Although hyperhomocysteinemia (HHcy) occurs due to the deficiency in cystathionine-β-synthase (CBS) causing skeletal muscle dysfunction, it is still unclear whether this effect is mediated through oxidative/endoplasmic reticulum (ER)-stress or both. Nevertheless, there is no treatment option available to improve HHcy-mediated muscle injury. Hydrogen sulfide (HS) is an anti-oxidant compound and patients with CBS mutation do not produce HS. In this study, we hypothesized that HS mitigates HHcy-induced redox imbalance/ER-stress during skeletal muscle atrophy via JNK-phosphorylation. We used CBS mice to study HHcy-mediated muscle atrophy and treated them with sodium hydrogen sulfide (NaHS, an HS donor). Proteins and mRNAs were examined by Western blots and qPCR. Pro-inflammatory cytokines were also measured. Muscle mass and strength were studied via fatigue-susceptibility test. Our data revealed that HHcy was detrimental to skeletal mass, particularly gastrocnemius and quadriceps muscles weights. We noticed that oxidative-stress were reversed by NaHS in Hcy-treated C2C12 cells. Interestingly, ER-stress markers (GRP78, ATF6, pIRE1α, and pJNK) were elevated in-vivo and in-vitro, and NaHS mitigated these effects. Additionally, we observed that JNK-phosphorylation was upregulated in C2C12 after Hcy treatment, but NaHS could not reduce this effect. Furthermore, inflammatory cytokines IL-6 and TNF-α were higher in plasma from CBS as compared to wild-type mice. FOXO1-mediated Atrogin-1 and MuRF-1 upregulation were attenuated by NaHS. Functional studies revealed that NaHS administration improved muscle fatigability in CBS mice. In conclusion, our work provides evidence that NaHS is beneficial in mitigating HHcy-mediated skeletal injury incited by oxidative/ER-stress responses.

Diabetic patients suffer from a host of physiological abnormalities beyond just those of glucose metabolism. These abnormalities often lead to systemic inflammation via modulation of several inflammation-related genes, their respective gene products, homocysteine metabolism, and pyroptosis. The very nature of this homeostatic disruption re-sets the overall physiology of diabetics via upregulation of immune responses, enhanced retinal neovascularization, upregulation of epigenetic events, and disturbances in cells’ redox regulatory system. This altered pathophysiological milieu can lead to the development of diabetic retinopathy (DR), a debilitating vision-threatening eye condition with microvascular complications. DR is the most prevalent cause of irreversible blindness in the working-age adults throughout the world as it can lead to severe structural and functional remodeling of the retina, decreasing vision and thus diminishing the quality of life. In this manuscript, we attempt to summarize recent developments and new insights to explore the very nature of this intertwined crosstalk between components of the immune system and their metabolic orchestrations to elucidate the pathophysiology of DR. Understanding the multifaceted nature of the cellular and molecular factors that are involved in DR could reveal new targets for effective diagnostics, therapeutics, prognostics, preventive tools, and finally strategies to combat the development and progression of DR in susceptible subjects.

In the United States, breast cancer is the second leading cause of death among women, and even though different therapies can treat primary breast tumors, most breast cancer-related deaths (>95%) occur due to metastasis. A majority (~70%) of breast tumors are found to express estrogen receptor, and a significant portion (~90%) of ER-positive (ER+) breast tumors are also androgen receptor-positive (AR+). Although ER is known to promote tumorigenesis, the role and underlying mechanism(s) of AR in these closely knit processes remain controversial. Endocrine therapies are the most commonly used treatment for patients with ER+ breast tumors; but, ~30%-50% of initially responsive patients develop resistance to these therapies. Whereas 70%–90% of all breast tumors are AR+ and AR overexpression is correlated with endocrine resistance, but the precise molecular mechanism(s) for this association is yet to be studied. Multiple mechanisms have been proposed to show AR and ER interactions, which indicate that AR may preferentially regulate expression of a subset of ER-responsive genes and that may be responsible for breast cancer and its progression in affected patients. On the other hand, most of the ER+ breast tumors found in post-menopausal women (~80%); and they have very low 17β-estradiol and high androgen levels, but how these hormonal changes make someone more prone to cancer phenotype has long been a disputed issue. In this study, we have discussed multiple molecular mechanisms that we believe are central to the understanding of the overall contributions of AR in breast cancer and its metastasis in post-menopausal women.

Neoangiogenesis is a fundamental process which helps to meet energy requirements, tissue growth, and wound healing. Although previous studies showed that Peroxisome proliferator‐activated receptor (PPAR‐γ) regulates neoangiogenesis via upregulation of vascular endothelial growth factor (VEGF), and both VEGF and PPAR‐γ expressions were inhibited during hyperhomocysteinemic (HHcy), whether these two processes could trigger pathological effects in skeletal muscle via compromising neoangiogenesis has not been studied yet. Unfortunately, there are no treatment options available to date for ameliorating HHcy‐mediated neoangiogenic defects. Hydrogen sulfide (H2S) is a novel gasotransmitter that can induce PPAR‐γ levels. However, patients with cystathionine‐β‐synthase (CBS) mutation(s) cannot produce a sufficient amount of H2S. We hypothesized that exogenous supplementation of H2S might improve HHcy‐mediated poor neoangiogenesis via the PPAR‐γ/VEGF axis. To examine this, we created a hind limb femoral artery ligation (FAL) in CBS +/− mouse model and treated them with GYY4137 (a long‐acting H2S donor compound) for 21 days. To evaluate neoangiogenesis, we used barium sulfate angiography and laser Doppler blood flow measurements in the ischemic hind limbs of experimental mice post‐FAL to assess blood flow. Proteins and mRNAs levels were studied by Western blots and qPCR analyses. HIF1‐α, VEGF, PPAR‐γ and p‐eNOS expressions were attenuated in skeletal muscle of CBS +/− mice after 21 days of FAL in comparison to wild‐type (WT) mice, that were improved via GYY4137 treatment. We also found that the collateral vessel density and blood flow were significantly reduced in post‐FAL CBS +/− mice compared to WT mice and these effects were ameliorated by GYY4137. Moreover, we found that plasma nitrite levels were decreased in post‐FAL CBS +/− mice compared to WT mice, which were mitigated by GYY4137 supplementation. These results suggest that HHcy can inhibit neoangiogenesis via antagonizing the angiogenic signal pathways encompassing PPAR‐γ/VEGF axis and that GYY4137 could serve as a potential therapeutic to alleviate the harmful metabolic effects of HHcy conditions.

A detrimental consequence of hypermethylation is hyperhomocysteinemia (HHcy), that causes oxidative stress, inflammation, and matrix degradation, which leads to multi-pathology in different organs. Although, it is well known that hypermethylation leads to overall gene silencing and hypomethylation leads to overall gene activation, the role of such process in skeletal muscle dysfunction during HHcy condition is unclear. In this study, we emphasized the multiple mechanisms including epigenetic alteration by which HHcy causes skeletal muscle myopathy. This review also highlights possible role of methylation, histone modification, and RNA interference in skeletal muscle dysfunction during HHcy condition and potential therapeutic molecules, putative challenges, and methodologies to deal with HHcy mediated skeletal muscle dysfunction. We also highlighted that B vitamins (mainly B12 and B6), with folic acid supplementation, could be useful as an adjuvant therapy to reverse these consequences associated with this HHcy conditions in skeletal muscle. However, we would recommend to further study involving long-term trials could help to assess efficacy of the use of these therapeutic agents. J. Cell. Biochem. 118: 2108-2117, 2017. © 2017 Wiley Periodicals, Inc.