Hydrogen sulfide has been implicated in a large number of physiological processes including cell survival and death, encouraging research into its mechanisms of action and therapeutic potential. Results from recent studies suggest that the cellular effects of hydrogen sulfide are mediated in part by sulfane sulfur species, including persulfides and polysulfides. In the present study, we investigated the apoptosis-modulating effects of polysulfides, especially on the caspase cascade, which mediates the intrinsic apoptotic pathway. Biochemical analyses revealed that organic or synthetic polysulfides strongly and rapidly inhibit the enzymatic activity of caspase-3, a major effector protease in apoptosis. We attributed the caspase-3 inhibition to persulfidation of its catalytic cysteine. In apoptotically stimulated HeLa cells, short-term exposure to polysulfides triggered the persulfidation and deactivation of cleaved caspase-3. These effects were antagonized by the thioredoxin/thioredoxin reductase system (Trx/TrxR). Trx/TrxR restored the activity of polysulfide-inactivated caspase-3 in vitro, and TrxR inhibition potentiated polysulfide-mediated suppression of caspase-3 activity in situ. We further found that under conditions of low TrxR activity, early cell exposure to polysulfides leads to enhanced persulfidation of initiator caspase-9 and decreases apoptosis. Notably, we show that the proenzymes procaspase-3 and -9 are basally persulfidated in resting (unstimulated) cells and become depersulfidated during their processing and activation. Inhibition of TrxR attenuated the depersulfidation and activation of caspase-9. Taken together, our results reveal that polysulfides target the caspase-9/3 cascade and thereby suppress cancer cell apoptosis, and highlight the role of Trx/TrxR-mediated depersulfidation in enabling caspase activation.

pharmacological treatment of mental disorders is currently decided based on "trial and error" strategy. Mitochondrial multifaceted dysfunction is assumed to be a major factor in the pathophysiology and treatment of schizophrenia (SZ) and bipolar disorder (BD). This study aimed to explore the feasibility of using a profile of mitochondrial function parameters as a tool to predict the optimal drug for an individual patient (personalized medicine). Healthy controls (n = 40), SZ (n = 48) and BD (n = 27) patients were recruited. Mental and global state of the subjects, six mitochondrial respiration parameters and 14 mitochondrial function-related proteins were assessed in fresh lymphocytes following in-vitro or in-vivo treatment with five antipsychotic drugs and two moodstabilizers. In healthy controls, hierarchal clustering shows a drug-specific effect profile on the different mitochondrial parameters following in-vitro exposure. Similar changes were observed in untreated SZ and BD patients with psychosis. Following a month of treatment of the latter patients, only responders showed a significant correlation between drug-induced in-vitro effect (prior to in-vivo treatment) and short-term in-vivo treatment effect for 45% of the parameters. Long-but not shortterm psychotropic treatment normalized mitochondria-related parameters in patients with psychosis. Taken together, these data substantiate mitochondria as a target for psychotropic drugs and provide a proof of concept for selective mitochondrial function-related parameters as a predictive tool for an optimized psychotropic treatment in a given patient. This, however, needs to be repeated with an expanded sample size and additional mitochondria related parameters. Schizophrenia (SZ) and bipolar-disorder (BD) share emotional and cognitive abnormalities and psychotic symptoms, commonly affecting young adults. Both disorders also share genetic risks and endophenotypes 1-3. The research domain criteria (RDoC), based on observable behavioral (symptoms) and neurobiological dimensions rather than traditional diagnostic measures 4 claims a lack of clear boundaries between SZ and BD. Henceforth, in the present study, we studied SZ and BD as a single entity 5. More than 40 different antipsychotic and mood stabilizing drugs are currently available. It has long been held that there is little difference in the therapeutic efficacy of antipsychotics other than clozapine and differences in clinical effects were mainly ascribed to variability in sedative and adverse effect profiles. The truth of this assertion

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