HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration-approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin-dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.

Human hepatocytes and hematolymphoid dual reconstitution in treosulfan-conditioned uPA-NOG mice.

Human-specific HIV-1 and hepatitis co-infections significantly affect patient management and call for new therapeutic options. Small xenotransplantation models with human hepatocytes and hematolymphoid tissue should facilitate antiviral/antiretroviral drug trials. However, experience with mouse strains tested for dual reconstitution is limited, with technical difficulties such as risky manipulations with newborns and high mortality rates due to metabolic abnormalities. The best animal strains for hepatocyte transplantation are not optimal for human hematopoietic stem cell (HSC) engraftment, and vice versa. We evaluated a new strain of highly immunodeficient nonobese diabetic/Shi-scid (severe combined immunodeficiency)/IL-2Rγc(null) (NOG) mice that carry two copies of the mouse albumin promoter-driven urokinase-type plasminogen activator transgene for dual reconstitution with human liver and immune cells. Three approaches for dual reconstitution were evaluated: i) freshly isolated fetal hepatoblasts were injected intrasplenically, followed by transplantation of cryopreserved HSCs obtained from the same tissue samples 1 month later after treosulfan conditioning; ii) treosulfan conditioning is followed by intrasplenic simultaneous transplantation of fetal hepatoblasts and HSCs; and iii) transplantation of mature hepatocytes is followed by mismatched HSCs. The long-term dual reconstitution was achieved on urokinase-type plasminogen activator-NOG mice with mature hepatocytes (not fetal hepatoblasts) and HSCs. Even major histocompatibility complex mismatched transplantation was sustained without any evidence of hepatocyte rejection by the human immune system.

IL-23 in infections, inflammation, autoimmunity and cancer: possible role in HIV-1 and AIDS.

The growing family of interleukin (IL)-12-like cytokines produced by activated macrophages and dendritic cells became the important players in the control of infections, development of inflammation, autoimmunity and cancer. However, the role of one of them-heterodimer IL-23, which consists of IL12p40 and the unique p19 subunit in HIV-1 infection pathogenesis and progression to AIDS, represent special interest. We overviewed findings of IL-23 involvement in control of peripheral bacterial pathogens and opportunistic infection, central nervous system (CNS) viral infections and autoimmune disorders, and tumorogenesis, which potentially could be applicable to HIV-1 and AIDS.

Mitochondriopathy of peripheral arterial disease.

The signs and symptoms of peripheral arterial occlusive disease (PAD), including claudication, rest pain, and tissue loss, are consequences of compromised bioenergetics and oxidative tissue injury within the affected lower extremities. Compromised bioenergetics is the result of a combination of low blood flow through diseased arteries and diminished adenosine triphosphate production by dysfunctional mitochondria. The tissue injury appears to be secondary to increased production of reactive oxygen species by dysfunctional mitochondria and by inflammation, in association with ischemia and ischemia/reperfusion. In this review, we present the current histomorphologic, physiologic, and biochemical evidence defining the nature of this mitochondriopathy and discuss its contribution to the pathogenesis and clinical manifestations of PAD.