Role of Mitochondrial Therapy for Ischemic-Reperfusion Injury and Acute Kidney Injury

Acute kidney injury (AKI) is a common clinical disorder associated with decline in renal function because of ischemic and nephrotoxic insults. The pathophysiology of AKI involves multiple cellular mechanisms, such as kidney parenchymal cell (epithelial and endothelial) dysfunction and immune-cell infiltration. Mitochondrial injury which causes ATP depletion and triggers apoptosis and necrosis is at the heart of ischemia reperfusion injury (IRI). Pharmacological (SS-31 or MitoQ), cellular (dendritic cells or mesenchymal stem cells), or genetic strategies that either directly or indirectly preserve mitochondrial integrity and function have been shown to mitigate IRI-linked AKI in preclinical models. Interestingly, isolated mitochondria have been recently shown to be taken up by various mammalian cells resulting in incorporation of transplanted mitochondria into the endogenous mitochondrial network of recipient cells and contributing to protection from ischemic injury in various preclinical models of ischemia including the heart, liver, and kidneys. The mini review summarizes the current available therapeutic strategies that improve kidney function by targeting mitochondria health.

The Endothelial Barrier Restricts Endocrine Actions to the Luminal Vascular Receptors: Changing the Paradigm: A Didactic Approach

In 1849, the first list of endocrine hormones was discovered and proposed that the synthesizing gland delivers it to the circulation. The circulatory hormone reaches the target organ, physically unimpeded acts directly on the parenchymal cells. Such a simplistic view persists despite new knowledge of an endothelial wall barrier and implications for every parenchymal cell in the body. This misconception leads to inadequate interpretations of data, wrong diagnosis and therapeutic expectations, erroneous hypotheses, and misleads further research work. The quest of this review is to play down this misconception by pointing out key overlooked findings of the vascular endothelial wall: 1) The selective endothelial barrier physically separates two same-hormone-containing compartments; the endocrine and the interstitial autocrine hormone compartments, 2) the hormone concentrations values in these compartments are independent of each other, 3) in each compartment the hormone acts solely on the receptors of that particular compartment, 4) multiple intravascular endocrine hormones act solely on their corresponding luminal endothelial membrane receptor (LEMR), without directly acting on the parenchymal cells, 5) Agonist-activation of LEMR triggers the release of specific paracrine endothelial agents that in conjunction with autocrine interstitial hormone modulate parenchymal function(s) and perhaps the turnover of the interstitial autocrine hormone, 6) these hormone compartments, functionally interact via paracrine exchange signaling, and the integrated intercourse of all these events result in the final hormonal organ effect. The present challenges to achieving more rationale therapeutic effects are to design agonists or antagonists that exclusively gain access to a target compartment and have high specificity for the receptor of the cells in that compartment.

Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis

Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

Microchannelled alkylated chitosan sponge to treat noncompressible hemorrhages and facilitate wound healing

Developing an anti-infective shape-memory hemostatic sponge able to guide in situ tissue regeneration for noncompressible hemorrhages in civilian and battlefield settings remains a challenge. Here we engineer hemostatic chitosan sponges with highly interconnective microchannels by combining 3D printed microfiber leaching, freeze-drying, and superficial active modification. We demonstrate that the microchannelled alkylated chitosan sponge (MACS) exhibits the capacity for water and blood absorption, as well as rapid shape recovery. We show that compared to clinically used gauze, gelatin sponge, CELOX™, and CELOX™-gauze, the MACS provides higher pro-coagulant and hemostatic capacities in lethally normal and heparinized rat and pig liver perforation wound models. We demonstrate its anti-infective activity against S. aureus and E. coli and its promotion of liver parenchymal cell infiltration, vascularization, and tissue integration in a rat liver defect model. Overall, the MACS demonstrates promising clinical translational potential in treating lethal noncompressible hemorrhage and facilitating wound healing.

Review on Parkinson’s Disease, a Neurodegenerative Disorder and The Role of Ceruloplasmin Protein in It

Parkinson’s disease (PD), a neurodegenerative disease is becoming major health concern mainly for elder people of age over 60 years. The main cause of PD is permanent loss/death of dopaminergic nerve cells present in brain part called substantia nigra, which is responsible for dopamine synthesis. MAO-B, monoamine oxidase B, regulates dopamine metabolism and increased activity of MAO-B causes dopamine degradation which in turn promotes the accumulation of glutamate and oxidative stress with free radical liberation. Several factors like oxidative stress, free radical formation, increased cholesterol, mitochondrial dysfunction, nitric oxide toxicity, signal-mediated apoptosis, head trauma, and environmental toxins and gene mutations like VPS35, SNCA, EIF4G1, GBA, CHCHD, LRRK2, PINK1, DNAJC13 and SOD2 are associated with PD. Symptoms of PD include bradykinesia, muscle rigidity, resting tremors, postural instability and shuffling gait, constipation, sleep problems, fatigue, apathy, loss of smell and taste, excessive sweating, frequent nightmares, dream enacting behaviour, anxiety, depression, daytime drowsiness. In PD, low levels of ceruloplasmin were observed in people with early onset of PD. Ceruloplasmin, a ferroxidase enzyme which is synthesized in liver parenchymal cell, regulates iron metabolism and lower level of which causes iron accumulation in brain which is responsible for the early onset of PD. Levodopa-based preparations, Dopamine agonists, Catechol-o-methyltransferase (COMT) inhibitors, MOA-B inhibitors, Adjunctive therapy, Antiglutamatergics drugs are currently used for the treatment of PD.

Volumetric Assessment and Clinical Predictor of Cirrhotic Livers With Normal Liver Function Undergoing Hepatectomy

Aim: Indocyanine green retention rate at 15 minutes (ICGR15) is a frequently-used indicator of liver function. However, cirrhotic liver is sometimes observed intraoperatively despite a normal preoperative ICGR15 (<10 %). Herein, we conducted clinical and volumetric assessments of cirrhotic livers with normal ICGR15.Methods: Patients undergoing hepatectomy for hepatocellular carcinoma were divided into 3 groups: non-cirrhotic livers (Group A, n=112): cirrhotic livers with ICGR15 <10% (Group B, n=71): and cirrhotic livers with ICGR15 >10% (Group C, n=296). Background characteristics and surgical outcomes were compared between groups. Functional liver volume (FLV) was computed using total liver volume and signal intensity ratio. Liver parenchymal cell volume ratio was measured in non-cancerous tissue obtained from resected specimens. Univariate and multivariate analyses were performed to detect clinical characteristics correlating with cirrhotic liver pathology with normal ICGR15.Results: There was no significant difference between groups in TLV. FLV was gradually reduced from Group A toward Group C. Liver parenchymal cell volume ratio was also gradually reduced from Group A toward Group C. Multivariate analysis revealed that platelet count (<12 x104/mm3) (P = 0.001) and prothrombin time (<80 %) (P = 0.025) were significantly associated with cirrhotic liver pathology among patients with normal ICGR15.Conclusion: Our results suggested that cirrhotic liver pathology despite normal liver function was characterized by slightly decreasing liver parenchyma as well as slight degree of fibrosis. Platelet count and PT% are useful for predicting liver cirrhosis with normal ICGR15.

Longitudinal hippocampal volumetric changes in mice following brain infarction

Hippocampal atrophy is increasingly described in many neurodegenerative syndromes in humans, including stroke and vascular cognitive impairment. However, the progression of brain volume changes after stroke in rodent models is poorly characterized. We aimed to monitor hippocampal atrophy occurring in mice up to 48-weeks post-stroke. Male C57BL/6J mice were subjected to an intraluminal filament-induced middle cerebral artery occlusion (MCAO). At baseline, 3-days, and 1-, 4-, 12-, 24-, 36- and 48-weeks post-surgery, we measured sensorimotor behavior and hippocampal volumes from T2-weighted MRI scans. Hippocampal volume—both ipsilateral and contralateral—increased over the life-span of sham-operated mice. In MCAO-subjected mice, different trajectories of ipsilateral hippocampal volume change were observed dependent on whether the hippocampus contained direct infarction, with a decrease in directly infarcted tissue and an increase in non-infarcted tissue. To further investigate these volume changes, neuronal and glial cell densities were assessed in histological brain sections from the subset of MCAO mice lacking hippocampal infarction. Our findings demonstrate previously uncharacterized changes in hippocampal volume and potentially brain parenchymal cell density up to 48-weeks in both sham- and MCAO-operated mice.

Optimal liver metabolism and proliferation require the tight junction protein claudin-3

Objective The expression of hepatic tight junction proteins and their contribution to homeostasis and regeneration remained largely unexplored. Here, we determine the cell type specific expression of tight junction genes in murine livers. We further explore the regulation and functional importance of the transmembrane protein CLDN3 in normal and regenerating livers. Methods Murine livers were used for tissue- and single cell RNA-seq. CLDN3 localization was determined by immunofluorescence. CLDN3+/+ or CLDN3-/- livers were analysed by electron microscopy, fluorescence-activated cell sorting and liquid chromatography mass spectrometry. Lipid content was quantified with oil-red. Mice were subjected to 2/3 partial hepatectomy. Proliferation was quantified with Ki67 and pHH3 stainings. Cell cycle gene expression was determined by RT-qPCR. Barrier impairments were assessed with total bile acid measurements. Differential gene expression was analysed by tissue RNAseq with DESeq2. Results We determined the profile of tight junction gene expression the main liver cell types, showing that tight junction transcripts can be found in hepatocytes and cholangiocytes but also on non-parenchymal cell populations. CLDN3 was among the highly expressed- and regulated genes in native and regenerating livers. CLDN3 had a zonated expression pattern. CLDN3-/- mice had microscopically intact tight junctions, but showed significantly downregulated hepatic energy metabolism and suboptimal cell proliferation in the regeneration model. Conclusion Our data suggests a functional role of CLDN3 for maintenance of energy homeostasis and optimal regeneration, proving that the function of hepatic tight junction proteins extends beyond basic membrane sealing.

Integrated Transcriptome and Metabolome Analysis Reveals an Essential Role for Auxin in Hypocotyl Elongation during End-of-Day Far-Red Treatment of Cucurbita moschata (Duch. Ex Lam.)

Long, robust hypocotyls are important for facilitating greenhouse transplant production. The use of far-red light at the end of the day (end-of-day far-red, EOD-FR) is known to prompt hypocotyl elongation, but the mechanism of EOD-FR-mediated hypocotyl elongation in pumpkin remains unclear. Here, we found that hypocotyl length, parenchymal cell size in hypocotyls, and plant IAA levels were significantly greater in pumpkin after EOD-FR treatment. This effect was counteracted by the application of the polar auxin transport inhibitor 1-N-naphthylphthalamic acid. Integrated transcriptomic and metabolomic analysis of pumpkin hypocotyls revealed that the expression of auxin-related genes changed significantly after EOD-FR treatment, and the contents of the auxin biosynthetic precursors tryptophan and indole were also significantly higher. Our results show that auxin plays an essential role in EOD-FR-mediated hypocotyl elongation, shed light on the mechanisms of EOD-FR mediated hypocotyl elongation, and provide a theoretical basis for the use of EOD-FR in facility cultivation.