Targeting cellular senescence in cancer by plant secondary metabolites: A systematic review.

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications.

Tinnitus and auditory cortex; Using adapted functional near-infrared-spectroscopy to expand brain imaging in humans.

OBJECTIVES: Phantom sound perception (tinnitus) may arise from altered brain activity within auditory cortex. Auditory cortex neurons in tinnitus animal models show increased spontaneous firing rates. This may be a core characteristic of tinnitus. Functional near-infrared spectroscopy (fNIRS) has shown similar findings in human auditory cortex. Current fNIRS approaches with cap recordings are limited to ∼3 cm depth of signal penetration due to the skull thickness. To address this limitation, we present an innovative fNIRS approach via probes adapted to the external auditory canal. The adapted probes were placed deeper and closer to temporal lobe of the brain to bypass confining skull bone and improve neural recordings. METHODS: Twenty adults with tinnitus and 20 nontinnitus controls listened to periods of silence and broadband noise (BBN) during standard cap and adapted ear canal fNIRS neuroimaging. The evaluators were not blinded, but the protocol and postprocessing for the two groups were identical. RESULTS: Standard fNIRS measurements in participants with tinnitus revealed increased auditory cortex activity during silence that was suppressed during auditory stimulation with BBN. Conversely, controls displayed increased activation with noise but not during silence. Importantly, adapted ear canal fNIRs probes showed similar hemodynamic responses seen with cap probes in both tinnitus and controls. CONCLUSIONS: In this proof of concept study, we have successfully fabricated, adapted, and utilized a novel fNIRS technology that replicates established findings from traditional cap fNIRS probes. This exciting new innovation, validated by replicating previous and current cap findings in auditory cortex, may have applications to future studies to investigate brain changes not only in tinnitus but in other pathologic states that may involve the temporal lobe and surrounding brain regions. LEVEL OF EVIDENCE: NA.

Tinnitus and auditory cortex: using adapted functional near-infrared spectroscopy to measure resting-state functional connectivity.

OBJECTIVE: Tinnitus, phantom sound perception, arises from aberrant brain activity within auditory cortex. In tinnitus animal models, auditory cortex neurons show increased spontaneous firing and neural synchrony. In humans, similar hyperactivation in auditory cortex has been displayed with functional near-infrared spectroscopy (fNIRS). Resting-state functional connectivity (RSFC) or increased connectivity between brain regions has also been shown in tinnitus using fNIRS. However, current fNIRS technology utilizes infrared (IR)-sources and IR-detectors placed on the scalp that restricts (~3 cm depth IR penetration) signal capture to outer cerebral cortex due to skin and skull bone. To overcome this limitation, in this proof of concept study, we adapted fNIRS probes to fit in the external auditory canal (EAC) to physically place IR-probes deeper within the skull thereby extracting neural signals from deeper auditory cortex. METHODS: Twenty adults with tinnitus and 20 nontinnitus controls listened to periods of silence and broadband noise before and after 5 min of silence to calculate RSFC. Concurrent scalp probes over auditory cortex and an adapted probe placed in the right EAC were utilized. RESULTS: For standard probes, left and right auditory cortex in tinnitus showed increased RSFC to each other and to other nonauditory cortices. Interestingly, adapted fNIRS probes showed trends toward increased RSFC. CONCLUSION: While many areas for the adapted probes did not reach significance, these data using a highly innovative and newly created probe adapting fNIRS technology to the EAC substantiates our previously published data in human tinnitus and concurrently validates this technology as a useful and expanded brain imaging modality.