Metabolomics in aging research: aging markers from organs.

Metabolism plays an important role in regulating aging at several levels, and metabolic reprogramming is the main driving force of aging. Due to the different metabolic needs of different tissues, the change trend of metabolites during aging in different organs and the influence of different levels of metabolites on organ function are also different, which makes the relationship between the change of metabolite level and aging more complex. However, not all of these changes lead to aging. The development of metabonomics research has opened a door for people to understand the overall changes in the metabolic level in the aging process of organisms. The omics-based "aging clock" of organisms has been established at the level of gene, protein and epigenetic modifications, but there is still no systematic summary at the level of metabolism. Here, we reviewed the relevant research published in the last decade on aging and organ metabolomic changes, discussed several metabolites with high repetition rate, and explained their role in vivo, hoping to find a group of metabolites that can be used as metabolic markers of aging. This information should provide valuable information for future diagnosis or clinical intervention of aging and age-related diseases.

The Epidermal Keratinocyte as a Therapeutic Target for Management of Diabetic Wounds.

Diabetes mellitus (DM) is an important cause of chronic wounds and non-traumatic amputation. The prevalence and number of cases of diabetic mellitus are increasing worldwide. Keratinocytes, the outermost layer of the epidermis, play an important role in wound healing. A high glucose environment may disrupt the physiologic functions of keratinocytes, resulting in prolonged inflammation, impaired proliferation, and the migration of keratinocytes and impaired angiogenesis. This review provides an overview of keratinocyte dysfunctions in a high glucose environment. Effective and safe therapeutic approaches for promoting diabetic wound healing can be developed if molecular mechanisms responsible for keratinocyte dysfunction in high glucose environments are elucidated.

High-temperature and high-efficiency operation of a membrane optical link with a buried-ridge-waveguide bonded on a Si substrate.

We demonstrate a membrane photonic integrated circuit (MPIC) that includes a membrane distributed feedback (DFB) laser and a p-i-n photodiode with a buried-ridge-waveguide (BRW) on a Si substrate, using a-Si nanofilm-assisted room-temperature surface activated bonding (SAB) for on-chip optical interconnection. The BRW structure enhanced the lateral optical confinement compared with that of the conventional flat structure. The directly bonded membrane DFB laser using SAB had a lower thermal resistance and higher output power than the previous structure using a benzocyclobutene (BCB) bonding layer. The DFB laser had a low threshold current of 0.27 mA at 25 °C. The maximum detected photocurrent and slope efficiency were 0.95 mA and 0.203 mA/mA, respectively, at 25 °C. The MPIC was successfully operated at temperatures up to 120 °C. The 3-dB bandwidths of 16.8 GHz and 10.1 GHz were achieved at 25 °C and 80 °C, respectively, and 25 Gbps and 15 Gbps non-return-to-zero (NRZ) 215-1 pseudo-random bit sequence signals were recorded at 25 °C and 80 °C, respectively.

Optical ReLU using membrane lasers for an all-optical neural network.

In this study, we propose low power consumption, programmable on-chip optical nonlinear units (ONUs) for all-optical neural networks (all-ONNs). The proposed units were constructed using a III-V semiconductor membrane laser, and the nonlinearity of the laser was used as the activation function of a rectified linear unit (ReLU). By measuring the relationship of the output power and input light, we succeeded in obtaining the response as an activation function of the ReLU with low power consumption. With its low-power operation and high compatibility with silicon photonics, we believe that this is a very promising device for realizing the ReLU function in optical circuits.

Low-dose tofacitinib with 308-nm excimer therapy successfully induced repigmentation in patients with refractory vitiligo.

Combining low-dose tofacitinib with 308-nm excimer may be an effective treatment for patients with nonsegmental vitiligo who were refractory to conventional therapies.

Mitochondrial Lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity.

Mitochondrial Lon is a multi-function matrix protease with chaperone activity. However, little literature has been undertaken into detailed investigations on how Lon regulates apoptosis through its chaperone activity. Accumulating evidences indicate that various stresses induce transportation of p53 to mitochondria and activate apoptosis in a transcription-independent manner. Here we found that increased Lon interacts with p53 in mitochondrial matrix and restrains the apoptosis induced by p53 under oxidative stress by rescuing the loss of mitochondrial membrane potential (Δψm) and the release of cytochrome C and SMAC/Diablo. Increased chaperone Lon hampers the transcription-dependent apoptotic function of p53 by reducing the mRNA expression of p53 target genes. The ATPase mutant (K529R) of chaperone Lon decreases the interaction with p53 and fails to inhibit apoptosis. Furthermore, the chaperone activity of Lon is important for mitochondrial p53 accumulation in an mtHsp70-dependent manner, which is also important to prevent the cytosolic distribution of p53 from proteasome-dependent degradation. These results indicate that the chaperone activity of Lon is important to bind with mitochondrial p53 by which increased Lon suppresses the apoptotic function of p53 under oxidative stress. Furthermore, mitochondrial Lon-mtHsp70 increases the stability/level of p53 through trafficking and retaining p53 in mitochondrial matrix and preventing the pool of cytosolic p53 from proteasome-dependent degradation in vitro and in clinic.

Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints.

Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and (-)-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzyme-based screening, we identified two small-molecule compounds, obtusilactone A (OA) and (-)-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and (-)-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and (-)-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G(1) /S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G(1) accumulation. In conclusion, OA and (-)-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics.