Structural and (Pseudo-)Enzymatic Properties of Neuroglobin: Its Possible Role in Neuroprotection

Neuroglobin (Ngb), the third member of the globin family, was discovered in human and murine brains in 2000. This monomeric globin is structurally similar to myoglobin (Mb) and hemoglobin (Hb) α and β subunits, but it hosts a bis-histidyl six-coordinated heme-Fe atom. Therefore, the heme-based reactivity of Ngb is modulated by the dissociation of the distal HisE7-heme-Fe bond, which reflects in turn the redox state of the cell. The high Ngb levels (~100–200 μM) present in the retinal ganglion cell layer and in the optic nerve facilitate the O2 buffer and delivery. In contrast, the very low levels of Ngb (~1 μM) in most tissues and organs support (pseudo-)enzymatic properties including NO/O2 metabolism, peroxynitrite and free radical scavenging, nitrite, hydroxylamine, hydrogen sulfide reduction, and the nitration of aromatic compounds. Here, structural and (pseudo-)enzymatic properties of Ngb, which are at the root of tissue and organ protection, are reviewed, envisaging a possible role in the protection from neuronal degeneration of the retina and the optic nerve.

TFEB Dependent Autophagy-Lysosomal Pathway: An Emerging Pharmacological Target in Sepsis

Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis.

Hydrogen: Potential Applications in Solid Organ Transplantation

Ischemia reperfusion injury (IRI) in organ transplantation has always been an important hotspot in organ protection. Hydrogen, as an antioxidant, has been shown to have anti-inflammatory, antioxidant, and antiapoptotic effects. In this paper, the protective effect of hydrogen against IRI in organ transplantation has been reviewed to provide clues for future clinical studies.

Cynanchum auriculatum Royle ex Wight., Cynanchum bungei Decne. and Cynanchum wilfordii (Maxim.) Hemsl.: Current Research and Prospects

Cynanchum auriculatum Royle ex Wight. (CA), Cynanchum bungei Decne. (CB) and Cynanchum wilfordii (Maxim.) Hemsl. (CW) are three close species belonging to the Asclepiadaceous family, and their dry roots as the bioactive part have been revealed to exhibit anti-tumor, neuroprotection, organ protection, reducing liver lipid and blood lipid, immunomodulatory, anti-inflammatory, and other activities. Until 2021, phytochemistry investigations have uncovered 232 compounds isolated from three species, which could be classified into C21-steroids, acetophenones, terpenoids, and alkaloids. In this review, the morphology characteristics, species identification, and the relationship of botany, extraction, and the separation of chemical constituents, along with the molecular mechanism and pharmacokinetics of bioactive constituents of three species, are summarized for the first time, and their phytochemistry, pharmacology, and clinical safety are also updated. Moreover, the direction and limitation of current research on three species is also discussed.

Calcium channel blocker in patients with chronic kidney disease

Background Chronic kidney disease (CKD) is involved in a progressive deterioration in renal function over the years and is now a global public health problem. Currently, reducing the number of patients progressing to end-stage renal failure is urgently necessary. Hypertension and CKD interact with each other, and good control of blood pressure (BP) can improve CKD patients’ prognosis. With the current global trend for more strict BP control, the importance of BP management and the need for medication to achieve this strict goal are increasing. Calcium channel blockers (CCBs), which target voltage-dependent calcium channels, are frequently used in combination with renin–angiotensin–aldosterone system inhibitors for CKD patients because of their strong BP-lowering properties and relatively few adverse side effects. Calcium channels have several subtypes, including L, N, T, P/Q, and R, and three types of CCBs, L-type CCBs, L-/T-type CCBs, and L-/N-type CCBs, that are available. Nowadays, the new functions and effects of the CCBs are being elucidated. Conclusion We should use different types of CCBs properly depending on their pharmacological effects, such as the strength of antihypertensive effects and the organ protection effects, taking into account the pathophysiology of the patients. In this article, the role and the use of CCBs in CKD patients are reviewed.

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

The incidence of type 2 diabetes (T2D) has been increasing worldwide, and diabetic kidney disease (DKD) remains one of the leading long-term complications of T2D. Several lines of evidence indicate that glucose-lowering agents prevent the onset and progression of DKD in its early stages but are of limited efficacy in later stages of DKD. However, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor (GLP-1R) antagonists were shown to exert nephroprotective effects in patients with established DKD, i.e., those who had a reduced glomerular filtration rate. These effects cannot be solely attributed to the improved metabolic control of diabetes. In our review, we attempted to discuss the interactions of both groups of agents with inflammation and oxidative stress—the key pathways contributing to organ damage in the course of diabetes. SGLT2i and GLP-1R antagonists attenuate inflammation and oxidative stress in experimental in vitro and in vivo models of DKD in several ways. In addition, we have described experiments showing the same protective mechanisms as found in DKD in non-diabetic kidney injury models as well as in some tissues and organs other than the kidney. The interaction between both drug groups, inflammation and oxidative stress appears to have a universal mechanism of organ protection in diabetes and other diseases.

A systematic analysis of diet-induced nephroprotection reveals overlapping and conserved changes in cysteine catabolism

Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection as well as overlapping metabolic consequences has not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H2S)-dependent cysteine catabolism as a potential common mechanism of organ protection. Importantly, these metabolic changes can be recapitulated in patients preconditioned by a diet limiting sulfur-containing amino acids indicating conserved diet-induced mechanisms of stress-resistance that may ultimately lead to clinical application.

Remote Ischemic Preconditioning Reduces Marathon-Induced Oxidative Stress and Decreases Liver and Heart Injury Markers in the Serum

Clinical studies continue to provide evidence of organ protection by remote ischemic preconditioning (RIPC). However, there is lack of insight into impact of RIPC on exercise-induce changes in human organs’ function. We here aimed to elucidate the effects of 10-day RIPC training on marathon-induced changes in the levels of serum markers of oxidative stress, and liver and heart damage. The study involved 18 male amateur runners taking part in a marathon. RIPC training was performed in the course of four cycles, by inflating and deflating a blood pressure cuff at 5-min intervals (RIPC group, n=10); the control group underwent sham training (n=8). The effects of RIPC on levels of oxidative stress, and liver and heart damage markers were investigated at rest after 10 consecutive days of training and after the marathon run. The 10-day RIPC training decreased the serum resting levels of C-reactive protein (CRP), alanine transaminase (ALT), γ-glutamyl transpeptidase (GGT), and malondialdehyde (MDA). After the marathon run, creatinine kinase MB (CK-MB), lactate dehydrogenase (LDH), cardiac troponin level (cTn), aspartate aminotransferase (AST), alkaline phosphatase (ALP), ALT, total bilirubin (BIL-T), and MDA levels were increased and arterial ketone body ratio (AKBR) levels were decreased in all participants. The changes were significantly diminished in the RIPC group compared with the control group. The GGT activity remained constant in the RIPC group but significantly increased in the control group after the marathon run. In conclusion, the study provides evidence for a protective effect of RIPC against liver and heart damage induced by strenuous exercise, such as the marathon.

Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.