Glomerulosclerosis, interstitial fibrosis, and tubular atrophy occur with end-stage kidney failure, irrespective of the primary etiology. The transforming growth factor-β (TGF-β) is a key factor in ...these alterations either directly, by stimulating synthesis of extracellular matrix components and reducing collagenase production, or indirectly through other profibrogenic factors such as connective tissue growth factor (CTGF). TGF-β is important for the proliferation of intrarenal fibroblasts and the epithelial–mesenchymal transition through which tubular cells become fibroblasts. Although several factors induce TGF-β expression in the kidney, one very interesting aspect is the link between the renin–angiotensin—aldosterone (Aldo) system (RAAS) and TGF-β. Angiotensin II (ANG II) stimulates TGF-β expression in the kidney by various mechanisms and upregulates receptors for TGF-β. ANG II can directly phosphorylate Smads without inducing TGF-β. Recent data provide compelling evidence that other components of the RAAS including ANG III, renin, and Aldo also activate the TGF-β system. As direct modulation of the TGF-β system is not yet feasible in humans, angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1)-receptor blockers are currently the most potential drugs to interfere with this ANG II-mediated TGF-β expression. This review highlights some current aspects of the interaction between the RAAS and the TGF-β axis.
Cytokine‐induced killer (CIK) cells represent an exceptional T‐cell population uniting a T cell and natural killer cell‐like phenotype in their terminally differentiated CD3+CD56+ subset, which ...features non‐MHC‐restricted tumor‐killing activity. CIK cells have provided encouraging results in initial clinical studies and revealed synergistic antitumor effects when combined with standard therapeutic procedures. We established the international registry on CIK cells (IRCC) to collect and evaluate clinical trials for the treatment of cancer patients in 2010. Moreover, our registry set new standards on the reporting of results from clinical trials using CIK cells. In the present update, a total of 106 clinical trials including 10,225 patients were enrolled in IRCC, of which 4,889 patients in over 30 distinct tumor entities were treated with CIK cells alone or in combination with conventional or novel therapies. Significantly improved median progression‐free survival and overall survival were shown in 27 trials, and 9 trials reported a significantly increased 5‐year survival rate. Mild adverse effects and graft‐versus‐host diseases were also observed in the studies. Recently, more efforts have been put into the improvement of antitumoral efficacy by CIK cells including the administration of immune checkpoint inhibitors and modification with chimeric antigen receptorc. The minimal toxicity and multiple improvements on their tumor‐killing activity both make CIK cells a favorable therapeutic tool in the clinical practice of cancer immunotherapy.
Cytokine‐induced killer (CIK) cells featuring non‐MHC‐restricted tumor‐killing activity have provided encouraging results in clinical studies. Here, we update the clinical data including a total of 106 trials enrolled in the international registry on CIK cells (IRCC) established in 2010. The recent multiple improvements both on antitumoral efficacy and toxicity make CIK cells an important therapeutic approach in clinical practice of cancer immunotherapy.
Although debated for many years whether haemodynamic or structural changes are more important in the development of diabetic nephropathy, it is now clear that these processes are interwoven and ...present two sides of one coin. On a molecular level, hyperglycaemia and proteins altered by high blood glucose such as Amadori products and advanced glycation end‐products (AGEs) are key players in the development of diabetic nephropathy. Recent evidence suggests that an increase in reactive oxygen species (ROS) formation induced by high glucose‐mediated activation of the mitochondrial electron‐transport chain is an early event in the development of diabetic complications. A variety of growth factors and cytokines are then induced through complex signal transduction pathways involving protein kinase C, mitogen‐activated protein kinases, and the transcription factor NF‐κB. High glucose, AGEs, and ROS act in concert to induce growth factors and cytokines. Particularly, TGF‐β is important in the development of renal hypertrophy and accumulation of extracellular matrix components. Activation of the renin‐angiotensin system by high glucose, mechanical stress, and proteinuria with an increase in local formation of angiotensin II (ANG II) causes many of the pathophysiological changes associated with diabetic nephropathy. In fact, it has been shown that angiotensin II is involved in almost every pathophysiological process implicated in the development of diabetic nephropathy (haemodynamic changes, hypertrophy, extracellular matrix accumulation, growth factor/cytokine induction, ROS formation, podocyte damage, proteinuria, interstitial inflammation). Consequently, blocking these deleterious effects of ANG II is an essential part of every therapeutic regiment to prevent and treat diabetic nephropathy. Recent evidence suggests that regression of diabetic nephropathy could be achieved under certain circumstances.
Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine ...was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.
Protein crystallization is important in structural biology, disease research and pharmaceuticals. It has recently been recognized that nonclassical crystallization-involving initial formation of an ...amorphous precursor phase-occurs often in protein, organic and inorganic crystallization processes
. A two-step nucleation theory has thus been proposed, in which initial low-density, solvated amorphous aggregates subsequently densify, leading to nucleation
. This view differs from classical nucleation theory, which implies that crystalline nuclei forming in solution have the same density and structure as does the final crystalline state
. A protein crystallization mechanism involving this classical pathway has recently been observed directly
. However, a molecular mechanism of nonclassical protein crystallization
has not been established
. To determine the nature of the amorphous precursors and whether crystallization takes place within them (and if so, how order develops at the molecular level), three-dimensional (3D) molecular-level imaging of a crystallization process is required. Here we report cryogenic scanning transmission microscopy tomography of ferritin aggregates at various stages of crystallization, followed by 3D reconstruction using simultaneous iterative reconstruction techniques to provide a 3D picture of crystallization with molecular resolution. As crystalline order gradually increased in the studied aggregates, they exhibited an increase in both order and density from their surface towards their interior. We observed no highly ordered small structures typical of a classical nucleation process, and occasionally we observed several ordered domains emerging within one amorphous aggregate, a phenomenon not predicted by either classical or two-step nucleation theories. Our molecular-level analysis hints at desolvation as the driver of the continuous order-evolution mechanism, a view that goes beyond current nucleation models, yet is consistent with a broad spectrum of protein crystallization mechanisms.
Emerging evidence from the numerous clinical trials involving cytokine-induced killer (CIK) cell therapy suggests that its optimization in combination with other contemporary cancer therapies in a ...complementary manner (rather than as competition) will be a key to combat cancer.
Toxic DNA-protein crosslinks (DPCs) arise by ionizing irradiation and UV light, are particularly caused by endogenously produced reactive compounds such as formaldehyde, and also occur during ...compromised topoisomerase action. Although nucleotide excision repair and homologous recombination contribute to cell survival upon DPCs, hardly anything is known about mechanisms that target the protein component of DPCs directly. Here, we identify the metalloprotease Wss1 as being crucial for cell survival upon exposure to formaldehyde and topoisomerase 1-dependent DNA damage. Yeast mutants lacking Wss1 accumulate DPCs and exhibit gross chromosomal rearrangements. Notably, in vitro assays indicate that substrates such as topoisomerase 1 are processed by the metalloprotease directly and in a DNA-dependent manner. Thus, our data suggest that Wss1 contributes to survival of DPC-harboring cells by acting on DPCs proteolytically. We propose that DPC proteolysis enables repair of these unique lesions via downstream canonical DNA repair pathways.
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•The metalloprotease Wss1 targets DNA-protein crosslinks•Wss1 cleaves its substrates in a DNA-dependent manner•DNA-protein crosslink repair by Wss1 promotes genome stability•Wss1 action enables translesion synthesis of DNA-protein crosslinks
The metalloprotease Wss1 enables the repair of DNA-protein crosslinks by targeting their protein components in a DNA-dependent manner.
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