Prevent Cell Death Research Articles

Pharmacological Evaluation of Newly Synthesized Cannabidiol Derivates on H9c2 Cells.

Cannabidiol (CBD) is a nonpsychoactive phytocannabinoid that can be found in Cannabis sativa and possesses numerous pharmacological effects. Due to these promising effects, CBD can be used in a wide variety of diseases, for instance cardiovascular diseases. However, CBD, like tetrahydrocannabinol (THC), has low bioavailability, poor water solubility, and a variable pharmacokinetic profile, which hinders its therapeutic use. Chemical derivatization of CBD offers us potential ways to overcome these issues. We prepared three new CBD derivatives substituted on the aromatic ring by Mannich-type reactions, which have not been described so far for the modification of cannabinoids, and studied the protective effect they have on cardiomyocytes exposed to oxidative stress and hypoxia/reoxygenation (H/R) compared to the parent compound. An MTT assay was performed to determine the viability of rat cardiomyocytes treated with test compounds. Trypan blue exclusion and lactate dehydrogenase (LDH) release assays were carried out to study the effect of the new compounds in cells exposed to H2O2 or hypoxia/reoxygenation (H/R). Direct antioxidant activity was evaluated by a total antioxidant capacity (TAC) assay. To study antioxidant protein levels, HO-1, SOD, catalase, and Western blot analysis were carried out. pIC50 (the negative log of the IC50) values were as follows: CBD1: 4.113, CBD2: 3.995, CBD3: 4.190, and CBD: 4.671. The newly synthesized CBD derivatives prevented cell death induced by H/R, especially CBD2. CBD has the largest direct antioxidant activity. The levels of antioxidant proteins were increased differently after pretreatment with synthetic CBD derivatives and CBD. Taken together, our newly synthesized CBD derivatives are able to decrease cytotoxicity during oxidative stress and H/R. The compounds have similar or better effects than CBD on H9c2 cells.

SARS-CoV-2 infection of polarized human airway epithelium induces necroptosis that causes airway epithelial barrier dysfunction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause the ongoing pandemic of coronavirus disease 2019 (COVID19). One key feature associated with COVID-19 is excessive pro-inflammatory cytokine production that leads to severe acute respiratory distress syndrome. Although the cytokine storm induces inflammatory cell death in the host, which type of programmed cell death mechanism that occurs in various organs and cells remains elusive. Using an in vitro culture model of polarized human airway epithelium (HAE), we observed that necroptosis, but not apoptosis or pyroptosis, plays an essential role in the damage of the epithelial barrier of polarized HAE infected with SARS-CoV-2. Pharmacological inhibitors of necroptosis, necrostatin-2 and necrosulfonamide, efficiently prevented cell death and epithelial barrier dysfunction caused by SARS-CoV-2 infection. Moreover, the silencing of genes that are involved in necroptosis, RIPK1, RIPK3, and MLKL, ameliorated airway epithelial damage of the polarized HAE infected with SARS-CoV-2. This study, for the first time, confirms that SARS-CoV-2 infection triggers necroptosis that disrupts the barrier function of human airway epithelia in vitro.

Targeted inhibition of protein synthesis renders cancer cells vulnerable to apoptosis by unfolded protein response

Cellular stress responses including the unfolded protein response (UPR) decide over the fate of an individual cell to ensure survival of the entire organism. During physiologic UPR counter-regulation, protective proteins are upregulated to prevent cell death. A similar strategy induces resistance to UPR in cancer. Therefore, we hypothesized that blocking protein synthesis following induction of UPR substantially enhances drug-induced apoptosis of malignant cells. In line, upregulation of the chaperone BiP was prevented by simultaneous arrest of protein synthesis in B cell malignancies. Cytotoxicity by immunotoxins—approved inhibitors of protein synthesis—was synergistically enhanced in combination with UPR-inducers in seven distinct hematologic and three solid tumor entities in vitro. Synergistic cell death depended on mitochondrial outer membrane permeabilization via BAK/BAX, which correlated with synergistic, IRE1α-dependent reduction of BID, accompanied by an additive fall of MCL-1. The strong synergy was reproduced in vivo against xenograft mouse models of mantle cell lymphoma, Burkitt’s lymphoma, and patient-derived acute lymphoblastic leukemia. In contrast, synergy was absent in blood cells of healthy donors suggesting a tumor-specific vulnerability. Together, these data support clinical evaluation of blocking stress response counter-regulation using inhibitors of protein synthesis as a novel therapeutic strategy.

The novel cyclophilin inhibitor C105SR reduces hepatic ischaemia–reperfusion injury via mitoprotection

Mitochondrial permeability transition pore (mPTP) opening is critical for mediating cell death during hepatic ischaemia-reperfusion injury (IRI). Blocking mPTP opening by inhibiting cyclophilin D (CypD) is a promising pharmacological approach for the treatment of IRI. Here, we show that diastereoisomers of a new class of small-molecule cyclophilin inhibitors (SMCypIs) have properties that make them attractive candidates for the development of therapeutic agents against liver IRI. Derivatives of the parent SMCypI were synthesised and evaluated for their ability to inhibit CypD peptidyl-prolyl cis-trans isomerase (PPIase) activity and for their mitoprotective properties, evaluated by measuring mitochondrial swelling and calcium retention capacity in liver mitochondria. The ability of the selected compounds to inhibit mPTP opening was evaluated in cells subjected to hypoxia/reoxygenation using a calcein/cobalt assay. Their ability to inhibit cell death was evaluated in cells subjected to hypoxia/reoxygenation by measuring lactate dehydrogenase (LDH) release, propidium iodide staining, and cell viability. The compound performing best invitro was selected for invivo efficacy evaluation in a mouse model of hepatic IRI. The two compounds that showed the strongest inhibition of CypD PPIase activity and mPTP opening, C105 and C110, were selected. Their SR diastereoisomers carried the activity of the racemic mixture and exhibited mitoprotective properties superior to those of the known macrocyclic cyclophilin inhibitors cyclosporin A and alisporivir. C105SR was more potent than C110SR in inhibiting mPTP opening and prevented cell death in a model of hypoxia/reoxygenation. Finally, C105SR substantially protected against hepatic IRI invivo by reducing hepatocyte necrosis and apoptosis. We identified a novel cyclophilin inhibitor with strong mitoprotective properties both invitro and invivo that represents a promising candidate for cellular protection in hepatic IRI. Hepatic ischaemia-reperfusion injury (IRI) is one of the main causes of morbidity and mortality during or after liver surgery. However, no effective therapies are available to prevent or treat this devastating syndrome. An attractive strategy to prevent hepatic IRI aims at reducing cell death by targeting mitochondrial permeability transition pore opening, a phenomenon regulated by cyclophilin D. Here, we identified a new small-molecule cyclophilin inhibitor, and demonstrated the enhanced mitoprotective and hepatoprotective properties of one of its diastereoisomers both invitro and invivo, making it an attractive lead compound for subsequent clinical development.

Berberine-loaded albumin nanoparticles reverse aflatoxin B1-induced liver hyperplasia

Hepatocellular carcinoma (HCC) can be produced from aflatoxin B1 (AFB1) administration. Although berberine (BER) acts as an anticancer agent and can counteract the AFB1 effect, it has low bioavailability. Nanotechnology can overcome this problem. This research aimed to synthesize berberine nanoparticles (NPs) and then estimate their therapeutic effect compared to that of berberine against aflatoxin-induced hepatotoxicity. The desolvation method was used to prepare BER–NPs. Aflatoxicosis was induced by 5 consecutive intraperitoneal injections (IP) of 200 µg/kg/day AFB dissolved in dimethylsulfoxide (DMSO). After the induction period, two treatments were performed: the first with 100 mg/kg BER and the second with 10 mg/kg BER-NPs. Liver, kidney, and diabetic profiles were estimated by using standardized methods. Hepatic oxidative stress, inflammatory, cancer cell proliferation, and invasion markers were used by ELISA and qPCR techniques. The TEM image shows that both BSA NPs and BER-BSA NPs had spherical, regular, and uniform shapes. The BER encapsulation efficiency % was 78.5. The formed-BER-BSA NPs showed a loading capacity % of 7.71 and the synthesis yield % of 92.6. AFB1 increases pro-oxidant markers, decreases antioxidant systems, stimulates inflammatory enzymes, inhibits anti-inflammatory markers, decreases tumor suppressor enzymes, increases oncogenes, increases glycolytic activity, prevents cell death, and promotes cell growth. Most of the biochemical markers and hepatic architecture were normalized in the BER-BSA NP-treated group but not in the BER-treated group. Altogether, the obtained data proved that treatment with BER-NPs was more efficient than treatment with berberine against aflatoxicoses induced in rats.

Effects of Quince Gel and Hesperidin Mixture on Experimental Endometriosis.

Endometriosis (EM) is the presence of endometrial tissue outside the uterus. This study aimed to examine the effects of quince gel and hesperidin treatment on uterine tissue in an experimental endometriosis model. Thirty-two rats were categorized into four groups as sham, EM, EM+quince gel (QG), and EM+QG+Hesperidin (HES). The endometriosis (EM) model was induced with surgical intervention. Estradiol benzoate (EB) was used to induce endometrial hyperplasia. In the EM group, EB was given to rats for 7 days. The EM+QG group received 2 cc QG for 21 days. HES treatment was given for 21 days after EM induction. At the end of the experiment, blood was taken from the animals and the serum total antioxidant status (TAS) and total oxidant status (TOS) values were studied. Uterine tissues were dissected and processed for histological paraffin embedding. Tissues were fixed in 4% glutaraldehyde solution and processed for ultrastructural analysis. After EM, QG and HES treatment significantly increased the TAS and decreased the TOS value. EM caused epithelial and glandular degeneration, thinning of the basal membranes, and vascular dilatation with increased fibrosis and edema. QG+HES restored the pathology and showed protective effects in uterine tissues. Caspase-3 expression was increased in the epithelium, glands, and muscle layers of the EM group. In EM+QG+HES, hesperidin protected cell survival and decreased Caspase-3 expression in uterine tissues. TNF-α expression was intense in inflammatory cells and the muscle layer in the EM group. HES reduced inflammation by decreasing the TNF-α expression. MAPK expression was increased after EM induction in epithelial, glandular, and inflammatory cells in the EM group. After HES treatment, MAPK expression was mainly negative in cells of uterine tissue in the EM+QG+HES group. Ultrastructurally, in the EM group, organelles were disrupted and dilated and degenerated after EM induction. QG and HES treatment improved cellular organelles. Local vaginal applications can be an alternative treatment method in the endometriosis model via QG+HES treatment promoting cell proliferation and angiogenesis and preventing cell death.

Ability of metformin to deplete NAD+ contributes to cancer cell susceptibility to metformin cytotoxicity and is dependent on NAMPT expression.

Nicotinamide adenine dinucleotide (NAD+) is vital for not only energy metabolism but also signaling pathways. A major source of NAD+ depletion is the activation of poly (ADP-ribose) polymerase (PARP) in response to DNA damage. We have previously demonstrated that metformin can cause both caspase-dependent cell death and PARP-dependent cell death in the MCF7 breast cancer cells but not in the MDA-MB-231 (231) breast cancer cells while in high-glucose media. We hypothesize that depletion of NAD+ in MCF7 cells via activation of PARP contributes to the cell death caused by metformin. Nicotinamide phosphoribosyltransferase (NAMPT), a key rate-limiting step in converting nicotinamide (vitamin B3) into NAD+, is essential for regenerating NAD+ for normal cellular processes. Evidence shows that overexpression of NAMPT is associated with tumorigenesis. We hypothesize that NAMPT expression may determine the extent to which cancer cells are sensitive to metformin. In this study, we found that metformin significantly decreases NAD+ levels over time, and that this could be delayed by PARP inhibitors. Pretreatment with NAD+ in MCF7 cells also prevents cell death and the enlargement of mitochondria and protects mitochondria from losing membrane potential caused by metformin. This leads to MCF7 cell resistance to metformin cytotoxicity in a manner similar to 231 cells. By studying the differences in NAD+ regulation in these two breast cancer cell lines, we demonstrate that NAMPT is expressed at higher levels in 231 cells than in MCF7 cells. When NAMPT is genetically repressed in 231 cells, they become much more sensitive to metformin-induced cell death. Conversely, overexpressing NAMPT in HEK-293 (293) cells causes the cells to be more resistant to metformin's growth inhibitory effects. The addition of a NAMPT activator also decreased the sensitivity of MCF7 cells to metformin, while the NAMPT activator, P7C3, protects against metformin-induced cytotoxicity. Depletion of cellular NAD+ is a key aspect of sensitivity of cancer cells to the cytotoxic effects of metformin. NAMPT plays a key role in maintaining sufficient levels of NAD+, and cells that express elevated levels of NAMPT are resistant to killing by metformin.

CD38 Inhibition Protects Fructose-Induced Toxicity in Primary Hepatocytes.

A fructose-enriched diet is thought to contribute to hepatic injury in developing non-alcoholic steatohepatitis (NASH). However, the cellular mechanism of fructose-induced hepatic damage remains poorly understood. This study aimed to determine whether fructose induces cell death in primary hepatocytes, and if so, to establish the underlying cellular mechanisms. Our results revealed that treatment with high fructose concentrations for 48 h induced mitochondria-mediated apoptotic death in mouse primary hepatocytes (MPHs). Endoplasmic reticulum stress responses were involved in fructose-induced death as the levels of phosho-eIF2α, phospho-C-Jun-N-terminal kinase (JNK), and C/EBP homologous protein (CHOP) increased, and a chemical chaperone tauroursodeoxycholic acid (TUDCA) prevented cell death. The impaired oxidation metabolism of fatty acids was also possibly involved in the fructose-induced toxicity as treatment with an AMP-activated kinase (AMPK) activator and a PPAR-α agonist significantly protected against fructose-induced death, while carnitine palmitoyl transferase I inhibitor exacerbated the toxicity. However, uric acid-mediated toxicity was not involved in fructose-induced death as uric acid was not toxic to MPHs, and the inhibition of xanthine oxidase (a key enzyme in uric acid synthesis) did not affect cell death. On the other hand, treatment with inhibitors of the nicotinamide adenine dinucleotide (NAD)+-consuming enzyme CD38 or CD38 gene knockdown significantly protected against fructose-induced toxicity in MPHs, and fructose treatment increased CD38 levels. These data suggest that CD38 upregulation plays a role in hepatic injury in the fructose-enriched diet-mediated NASH. Thus, CD38 inhibition may be a promising therapeutic strategy to prevent fructose-enriched diet-mediated NASH.

Novel XIAP mutation with early-onset Crohn’s disease complicated with acute heart failure: a case report

BackgroundThe X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn’s disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure.Case presentationA young male of 16 years of age was initially diagnosed with Crohn’s disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient’s condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient’s condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother.ConclusionA novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn’s disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.

ER Ca2+ overload activates the IRE1α signaling and promotes cell survival

BackgroundMaintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear.ResultsHere, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells.ConclusionsOur data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death.

Accelerated export of Dicer1 from lipid-challenged hepatocytes buffers cellular miRNA-122 levels and prevents cell death

Hepatocytes on exposure to high levels of lipids reorganize the metabolic program while fighting against the toxicity associated with elevated cellular lipids. The mechanism of this metabolic reorientation and stress management in lipid-challenged hepatocytes has not been well explored. We have noted the lowering of miR-122, a liver-specific miRNA, in the liver of mice fed with either a high-fat diet or a methionine-choline-deficient diet that is associated with increased fat accumulation in mice liver. Interestingly, low miR-122 levels are attributed to the enhanced extracellular export of miRNA processor enzyme Dicer1 from hepatocytes in the presence of high lipids. Export of Dicer1 can also account for the increased cellular levels of pre-miR-122-the substrate of Dicer1. Interestingly, restoration of Dicer1 levels in the mouse liver resulted in a strong inflammatory response and cell death in the presence of high lipids. Increasing death of hepatocytes was found to be caused by increased miR-122 levels in hepatocytes restored for Dicer1. Thus, the Dicer1 export by hepatocytes seems to be a key mechanism to combat lipotoxic stress by shunting out miR-122 from stressed hepatocytes. Finally, as part of this stress management, we determined that the Ago2-interacting pool of Dicer1, responsible for mature microribonucleoprotein formation in mammalian cells, gets depleted. miRNA-binder and exporter protein HuR is found to accelerate Ago2-Dicer1 uncoupling to ensure export of Dicer1 via extracellular vesicles in lipid-loaded hepatocytes.

Mechanistic insights into genomic structure and functions of a novel oncogene YEATS4.

As a novel oncogene, the role of YEATS domain-containing protein 4 (YEATS4) in the occurrence, development, and treatment of tumors is now beginning to be appreciated. YEATS4 plays an important role in regulating DNA repair during replication. The upregulation of YEAST4 promotes DNA damage repair and prevents cell death, whereas its downregulation inhibits DNA replication and induces apoptosis. Additionally, accumulating evidence indicates that the aberrant activation of YEATS4 leads to changes in drug resistance, epithelial-mesenchymal transition and also in the migration and invasion capacity of tumor cells. Therefore, specific inhibition of the expression or activity of YEATS4 protein may be an effective strategy for inhibiting the proliferation, motility, differentiation, and/or survival of tumor cells. Taken together, YEATS4 has emerged as a potential target for multiple cancers and is an attractive protein for the development of small-molecule inhibitors. However, research on YEAST4 in tumor-related fields is limited and its biological functions, metabolism, and the regulatory mechanism of YEATS4 in numerous cancers remain undetermined. This review comprehensively and extensively summarizes the functions, structure and oncogenic roles of YEATS4 in cancer progression and aims to further contribute to the study of its underlying molecular mechanism and targeted drugs.

Wheat phytase potentially protects HT-29 cells from inflammatory nucleotides-induced cytotoxicity.

The aim of this study was to investigate the protective effect of wheat phytase as a structural decomposer of inflammatory nucleotides, extracellular adenosine triphosphate (ATP), and uridine diphosphate (UDP) on HT-29 cells. Phosphatase activities of wheat phytase against ATP and UDP was investigated in the presence or absence of inhibitors such as L-phenylalanine and L-homoarginine using a Pi Color Lock gold phosphate detection kit. Viability of HT-29 cells exposed to intact- or dephosphorylated-nucleotides was analyzed with an EZ-CYTOX kit. Secretion levels of pro-inflammatory cytokines (IL-6 and IL-8) in HT-29 cells exposed to substrate treated with or without wheat phytase were measured with enzyme-linked immunosorbent assay kits. Activation of caspase-3 in HT-29 cells treated with intact ATP or dephosphorylated-ATP was investigated using a colorimetric assay kit. Wheat phytase dephosphorylated both nucleotides, ATP and UDP, in a dosedependent manner. Regardless of the presence or absence of enzyme inhibitors (L-phenylalanine and L-homoarginine), wheat phytase dephosphorylated UDP. Only L-phenylalanine inhibited the dephosphorylation of ATP by wheat phytase. However, the level of inhibition was less than 10%. Wheat phytase significantly enhanced the viability of HT-29 cells against ATP- and UDP-induced cytotoxicity. Interleukin (IL)-8 released from HT-29 cells with nucleotides dephosphorylated by wheat phytase was higher than that released from HT-29 cells with intact nucleotides. Moreover, the release of IL-6 was strongly induced from HT-29 cells with UDP dephosphorylated by wheat phytase. HT-29 cells with ATP degraded by wheat phytase showed significantly (13%) lower activity of caspase-3 than HT-29 cells with intact ATP. Wheat phytase can be a candidate for veterinary medicine to prevent cell death in animals. In this context, wheat phytase beyond its nutritional aspects might be a novel and promising tool for promoting growth and function of intestinal epithelial cells under luminal ATP and UDP surge in the gut.

The Arabidopsis DNA glycosylase MBD4L repairs the nuclear genome in vivo.

DNA glycosylases remove mispaired or modified bases from DNA initiating the base excision repair (BER) pathway. The DNA glycosylase MBD4 (methyl-CpG-binding domain protein 4) has been functionally characterized in mammals, but not yet in plants, where it is called MBD4-like (MBD4L). Mammalian MBD4 and Arabidopsis recombinant MBD4L excise U and T mispaired with G, as well as 5-fluorouracil (5-FU) and 5-bromouracil (5-BrU) in vitro. Here, we investigate the ability of Arabidopsis MBD4L to remove some of these substrates from the nuclear genome in vivo in coordination with uracil DNA glycosylase (AtUNG). We found that mbd4l mutants are hypersensitive to 5-FU and 5-BrU, as they displayed smaller size, less root growth, and higher cell death than control plants in both media. Using comet assays, we determined BER-associated DNA fragmentation in isolated nuclei and observed reduced DNA breaks in mbd4l plants under both conditions, but particularly with 5-BrU. The use of ung and ung x mbd4l mutants in these assays indicated that both MBD4L and AtUNG trigger nuclear DNA fragmentation in response to 5-FU. Consistently, we here report the nuclear localization of AtUNG based on the expression of AtUNG-GFP/RFP constructs in transgenic plants. Interestingly, MBD4L and AtUNG are transcriptionally coordinated but display not completely overlapping functions. MBD4L-deficient plants showed reduced expression of BER genes and enhanced expression of DNA damage response (DDR) gene markers. Overall, our findings indicate that Arabidopsis MBD4L is critical for maintaining nuclear genome integrity and preventing cell death under genotoxic stress conditions.

Unique evolution of foraminiferal calcification to survive global changes

Foraminifera, the most ancient known calcium carbonate–producing eukaryotes, are crucial players in global biogeochemical cycles and well-used environmental indicators in biogeosciences. However, little is known about their calcification mechanisms. This impedes understanding the organismal responses to ocean acidification, which alters marine calcium carbonate production, potentially leading to biogeochemical cycle changes. We conducted comparative single-cell transcriptomics and fluorescent microscopy and identified calcium ion (Ca 2+ ) transport/secretion genes and α-carbonic anhydrases that control calcification in a foraminifer. They actively take up Ca 2+ to boost mitochondrial adenosine triphosphate synthesis during calcification but need to pump excess intracellular Ca 2+ to the calcification site to prevent cell death. Unique α-carbonic anhydrase genes induce the generation of bicarbonate and proton from multiple CO 2 sources. These control mechanisms have evolved independently since the Precambrian to enable the development of large cells and calcification despite decreasing Ca 2+ concentrations and pH in seawater. The present findings provide previously unknown insights into the calcification mechanisms and their subsequent function in enduring ocean acidification.

Targeting Cellular Senescence in Organ Transplantation.

Targeting Cellular Senescence in Organ Transplantation.

Swimming prevents cell death of chondrocytes via PI3K/AKT pathway in an experimental model

BackgroundKnee Osteoarthritis (KOA) is one of the main causes of disability in the elderly and with limited treatment options. Swimming was considered as an ideal form of non-surgical management of KOA. Nevertheless, the mechanism of swimming intervene OA remains unclear. ACLT induced OA model was often used to study the pathogenesis and treatment of OA. Thus, we evaluated the protective effect of swimming on KOA mouse and tried to explore the underlying mechanism.MethodsForty C57BL/6 mice were randomly divided into five groups: Blank group, ACLT group, ACLT + Swim group, Sham group and Sham + Swim group (n = 8). OA model was established by Anterior Cruciate Ligament Transection surgery (ACLT). After modeling, mice in ACLT + Swim and Sham + Swim groups were trained with a moderate swimming program, 5 d/week, for 6 weeks. HE and Safranin-O/fast staining, Immunohistochemistry, TUNEL assay and Western blot were used to detect the effect of swimming on pathological changes, cell death and the mechanism in KOA mouse.ResultsSwimming significantly enhanced CoII expression and suppressed ADAMTS5 expression in cartilage of KOA mouse, thus ameliorated KOA development. Apoptotic and autophagic processes were enhanced in OA cartilage, which might be caused by down-regulation of PI3K/AKT pathway; swimming could activate PI3K/AKT pathway and thus regulate apoptosis and autophagy processes of chondrocytes.ConclusionSwimming could prevent cell death of chondrocytes via PI3K/AKT pathways, thus delayed the progression of KOA in an experimental model.

Functional consequences of inhibition of Bruton's tyrosine kinase by ibrutinib in chronic lymphocytic leukemia.

The leukemic B cells from patients with chronic lymphocytic leukemia (CLL) require interactions with non-malignant cells and matrix in the tissue microenvironment to survive and grow. These interactions are mediated through the B-cell antigen receptor (BCR), C-X-C chemokine receptor type 4 (CXCR4), and a variety of integrins, including VLA-4. Exciting each receptor type leads to activation of Bruton's tyrosine kinase (BTK), which in turn helps initiate trophic signals that prevent cell death and promote cell activation and growth as well as allowing cells to return to anatomic sites for rescue signals. These represent the two major functional actions targeted by inhibitors of Btk. Here we relate some of the therapeutic actions of ibrutinib, a Btk inhibitor that is extremely helpful for patients with CLL, certain Diffuse Large B-cell Lymphomas (ABC type), and other non-Hodgkin's lymphomas, emphasizing that ibrutinib's value results from blocking beneficial signals, not by inducing lethal ones.

Human placental extract: a potential therapeutic in treating osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease marked by cartilage degradation and loss of function. Recently, there have been increased efforts to attenuate and reverse OA by stimulating cartilage regeneration and preventing cartilage degradation. Human placental extract (HPE) may be an option due to its anti-inflammatory, antioxidant, and growth stimulatory properties. These properties are useful in preventing cell death and senescence, which may optimize in-situ cartilage regeneration. In this review, we discuss the anatomy and physiology of the placenta, as well as explore in vivo and in vitro studies assessing its effects on tissue regeneration. Finally, we assess the potential role of HPE in cartilage regenerative medicine and OA. The Medline database was utilized for all studies that involved the use of HPE or human placenta hydrolysate. Exclusion criteria included articles not written in English, conference reviews, editorials, letters to the editor, surveys, case reports, and case series. HPE had significant anti-inflammatory and regenerative properties in vitro and in vivo. Furthermore, HPE had a role in attenuating cellular senescence and cell apoptosis via reduction of reactive oxidative species both in vitro and in vivo. One study explored the effects of HPE in OA and demonstrated reduction in cartilage catabolic gene expression, indicating HPE's effect in attenuating OA. HPE houses favorable properties that can attenuate and reverse tissue damage. This may be a beneficial therapeutic in OA as it creates a more favorable environment for in-situ cartilage regeneration. More well designed in-vitro and in-vivo studies are needed to define the role of HPE in treating OA.

NF-κB in Cell Deaths, Therapeutic Resistance and Nanotherapy of Tumors: Recent Advances.

The transcription factor nuclear factor-κB (NF-κB) plays a complicated role in multiple tumors. Mounting evidence demonstrates that NF-κB activation supports tumorigenesis and development by enhancing cell proliferation, invasion, and metastasis, preventing cell death, facilitating angiogenesis, regulating tumor immune microenvironment and metabolism, and inducing therapeutic resistance. Notably, NF-κB functions as a double-edged sword exerting positive or negative influences on cancers. In this review, we summarize and discuss recent research on the regulation of NF-κB in cancer cell deaths, therapy resistance, and NF-κB-based nano delivery systems.