It is generally accepted that healthy cells degrade their own mitochondria. Here, we report that retinal ganglion cell axons of WT mice shed mitochondria at the optic nerve head (ONH), and that these mitochondria are internalized and degraded by adjacent astrocytes. EM demonstrates that mitochondria are shed through formation of large protrusions that originate from otherwise healthy axons. A virally introduced tandem fluorophore protein reporter of acidified mitochondria reveals that acidified axonal mitochondria originating from the retinal ganglion cell are associated with lysosomes within columns of astrocytes in the ONH. According to this reporter, a greater proportion of retinal ganglion cell mitochondria are degraded at the ONH than in the ganglion cell soma. Consistently, analyses of degrading DNA reveal extensive mtDNA degradation within the optic nerve astrocytes, some of which comes from retinal ganglion cell axons.Together, these results demonstrate that surprisingly large proportions of retinal ganglion cell axonal mitochondria are normally degraded by the astrocytes of the ONH. This transcellular degradation of mitochondria, or transmitophagy, likely occurs elsewhere in the CNS, because structurally similar accumulations of degrading mitochondria are also found along neurites in superficial layers of the cerebral cortex. Thus, the general assumption that neurons or other cells necessarily degrade their own mitochondria should be reconsidered.mitophagy | phagocytosis T he number, half-life, and morphology of mitochondria vary widely across cell types and are regulated by both intrinsic and extrinsic mechanisms. Mitochondria number is controlled through regulated production (1) and degradation (2), as well as by the regulated fusion and fission of existing mitochondria (3). Damaged mitochondria are removed by mitophagy, a subtype of autophagy that involves the enwrapping of mitochondria in autophagosomes that subsequently fuse with lysosomes to become autophagolysosomes (2). Implicit in the categorization of mitophagy as a subtype of autophagy is the assumption that each cell degrades its own mitochondria.Recently, we described a phenomenon at the optic nerve head (ONH) of WT mice, where evulsions originating from otherwise intact axons are engulfed and degraded by resident phagocytic astrocytes (4). Serial section-based 3D reconstructions obtained through serial block-face scanning electron microscopy (SBEM) revealed that the protrusions on axons and the evulsions near axons were common throughout the ONH in both the glial lamina, where retinal ganglion cell axons are unmyelinated, and in the adjacent myelination transition zone (MTZ). The axonal protrusions and evulsions were, on average, larger than the mean diameter of axons and contained membrane-bound organelles of unknown identity. Results Axonal Protrusions and Evulsions Within the ONH Contain Mitochondria.To determine the identity of the membranous material contained within the axonal evulsions at the ONH, a 3-mo-old WT C57BL/6J mouse was an...

Summary It is widely believed that damaged axons in the adult mammalian brain have little capacity to regrow, thereby impeding functional recovery after injury. Studies using fixed tissue have suggested that serotonin neurons might be a notable exception, but remain inconclusive. We have employed in vivo two-photon microscopy to produce time-lapse images of serotonin axons in the neocortex of the adult mouse. Serotonin axons undergo massive retrograde degeneration following amphetamine treatment and subsequent slow recovery of axonal density which is dominated by new growth with little contribution from local sprouting. A stab injury that transects serotonin axons running in the neocortex is followed by local regression of cut serotonin axons and followed by regrowth from cut ends into and across the stab rift zone. Regrowing serotonin axons do not follow the pathways left by degenerated axons. The regrown axons release serotonin and their regrowth is correlated with recovery in behavioral tests.

Our findings suggest that APTG-CM is able to provide a cementogenic microenvironment and induce differentiation of PDLSCs along the cementoblastic lineage. This has important implications for periodontal engineering.

A new natural product (N-acetyltryptophan), together with 22 known constituents, including seven alkaloids, six flavonoids, six organic acids, and other compounds, were isolated from Salsola collina Pall. Their structures were elucidated on the basis of chemical reaction and spectral evidence. Among the isolated compounds, N-acetyltryptophan (8) showed moderate inhibition of D-amylase activity, and terrestric acid (9) showed positive antifungal activity.Salsola collina Pall., which is widely distributed in northeastern and southwestern China, has been used as food or folk medicine for the treatment of hypertension, headache, and vertigo in China. Few phytochemical investigations of the plant have been previously reported, and they mainly refer to the isolation of sterols >1@, sugars, sugar esters >2@, flavonoids >3-6@, and alkaloids >7, 8@. Salsoline A, an alkaloid isolated from Salsola collina Pall., showed appreciable antibacterial activity and moderate antiviral activity against influenza virus A and B >9@. To isolate new compounds and to search for biologically active compounds from Salsola collina Pall., we have carried out a phytochemical investigation of it, obtaining 23 compounds, which were pericampylinone-A (1) >10@, salsoline A (2) >7@, moupinamide (3) >11@, 7c-hydroxymoupinamide (4) >12@, 7c-hydroxy-3c-methylmoupinamide (5) >12@, uracil (6) >13@, uridine (7) >14@, N-acetyltryptophan (8) >15, 16@ terrestric acid (9) >17@, anisic acid (10), protocatechuic aldehyde (11), vanillin (12) >18@, corchoionoside C (13) >19@, acetyl ferulic acid (14) >20@, p-hydroxycinnamic acid (15) >8@, salicylic acid (16), isorhamnetin (17) >21], tricin (18) >22@, tricin-7-O-E-Dglucopyranoside (19) >8@, 5,2c-dihydroxy-6,7-methylenedioxyisoflavone (20) >23@, quercetin (21) >24@, rutin (22) >25@ and p-hydroxybenzoic acid (23). Among these compounds, N-acetyltryptophan (8) was a new natural product, and compounds 1-9 and 11-14 were isolated from this plant for the first time. The biologically active results showed that N-acetyltryptophan (8) had moderate D-amylase inhibitory activity (Table 1), and terrestric acid (9) had positive antifungal activity (Table 2). NH O HO HO 1 N O HO HO 2 HN N O O R 6, 7 6: R = H; 7: R = ribose N H 3 CO HO O R 2 R 1 OH H 3 -5 3: R 1 = R 2 = H; 4: R 1 = H, R 2 = OH 5: R 1 = OCH 3 , R 2 = OH

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It is important to monitor serotonin neurochemistry in the context of brain disorders. Specifically, a better understanding of biophysical alterations and associated biochemical functionality within subregions of the brain will enable better of understanding of diseases such as depression. Fast voltammetric tools at carbon fiber microelectrodes provide an opportunity to make direct evoked and ambient serotonin measurements in vivo in mice. In this study, we characterize novel stimulation and measurement circuitries for serotonin analyses in brain regions relevant to psychiatric disease. Evoked and ambient serotonin in these brain areas, the CA2 region of the hippocampus and the medial prefrontal cortex, are compared to ambient and evoked serotonin in the substantia nigra pars reticulata, an area well established previously for serotonin measurements with fast voltammetry. Stimulation of a common axonal location evoked serotonin in all three brain regions. Differences are observed in the serotonin release and reuptake profiles between these three brain areas which we hypothesize to arise from tissue physiology heterogeneity around the carbon fiber microelectrodes. We validate this hypothesis mathematically and via confocal imaging. We thereby show that fast voltammetric methods can provide accurate information about local physiology and highlight implications for chemical mapping. Cover Image for this issue: doi: .

Glutamate produces both fast excitation through activation of ionotropic receptors and slower actions through metabotropic receptors (mGluRs). To date, ionotropic but not metabotropic neurotransmission has been shown to undergo long-term synaptic potentiation and depression. Burst stimulation of parallel fibers releases glutamate, which activates perisynaptic mGluR1 in the dendritic spines of cerebellar Purkinje cells. Here, we show that the mGluR1-dependent slow EPSC and its coincident Ca transient were selectively and persistently depressed by repeated climbing fiber-evoked depolarization of Purkinje cells in brain slices. LTD(mGluR1) was also observed when slow synaptic current was evoked by exogenous application of a group I mGluR agonist, implying a postsynaptic expression mechanism. Ca imaging further revealed that LTD(mGluR1) was expressed as coincident attenuation of both limbs of mGluR1 signaling: the slow EPSC and PLC/IP3-mediated dendritic Ca mobilization. Thus, different patterns of neural activity can evoke LTD of either fast ionotropic or slow mGluR1-mediated synaptic signaling.

Reactive oxygen species (ROS) are highly reactive oxidant molecules that can kill cancer cells through irreversible damage to biomacromolecules. ROS-mediated cancer therapies, such as chemodynamic (CDT) and photodynamic therapy (PDT), are often limited by the hypoxia tumor microenvironment (TME) with high glutathione (GSH) level. This paper reported the preparation, characterization, in vitro and in vivo antitumor bioactivity of a meso-tetra(4-carboxyphenyl)porphine (TCPP)-based therapeutic nanoplatform (CMMFTP) to overcome the limitations of TME. Using Cu2+ as the central ion and TCPP as the ligand, the 2D metal-organic framework Cu-TCPP was synthesized by the solvothermal method, then CMMFTP was prepared by modifying MnO2, folic acid (FA), triphenylphosphine (TPP), and poly (allylamine hydrochloride) (PAH) on the surface of Cu-TCPP MOFs. CMMFTP was designed as a self-oxygenating ROS nanoreactor based on the PDT process of TCPP MOFs and the CDT process by Cu(II) and MnO2 components (mainly through Fenton-like reaction). The in vitro assay suggested CMMFTP caused a 96% lethality rate against Hela cells (MTT analysis) in specific response to TME stimulation. Moreover, the Cu(II) and MnO2 in CMMFTP efficiently depleted the glutathione (80%) in tumor cells and consequently amplified ROS levels to improve CDT/PDT effects. The FA-induced tumor targeting and TPP-induced mitochondria targeting further enhanced the antitumor activity. Therefore, the nanoreactor based on dual targeting and self-oxygenation-enhanced ROS mechanism provided a new strategy for cancer therapy.