Effectiveness and Safety of Mesh Repair for Incarcerated or Strangulated Hernias: A Systematic Review and Meta-Analysis.

BACKGROUND: Hernia repair with mesh in patients with incarcerated or strangulated hernias is controversial. Moreover, the use of mesh for hernia repair with concomitant bowel resection poses a great dilemma. This study compared the outcomes of mesh and anatomic repairs in patients with acutely incarcerated or strangulated hernias. METHODS: PubMed, Embase, and Cochrane databases were searched for studies published before November 2019. Randomized controlled trials (RCTs) and prospective studies were included. We conducted meta-analyses using a random-effects model. The treatment outcome was measured by the incidence of surgical site infection (SSI), seroma formation, and hernia recurrence postoperatively. RESULTS: Two RCTs and six prospective studies with 978 patients were included. No significant difference in SSI incidence was observed between patients with incarcerated hernia from the mesh and anatomic repair groups. Recurrence was significantly lower in mesh repair group than in anatomic repair group (odds ratio, 0.08; 95% confidence interval, 0.01-0.45). Only two patients needed to have mesh explantation due to mesh infection. In the setting of hernia repair with concomitant bowel resection, the SSI rate with mesh repair was slightly higher, but most cases of infections were well controlled with conservative antibiotic therapy. CONCLUSIONS: Mesh repair for incarcerated or strangulated hernias was feasible with a great benefit of lower recurrence rates. However, due to limited data, drawing conclusions regarding the use of mesh for hernia repair with concomitant bowel resection was difficult. Further studies with preset criteria for evaluating patients undergoing concomitant bowel resection may help elucidate this issue.

Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases.

The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.

All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells.

Aldehyde dehydrogenase 1 (ALDH1) is a cancer stem-like cell (CSC) marker in human cancers; however, the specific ALDH1-regulated function and its underlying signalling pathways have not been fully demonstrated. Here, we investigated the ALDH1-regulated function and its underlying signalling and tested whether all-trans retinoic acid (ATRA) can suppress ALDH1-regulated tumour behaviour in ovarian cancer cells. By modulating ALDH1 expression using flow cytometry enrichment and exogenous overexpression or knockdown, we showed that the ALDH1 activity is positively correlated with stemness in ovarian cancer cells according to measures such as sphere formation and CSC marker expression as well as tumourigenesis in a mouse xenograft model. The findings indicate that the ALDH1 directly regulates the functions of ovarian cancer cells. We also showed that ALDH1 can regulate the expression of FoxM1 and Notch 1, which are involved in the downstream signalling of ALDH1-mediated biofunctions. Inhibition of FoxM1 by Thiostrepton and of Notch1 by DAPT downregulated the sphere formation ability of cells. ATRA reduced ALDH1 expression, suppressed tumour formation and inhibited sphere formation, cell migration and invasion in ALDH1-abundant ovarian cancer cells. We conclude that ATRA downregulates ALDH1/FoxM1/Notch1 signalling and suppresses tumour formation in ovarian cancer cells.

Glycosylation regulates the function and membrane localization of KCC4.

Glycosylation plays a role in regulating many biological activities, including protein folding and cell surface expression of biomolecules. However, the importance of glycosylation for KCC4 function has not previously been demonstrated. Site-directed mutagenesis was performed on the four putative extracellular N-linked glycosylation sites of KCC4 to determine the role of these sites in KCC4 half-life, cell surface expression, and transporter activity, as well as in KCC4-dependent tumor formation. We showed that triple (N312/331/344/Q) and quadruple (N312/331/344/360/Q) mutations of N-linked glycosylation sites disrupt the N-linked glycosylation of KCC4, resulting in the accumulation of KCC4, predominantly in the endoplasmic reticulum (ER) and not at the cell surface. Further investigation indicated that mutations of the central two (N331/344/Q) N-linked glycosylation sites inhibit the membrane trafficking of KCC4. Our data suggest that the glycan moieties at the N331 and N344 sites were Endo H-resistant, complex-form structures, and that the N312 and N360 sites were Endo H-sensitive, high mannose-containing structures. Under hypotonic stress conditions, the ability to adapt to changes in intracellular chloride ion concentrations and RVD (regulatory volume decrease) activities were less efficient in cells containing the deglycosylated form of KCC4 that were not expressed at the cell surface. Deglycosylated forms of KCC4 also demonstrated decreased tumor formation and lung colonization in mouse xenografts. The difference in glycan complexity may account for the differential impact of each branch on the biological effects of KCC4. We propose that glycosylation is essential for the surface expression, stabilization, and bioactivity of KCC4.

Hyperphosphorylation-Mimetic TDP-43 Drives Amyloid Formation and Possesses Neuronal Toxicity at the Oligomeric Stage.

TDP-43 proteinopathies cover a range of neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Hyperphosphorylated TDP-43 was found within the inclusion bodies in disease lesions; however, the role of hyperphosphorylation and the toxic species are still ambiguous. To characterize the hyperphosphorylation effect of TDP-43, here, we employed five serine mutations implicated in the diseases at serine locations 379, 403, 404, 409, and 410 in the C-terminus to aspartate (S5D) and to alanine (S5A). We systematically characterized the conformation, liquid-liquid phase separation, oligomerization, and fibrillization of TDP-43 variants. Results revealed that the recombinant TDP-43 variants readily formed structurally similar spherical oligomers, as evidenced by circular dichroism spectroscopy, fluorescence spectroscopy, the TDP-43 oligomer-specific antibody assay, dynamic light scattering, and transmission electron microscopy. After incubation, only the phosphor-mimic S5D TDP-43 formed thioflavin-positive amyloid fibrils, whereas wild-type and S5A TDP-43 formed amorphous aggregates. We also examined membrane disruption, the cytotoxicity of human neuroblastoma, and the synaptic loss of primary neurons induced by oligomers and large aggregates of TDP-43. The results showed that all oligomeric TDP-43 variants were toxic regardless of hyperphosphorylation, but the fibrils and amorphous aggregates were not. Overall, our results demonstrated the hyperphosphorylation effect on fibril formation and the toxicity attributed from TDP-43 oligomers. This study facilitates the understanding and therapeutic development for TDP-43 proteinopathies.

Loss of Sigma-1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense.

Sigma-1 receptor (Sig-1R) functions as a chaperon that interacts with multiple proteins and lipids and is implicated in neurodegenerative and psychiatric diseases. Here, we used Sig-1R KO mice to examine brain expression profiles of astrocytes and ubiquitinated proteins, which are both hallmarks of central nervous system (CNS) pathologies. Our results showed that Sig-1R KO induces increased glial fibrillary acidic protein (GFAP) expression in primary neuron-glia cultures and in the whole brain of fetus mice with concomitantly increased accumulations of ubiquitinated proteins. Astrogliosis was also observed in the neuron-glia culture. Upon proteasome or autophagy inhibitor treatments, the pronounced ubiquitinated proteins were further increased in Sig-1R KO neurons, indicating that the Sig-1R regulates both protein degradation and quality control systems. We found that Nrf2 (nuclear factor erythroid 2-related factor 2), which functions to overcome the stress condition, was enhanced in the Sig-1R KO systems especially when cells were under stressful conditions. Mutation or deficiency of Sig-1Rs has been observed in neurodegenerative models. Our study identifies the critical roles of Sig-1R in CNS homeostasis and supports the idea that functional complementation pathways are triggered in the Sig-1R KO pathology.

Effect of Ha-rasval12 on nm23 expression, tumor formation and metastasis of the transformants, and immunomodulation in tumor-bearing mice.

Overexpression of the Ha-ras(val12) oncogene has frequently been detected in primary and metastatic carcinomas. NM23 is a metastasis inhibition factor and plays a suppressive role in metastasis in many types of cancer. In this study, a stable NIH/3T3 cell line harboring an inducible Ha-ras(val12) oncogene (designated as 7-4) and small interfering RNAs (siRNAs) were used to clarify the inverse correlation between nm23 and Ha-ras expression both in vitro and in vivo. A derivative 7-4/Z-3 cell line harboring a ß-galactosidase reporter gene was used to trace cell metastasis in a murine tumor model. The data presented here reveal that Ha-ras(val12) is able to cause cell morphological changes, induce tumor formation, and promote metastasis of tumor cells to the lungs. In mice with metastases, the immune surveillance against tumor formation was suppressed by Ha-ras(val12) overexpression through an increase in T-reg cells and a decrease of cytotoxic T lymphocytes and natural killer cell populations. Our results suggest that the Ha-ras oncogene regulates morphogenesis, tumorigenesis, and metastasis through suppressing nm23 expression and modulation of immune cell function.