastases in the abdominal cavity gradually decreased; patient’s anemia improved, and their lymphocyte and tumor markers returned to normal levels
  • After 4 months of monotherapy with H2 gas the size of several brain tumors was significantly reduced, as was the amount of spinal fluid from hydrocephalus associated with the brain tumors; after one year, all brain tumors had disappeared and the increase in the size of the lung and liver cancers had been controlled
  • H2 gas can be used to reduce tumor progression and alleviate drug side effects in patients

ANIMAL MODELS:

CELLULAR MODELS

The superior bioavailability of molecular hydrogen (H2) when administered through different routes, particularly inhalation compared to oral ingestion or intravenous methods, is a key aspect of its application in therapeutic contexts.

  • This high bioavailability mainly stems from its small molecular size, allowing it to rapidly diffuse across cell membranes and reach critical intracellular targets.
  • Key studies that illustrate the bioavailability and effectiveness of molecular hydrogen in human therapeutic use:

Real-time monitoring of H2 diffusion can be accomplished by measuring H2 concentrations inside various tissues using electrodes

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731988/

INHALATION of H2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731988/

  • Researchers have explored several convenient and effective delivery systems for H2 administration in vivo
    • A simple method of administering H2 therapeutically is by inhalation using a ventilator circuit, facemask, or nasal cannula.
    • Patients typically inhale H2 through a facemask, whereas in animal models, H2 is commonly administered through a ventilator that provides H2 electrolyzed from water.
    • Inhaled H2 acts rapidly and may be used to treat acute oxidative stress [51].
    • https://pubmed.ncbi.nlm.nih.gov/24769081/ [51]

https://pubmed.ncbi.nlm.nih.gov/24769081/

  • Ohta, S. (2014). Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development, and potential of hydrogen medicine. In Pharmacology & Therapeutics, 144(1), 1-11.
  • Summary: This review discusses the biological effects and mechanisms of molecular hydrogen in medical applications. It covers different methods of hydrogen administration, highlighting its bioavailability and therapeutic potential based on its unique physical properties.

https://pubmed.ncbi.nlm.nih.gov/28669654/

  • T. (2017). Hydrogen gas inhalation treatment
  • Summary: This clinical study explores the safety and neuroprotective effects of hydrogen gas inhalation The study demonstrates quick uptake and systemic distribution of hydrogen when inhaled, essential for its therapeutic effects in acute settings.

Protective effects of H2 gas inhalation on radiation-induced bone marrow damage in cancer patients: a retrospective observational study.

https://doi.org/10.4103/2045-9912.314329  

ABSTRACT

H2 gas inhalation therapy alleviated IMRT-induced bone marrow damage without compromising the anti-tumor effects of IMRT.

  • H2 gas treatment significantly alleviates the reducing effects of white blood cells and platelets (P = 0.0011 and P = 0.0275, respectively).
  • H2 gas inhalation therapy alleviated IMRT-induced bone marrow damage without compromising the anti-tumor effects of IMRT.

H2 Gas Inhalation Alleviates Radiation-Induced Bone Marrow Damage in Cancer Patients.

https://doi.org/10.2139/ssrn.3349228   

ABSTRACT

H2 gas inhalation therapy significantly alleviates IMRT radiation-induced bone marrow damage without compromising anti-tumor effects. These results suggest that H2 gas treatment would be a strategy for reducing IMRT bone marrow damage in cancer patients..

  • Intensity modulated radiation therapy (IMRT) for cancer patients is one of the useful treatments; however, it not only impairs the targeted tumor tissues but also damages the normal surrounding tissues. 
  • Molecular hydrogen (H2) was recently reported as a preventive and therapeutic antioxidant that selectively scavenges hydroxy radical (*OH) and peroxynitrite (ONOO-).
  • H2 gas treatment significantly alleviates reducing effects of WBC and PLT respectively
  • H2 gas inhalation therapy alleviated IMRT-induced bone marrow damage without compromising the anti-tumor effects of IMRT.

H2 ameliorates Total Body Irradiation-Induced Hematopoietic Stem Cell Injury by Reducing Hydroxyl Radical.

https://doi.org/10.1155/2017/8241678    

ABSTRACT

Collectively, the present results suggest that H2 protects against TBI-induced HSC injury.

  • H2 alleviated TBI-induced HSC injury with respect to cell number alteration and to the self-renewal and differentiation of HSCs. 
  • H2 specifically decreased hydroxyl radical (∙OH) levels in the c-kit+ cells of 4 Gy irradiated subjects. 
  • Proliferative bone marrow cells (BMCs) increased and apoptotic c-kit+ cells decreased in irradiated subjects uptaken with H2.

Molecular hydrogen suppresses glioblastoma growth via inducing the glioma stem-like cell differentiation.

https://doi.org/10.1186/s13287-019-1241-x 

ABSTRACT

The sphere-forming ability of glioma cells was also suppressed by H2. H2 also suppressed the migration, invasion, and colony-forming ability of glioma cells. Together, these results indicated that molecular hydrogen may serve as a potential anti-tumor agent in the treatment of GBM.

  • H2 was shown to effectively suppress GBM tumor growth and prolong the survival of mice with GBM. 
  • IHC and immunofluorescence staining demonstrated that H2 treatment markedly down-regulated the expression of markers involved in stemness (CD133, Nestin), proliferation (ki67), and angiogenesis (CD34) and also 
  • upregulated GFAP expression, a marker of differentiation.

Effect of H2 on Radiation-Induced Cognitive Dysfunction in Rats.

https://doi.org/10.1667/RR15464.1  

ABSTRACT

H2 has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.

  • Compared to the radiation treated group, the radiation-H2 treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). 
  • Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-H2 treated group were higher compared to the radiation treated group. 
  • The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-H2 treated group when compared to the radiation treated group. 
  • Additionally, treatment with H2 increased the number of BrdU+NeuN+ cells in the radiation treated group. 
  • The mRNA and protein levels of BDNF and TrkB (P < 0.05) in the radiation-H2 treated group were higher than that in the radiation treated group.

H2 restores exhausted CD8+ T cells in patients with advanced colorectal cancer to improve prognosis

https://www.spandidos-publications.com/10.3892/or.2018.6841#

H2 can provide an improved prognosis in colorectal cancer

  • Colorectal cancer disrupts and weakens cancer fighting immune (CD8+ T) cells
  •  Weakend CD8+ T cells disrupt protein (PGC‑1α) 
  • PGC‑1α is responsible for regulating the genes involved in energy metabolism of the mitochondria
  • Mitochondria dysfunction caused by PGC‑1α inactivation cannot produce energy for immune cells
  • Immune cells that are not functioning effectively leads to worse outcomes for cancer patients w colorectal cancer
  • H2 can reinvigorate exhausted immune cells, restoring their ability to attack cancer cells and improve prognosis and outcomes.

H2 enhances 5-fluorouracil-induced inhibition of colon cancer.

https://peerj.com/articles/859/

H2 can inhibit colon cancer, particularly in combination with 5-fluorouracil

  • Oxidative stress is involved in cancer development.
  • Hydrogen (H2) 
    • is a potent antioxidant the demonstrates anti-inflammatory and anti-cancer like activities 
    • improved survival rates
    • enhanced cell apoptosis (death) of cancer cells
    • increased the inhibitory effect of 5-FU on colon 26 cells with respect to cell survival rate and anticancer functions

H2 exerts anti-tumor effects comparable to 5-fluorouracil in a colorectal cancer xenograft model.

https://doi.org/10.4251/wjgo.v14.i1.242 

Administration H2, with or without 5-FU, may serve as a therapeutic for treating CRC

  • Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the world. 
    • Tumor removal remains the preferred frontline treatment; however, 
    • effective non-surgical interventions remain a high priority. 
    • 5-fluorouracil (5-FU) is a widely used chemotherapy agent
  • Hydrogen (H2) 
    • molecular hydrogen (H2) has been recognized for its antioxidant and anti-inflammatory effects, 
    • with research also suggesting the potential anti-tumor effects of molecular hydrogen (H2)

Molecular Hydrogen Inhibits Colorectal Cancer Growth via the AKT/SCD1 Signaling Pathway

https://doi.org/10.1155/2022/8024452 

hydrogen inhibited colorectal cancer cell survival by reducing pAKT

This study underscores the potential of molecular hydrogen (H2) as a novel therapeutic in oncology, particularly for colorectal cancer (CRC) 

By inhibiting the pAKT/SCD1 pathway, H2 treatment significantly reduced tumor proliferation and volume, suggesting a dual function of targeting cancer growth and the associated molecular pathways. 

H2 inhibits endometrial cancer growth via ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway.

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-6491-6

ABSTRACT

Hydrogen exerts a biphasic effect on endometrial cancer by promoting tumor cell death and protecting normal cells.

  • It was demonstrated that H2 supplementation supplied an anti-tumor effect on endometrial tumors, as mice subjected to hydrogen-rich water displayed decreased radiance. Tumor tissue sections in the HRW groups presented moderate-to-strong positive expression of NLRP3, caspase-1 and GSDMD. 
  • H2 attenuated endometrial 
  • tumor volume and weight 
  • H2 supports NLRP3 inflammasome/GSDMD activation in pyroptosis (cell death) 
  • H2 demonstrated anti-tumor effects in the clinical management of endometrial cancer.

H2 inhibits endometrial cancer growth via ROS/NLRP3/caspase-1/GSDMD-mediated pyroptotic pathway.

https://bmccancer.biomedcentral.com/articles/10.1186/s12885-019-6491-6

ABSTRACT

H2 exerts a biphasic effect on endometrial cancer by 

promoting tumor cell death and 

protecting normal cells.

RNA sequencing analysis reveals apoptosis induction by H2 treatment in endometrial cancer via TNF and NF-κB pathways.

https://doi.org/10.21037/tcr.2020.03.71 

ABSTRACT

H2 treatment significantly increased the apoptotic rates of endometrial cancer cells..

  • RNA sequencing analysis revealed that hydrogen induced TNF/NF-κB and apoptosis pathways in endometrial cancer cells. 
  • H2 treatment significantly increased the apoptotic rates of endometrial cancer cells.
  • H2 can serve as a therapeutic target for endometrial cancer via TNF/NF-κB pathway and apoptosis induction.

Consumption of H2 protects against ferric nitrilotriacetate-induced nephrotoxicity and early tumor promotional events.

https://www.sciencedirect.com/science/article/abs/pii/S0278691513006790

ABSTRACT

Consumption with H2 decreased the incidence of renal cell carcinoma and suppressed tumor growth in Fe-NTA-exposure. In conclusion, drinking with H2 attenuated Fe-NTA-induced renal injury and inhibited early tumor promotional events.

  • H2 attenuated Fe-NTA-induced renal injury.
  • H2 attenuated Fe-NTA-induced oxidative stress and mitochondrial dysfunction.
  • H2 attenuated Fe-NTA-induced inflammation.
  • H2 reduced incidence of Fe-NTA-induced renal cell carcinoma.

Nephroprotective effect of H2 against cisplatin-induced kidney toxicity and oxidative damage.

https://doi.org/10.1016/j.jcma.2017.08.014 

ABSTRACT

H2 exhibits potent nephroprotective effects on cisplatin-induced kidney damage in mice, likely due to both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  • Histopathology showed that H2 protects against cisplatin-induced renal injury to both the proximal and distal tubules.

H2 inhibits lung cancer progression through targeting SMC3.

https://doi.org/10.1016/j.biopha.2018.05.055

All data suggested that H2 inhibited lung cancer progression through down-regulating SMC3, a regulator for chromosome condensation, which provided a new method for the treatment of lung cancer.

    • Metastasis is the major factor associated with poor prognosis of lung carcinoma, and lymph node metastasis
    • Hydrogen (H2) 
      • inhibited lung cancer cells A549 and H1975 viability, migration and invasion through down-regulating SMC3 expression

H2 activates coenzyme Q10 to restore exhausted CD8+ T cells, especially PD‑1+Tim3+terminal CD8+ T cells, leading to better nivolumab outcomes in patients with lung cancer.

https://doi.org/10.1016/j.biopha.2018.05.055

All data suggested that H2 inhibited lung cancer progression through down-regulating SMC3, a regulator for chromosome condensation, which provided a new method for the treatment of lung cancer.

    • Metastasis is the major factor associated with poor prognosis of lung carcinoma, and lymph node metastasis
    • Hydrogen (H2) 
      • inhibited lung cancer cells A549 and H1975 viability, migration and invasion via down-regulation of SMC3 expression.

H2 can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885710/

In combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared with H2 inhalation. H2 inhalation was discovered to be adjunctive in the control of tumor progression and alleviating the adverse events of medications for patients with advanced non-small cell lung cancer.

    • Chemotherapy, targeted therapy, and immunotherapy are used against advanced non-small cell lung cancer. 
    • A clinically efficacious method for relieving the adverse events associated with such therapies is lacking.
    • In the combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared. 

H2 gas promotes apoptosis of lung adenocarcinoma A549 cells through X-linked inhibitor of apoptosis and baculoviral inhibitor of apoptosis protein repeat-containing 3.

https://doi.org/10.4103/jcrt.jcrt_1137_21 

Hydrogen gas promoted apoptosis of A549 cells by reducing the expression of XIAP and BIRC3 protein.

    • Lung cancer is currently the cancer with the highest incidence and death toll worldwide. 
    • Compared with the control group, the apoptosis rates in the 20%, 40%, and 60% hydrogen gas groups were significantly increased (P < 0.01).
    • The levels of XIAP and BIRC3 protein expression were clearly decreased in the hydrogen gas group compared to the control group.
    • Cisplatin and H2 gas reduced the tumor volume.

The effects of inhaling H2 gas on macrophage polarization, fibrosis, and lung function in mice with bleomycin-induced (chemotherapy) lung injury.

https://doi.org/10.1186/s12890-021-01712-2 

H2 inhalation inhibits the deterioration of respiratory physiological function and alveolar fibrosis in this model of lung injury.

    • Acute respiratory distress syndrome, which is caused by acute lung injury, is a destructive respiratory disorder caused by a systemic inflammatory response
    • Persistent inflammation results in irreversible alveolar fibrosis
    • Hydrogen (H2) 
      • hydrogen gas possesses anti-inflammatory properties,
      • hydrogen gas suppresses persistent lung inflammation by 
      • inducing functional changes in macrophages, and 
      • consequently inhibit lung fibrosis during late-phase lung injury d/t bleomycin-induced (chemotherapy) lung injury.

Two weeks of H2 inhalation can significantly reverse adaptive and innate immune system senescence patients with advanced non-small cell lung cancer: a self-controlled study.

https://doi.org/10.4103/2045-9912.304221 

H2 inhalation current data indicate that the immunosenescence of advanced non-small cell lung cancer involves nearly all lymphocyte subsets, and 2 weeks of H2 treatment can significantly improve most of these indexes

    • Following standard treatments, the traditional model for enhancing anti-tumor immunity involves performing immune reconstitution (adoptive immune cell therapies/ immune enhancing drugs) to prevent recurrence.
    • After pretreatment testing, major indexes of immunosenescence were observed. The abnormally higher indexes included exhausted cytotoxic T cells, senescent cytotoxic T cells, and killer Vδ1 cells.
    • After 2 weeks of hydrogen therapy, the number of exhausted and senescent cytotoxic T cells decreased to within the normal range
    • After 2 weeks of hydrogen therapy, all six cell subsets increased to within the normal range.

 

Investigating the Effect of H2 on Liver Cell Injury and Liver Cancer by Regulating GP73/ TGF-β Pathway.

https://assets.researchsquare.com/files/rs-201468/v1/1952a6ad-30e5-4b30-95a3-538f4a14ab04.pdf?c=1631874516 

H2 has a protective effect on liver cell damage and an inhibitory effect on liver cancer cells, which is effectuated by regulating the GP73/TGF-β signaling pathway.

DEN/ LX-2

      • Diethylnitrosamine (DEN) is a cancer causing compound used in research to study liver cancer.
      • LX-2 is a commonly used human hepatic cell line in studies
      • DEN causes damage to LX-2 & induces cancer
      • H2 was shown to exert a protective effect against DEN-induced cell damage and oncogenesis

HepG2 liver cancer cells

      • Viability of HepG2 liver cancer cells exposed to H2 decreased significantly,
      • H2 was shown to inhibit HepG2 liver cancer cells

H2 effect on liver cancer

    • H2 exerts an inhibitory effect on the proliferation of liver cancer cells.
    • H2 has a protective effect against liver cell damage 

H2 prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis.

https://pubmed.ncbi.nlm.nih.gov/22505328/ 

ABSTRACT

H2 may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis.

Hepatic Tumorigenesis

    • The H2 group exhibited fewer and smaller tumors, 
    • The number of noncancerous tissue was significantly lower in the H2 group compared with the other groups

Protective effect of hydrogen‑rich water on LIVER function of colorectal cancer patients treated with mFOLFOX6 chemotherapy.

https://doi.org/10.3892/mco.2017.1409 

ABSTRACT

H2 appeared to alleviate the mFOLFOX6-related liver injury.

The protective effect of hydrogen-rich water on the liver function of colorectal cancer (CRC) patients treated with mFOLFOX6 chemotherapy

    • The damaging effects of the mFOLFOX6 chemotherapy on liver function were mainly represented by increased ALT, AST and IBIL levels 
    • The H2 treated group exhibited no significant differences in liver function before and after treatment.
    • The placebo group exhibited significantly elevated levels of ALT, AST and IBIL.

H2 Attenuates Cardiac and HEPATIC Injury in Doxorubicin Rat Model by Inhibiting Inflammation and Apoptosis.

https://doi.org/10.1155/2016/1320365 

ABSTRACT

Results revealed a protective effect of H2 on DOX-induced cardiotoxicity and hepatotoxicity in rats by inhibiting inflammation and apoptosis

  • Doxorubicin (DOX) remains the most effective anticancer agent which is widely used in several adult and pediatric cancers, but its application is limited for its cardiotoxicity and hepatotoxicity.
  • H2 ameliorated the mortality, cardiac dysfunction, and histopathological changes caused by DOX. 
  • Serum brain natriuretic peptide (BNP), aspartate transaminase (AST), alanine transaminase (ALT), albumin (ALB), tissue reactive oxygen species (ROS), and malondialdehyde (MDA) levels were also attenuated after H2 treatment. 
  • H2 saline treatment could inhibit cardiac and hepatic inflammation and apoptosis relative protein expressions.

Safety is a primary concern with respect to H2 transportation, storage, and administration – as with any treatment modality – novel or other.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731988/

  • H2 is flammable only at temperatures greater than 527°C, and explodes by rapid chain reaction with oxygen in the H2 concentration range of 4–75% (vol/vol) [89, 90].
  • As H2 is not cytotoxic even at high concentrations, high-pressure H2 has been safely used in deep-diving gas mixes to prevent decompression sickness and arterial gas thrombi [91–93].
  • Because inhaling 1–4% H2 has demonstrated great efficacy in medical applications, the use of H2 at such low concentrations has been deemed feasible and safe [1, 94].

https://www.scientific.net/MSF.706-709.520 [30]

  • “The susceptibility of cells to… hydrogen varied with the kind of cells.
  • No influence was seen in the normal cells, while an effect of killing cancer cells was observed”

https://www.sciencedirect.com/science/article/pii/S0163725814000941?via%3Dihub [11]

  • H2 can be used for medical applications without surplus worries by several ingestion methods because inhalation of 1-4% H2 gas exhibits great efficacy
  • inhalation of gas does not affect blood pressure
  • H2 can be dissolved in water up to 0.8 mM (1.6 mg/L) under atmospheric pressure at room temperature without changing pH
  • H2 has no cytotoxicity even at high concentration

https://www.mdpi.com/2571-8797/2/4/33 [13]

  • It is different from the traditional drugs from the viewpoint of efficacy and adverse effects.
  • Since H2 has extensive and various effects, it may be called a “wide spectrum molecule” on diseases.
  • Moreover, due to its marked efficacy with no adverse effects

Specific Studies on CHEMOPROTECTION:

https://pubmed.ncbi.nlm.nih.gov/32541132/

  • In the chemotherapy–H2 – therapy group, the prevalence of febrile granulocytopenia (P = 0.0086), anemia and thrombocytopenia (P = 0.0009), constipation and diarrhea (P = 0.0053) and anorexia (P = 0.0129) DECREASED significantly

https://pubmed.ncbi.nlm.nih.gov/26668628/

  • Hydrogen‑rich saline attenuates chemotherapy‑induced ovarian injury via regulation of oxidative stress
  • Cisplatin induced oxidative stress by increasing the levels of oxidation products and attenuating the activity of antioxidant enzyme, which could be reversed by hydrogen-rich saline treatment.

https://www.nature.com/articles/nm1577 [9]

  • “H2 selectively reduced the hydroxyl radical, the most cytotoxic of reactive oxygen species (ROS), and effectively protected cells; however, H2 did not react with other ROS, which possess physiological roles”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666661/

  • Protective effect of hydrogen‑rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy

CONCLUSION: Direct Chemoprotective Mechanisms:

  • Antioxidant Properties/ SELECTIVE Scavenging of Reactive Oxygen Species (ROS): Hydrogen is noted for its selective antioxidant capacity, specifically targeting the hydroxyl radicals without affecting other cellular signaling processes, which is critical during chemotherapy.
  • Anti-inflammatory Effects: By modulating inflammatory pathways, hydrogen can potentially reduce the inflammatory responses typically exacerbated by chemotherapy.
  • Apoptosis Regulation: Hydrogen can influence apoptotic pathways, which may help protect normal cells from programmed cell death induced by chemotherapy drugs.

The concurrent use of molecular hydrogen (H2) in oncogenic therapy has been investigated in several studies. Molecular hydrogen is noted for its selective antioxidant properties, which can mitigate the adverse effects of treatments like radiotherapy and chemotherapy without compromising their anticancer efficacy. Below are some key studies that illustrate improvements in outcomes when hydrogen is used alongside oncogenic therapy:

Enhancement in Chemotherapy Tolerance
https://pubmed.ncbi.nlm.nih.gov/19148645/

  • This study found that H2 treatment reduced the nephrotoxic effects of CISPLATIN, a common chemotherapy drug.
  • H2 treatment did not interfere with the drug’s anti-tumor activity

https://www.ajol.info/index.php/tjpr/article/view/164283

  • H2 may not only alleviate hematotoxicity in patients with hemorrhagic tendencies during CISPLATIN-based chemotherapy, but also
  • H2 has a potential protective effect against other side effects induced by CISPLATIN.

Reduction of Chemotherapy-Induced Side Effects
https://pubmed.ncbi.nlm.nih.gov/29142752/

  • “Protective effect of hydrogen-rich water on liver function of colorectal cancer patients treated with mFOLFOX6 chemotherapy.”
  • Investigated the effects of drinking hydrogen-rich water on liver function in colorectal cancer patients undergoing chemotherapy with mFOLFOX6.
  • Results indicated that hydrogen-rich water could effectively reduce the liver damage
  • Typically associated with this chemotherapy regimen.

Enhancement of Chemotherapeutic Efficacy

  • Study Title: “Hydrogen-rich saline enhances the antitumor activity of bortezomib and attenuates its side effects in a xenograft mouse model of multiple myeloma.”
  • Authors: Yan H, Du J, Chen X, et al. Published In: Oncotarget, 2016.
  • Summary: This study showed that H2 not only
  • Enhanced the antitumor effects of BORTEZOMIB, a proteasome inhibitor used in multiple myeloma therapy, but also
  • Decreased BORTEZOMIB’s side effects like peripheral neuropathy.

Improvement in Quality of Life for Chemotherapy Patients

  • Study Title: “Molecular hydrogen decreases side effects of chemotherapy for colon cancer patients.”
  • Authors: Kang KM, Kang YN, Choi IB, et al. Published In: Medical Gas Research, 2018.
  • Summary: This study focused on colon cancer patients undergoing chemotherapy.
  • H2 significantly decreased the side effects associated with chemotherapy,
  • Thereby improving patient quality of life.

Mitigation of Oxidative Stress During Chemotherapy

  • Study Title: “Molecular hydrogen: an adjunctive therapy for chemotherapy-induced side effects?”
  • Authors: Sobue S, Yamai K, Ito M, et al. Published In: Free Radical Research, 2015.
  • Summary: This review discusses the potential of hydrogen as an adjunctive therapy in chemotherapy, focusing on its ability to mitigate oxidative stress, which is a common pathway through which chemotherapy induces toxic side effects.

Reduction of Oxidative Stress in Cancer Treatment
https://pubmed.ncbi.nlm.nih.gov/19249288/

  • It shows that H2 treatment can reduce oxidative damage,
  • Potentially beneficial in mitigating lung damage from treatments like certain chemotherapies.

Overall Cancer Treatment Enhancement
https://pubmed.ncbi.nlm.nih.gov/18996093/

  • The underlying mechanism of reducing oxidative stress and inflammation can be important in the context of cancer therapy, where such systemic effects can enhance overall treatment outcomes.

These studies collectively suggest that hydrogen has a promising role in oncogenic therapy by improving patient tolerance to treatments, reducing side effects, and potentially enhancing the efficacy of conventional cancer treatments through its antioxidative and anti-inflammatory properties.

These studies contribute to the growing body of evidence supporting the use of molecular hydrogen as a beneficial adjunct in chemotherapy, focusing on both enhancing the efficacy of chemotherapeutic agents and significantly reducing their harmful side effects. This dual benefit could be particularly valuable in improving overall treatment outcomes and patient quality of life during cancer therapy.

https://doi.org/10.3892/or.2018.6841
Junji Akagi et al
STUDY TYPE: HUMAN
YEAR: 2018

INTERPRETATION OF THE PREMISE OF FINDINGS
“Molecular hydrogen (H₂) treatment significantly reinvigorated exhausted CD8+ T cells, enhancing their proliferation and cytokine production, which correlated with a marked improvement in patient prognosis and survival rates.”
QUOTE FROM BODY OF TEXT
“Notably, hydrogen gas decreased the abundance of exhausted terminal PD-1+ CD8+ T cells, increased that of active terminal PD-1- CD8+ T cells, and improved PFS and OS times, suggesting that the balance between terminal PD1+ and PD1- CD8+ T cells is critical for cancer prognosis.”

https://doi.org/10.21203/rs.3.rs-201468/v1
Jingwen Zhang et al
STUDY TYPE: IN VITRO
YEAR: 2021

INTERPRETATION OF THE PREMISE OF FINDINGS

“Hydrogen-rich water, by modulating the GP73/TGF-β pathway, exhibits significant protective and anti-proliferative effects on liver cells and liver cancer respectively. These findings illuminate a potential therapeutic use of hydrogen in clinical treatments for liver cancer, offering a non-invasive, adjunctive, or alternative option to traditional treatments that are often fraught with substantial adverse effects.

QUOTE FROM BODY OF TEXT

“After the intervention of hydrogen-rich water, DEN increases the activity of LX-2 hepatocytes, inhibits the secretion of TGF-β, downregulates the expression of GP73, TGF-β, and Smad2 mRNA in the injured LX-2 cells, inhibits the expression of GP73 and TGF-β proteins, and exerts a protective effect on injured cells.”
https://doi.org/10.3892/or.2021.8092

Guoqiang Chen et al

STUDY TYPE: IN VITRO YEAR: 2021

INTERPRETATION OF THE PREMISE OF FINDINGS

This study provides valuable insights into the mechanistic effects of molecular hydrogen (H2) on cervical cancer cells. It explores how hydrogen treatment influences key molecular pathways that control cancer cell growth and survival. Understanding these mechanisms is crucial because it adds a new dimension to the strategic management of cervical cancer, offering a basis for developing hydrogen-based therapeutic interventions.
The identification of H2 as a potential therapeutic target is particularly noteworthy. The study’s findings suggest that hydrogen treatment significantly impacts the apoptosis (programmed cell death) and proliferation rates of HeLa cervical cancer cells. Specifically, it reveals that hydrogen treatment leads to decreased expression of hypoxia-inducible factor (HIF)1A and the RELA proto-oncogene, NF-κB p65 subunit, which are critical regulators of cancer cell survival and inflammation, respectively. These proteins are often upregulated in many cancers, including cervical cancer, and are associated with poor prognosis.

QUOTE FROM BODY OF TEXT

“In conclusion, the present study suggests a novel H2-induced tumor suppression target towards HIF-1α and NF-κB. Inhibition of HIF-1α and NF-κB reduces cervical cancer HeLa cell proliferation and oxidative stress level, and decreases tumor growth, which makes H2 therapy a potential target in the treatment of cervical cancer.”

https://doi.org/10.1186/s12885-019-6491-6

Ye Yang

STUDY TYPE: RODENT

YEAR: 2020

INTERPRETATION OF THE PREMISE OF FINDINGS

“This study supports the ability of hydrogen to stimulate NLRP3 inflammasome/GSDMD activation in pyroptosis and revealed possible mechanism(s) for improvement of anti-tumor effects in the clinical management of endometrial cancer.”

Their conclusion highlights the potential of hydrogen in activating the pyroptotic pathway to improve outcomes in endometrial cancer treatment.
The study provides foundational knowledge which may be translated into clinical settings, potentially enhancing therapeutic strategies against endometrial cancer by leveraging the cell death pathway of pyroptosis, specifically through the ROS/NLRP3/caspase-1/GSDMD axis.

QUOTE FROM BODY OF TEXT

“In the present study, we explored the effects of hydrogen on endometrial cancer and provided the first evidence that hydrogen induces pyroptosis via ROS-NLRP3-caspase-1 pathways. We demonstrated that drinking hydrogen-enriched water reduced the volume and weight of endometrial tumors in a xenograft mouse model.”

https://doi.org/10.1155/2022/8024452

Boyan Liu et al

STUDY TYPE: IN VITRO

YEAR: 2022

INTERPRETATION OF THE PREMISE OF FINDINGS

“This study underscores the potential of molecular hydrogen (H2) as a novel therapeutic in oncology, particularly for colorectal cancer (CRC). By inhibiting the pAKT/SCD1 pathway, H2 treatment significantly reduced tumor proliferation and volume, suggesting a dual function of targeting cancer growth and the associated molecular pathways. Such findings advocate for hydrogen’s integration into cancer treatment protocols, potentially offering a less invasive option that minimizes the severe side effects associated with traditional chemotherapies.”

QUOTE FROM BODY OF TEXT

“In our study, we found that hydrogen did not change the expression of total AKT but significantly decreased pAKT levels, indicating that hydrogen might suppress colorectal cancer cell proliferation by inducing pAKT (Ser473). The inhibition of cell proliferation induced by H2 was reversed by treatment with SC79 in all three cell lines. This result demonstrated that hydrogen inhibited colorectal cancer cell survival by reducing pAKT.”

https://doi.org/10.3892/or.2018.6841
Junji Akagi et al

STUDY TYPE: HUMAN

YEAR: 2018

INTERPRETATION OF THE PREMISE OF FINDINGS

“Molecular hydrogen (H₂) treatment significantly reinvigorated exhausted CD8+ T cells, enhancing their proliferation and cytokine production, which correlated with a marked improvement in patient prognosis and survival rates.”

QUOTE FROM BODY OF TEXT

“Notably, hydrogen gas decreased the abundance of exhausted terminal PD-1+ CD8+ T cells, increased that of active terminal PD-1- CD8+ T cells, and improved PFS and OS times, suggesting that the balance between terminal PD1+ and PD1- CD8+ T cells is critical for cancer prognosis.”

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