Cellular Stress Mechanisms Research Articles

Niacinamide Antimicrobial Efficacy and Its Mode of Action via Microbial Cell Cycle Arrest.

Niacinamide is a versatile compound widely used in the personal care industry for its ample skin benefits. As a precursor to nicotinamide adenine dinucleotide (NAD+), essential for ATP production and a substrate for poly-ADP-ribose polymerase-1 (PARP-1), studies have highlighted its roles in DNA repair, cellular stress mechanisms, and anti-aging benefits. Niacinamide was also studied for its antimicrobial activity, particularly in the context of host-infection via host immune response, yet its direct antimicrobial activity and the mechanisms of action remain unclear. Its multifunctionality makes it an appealing bioactive molecule for skincare products as well as a potential preservative solution. This study explores niacinamide's antimicrobial mode of action against four common cosmetic pathogens. Our findings indicate that niacinamide is causing microbial cell cycle arrest; while cells were found to increase their volume and length under treatment to prepare for cell division, complete separation into two daughter cells was prevented. Fluorescence microscopy revealed expanded chromatin, alongside a decreased RNA expression of the DNA-binding protein gene, dps. Finally, niacinamide was found to directly interact with DNA, hindering successful amplification. These unprecedented findings allowed us to add a newly rationalized preservative facete to the wide range of niacinamide multi-functionality.

Transcriptional control of a metabolic switch regulating cellular methylation reactions is part of a common response to stress in divergent bee species.

Recent global declines in bee health have elevated the need for a more complete understanding of the cellular stress mechanisms employed by diverse bee species. We recently uncovered the biomarker lethal (2) essential for life (l(2)efl) genes as part of a shared transcriptional program in response to a number of cell stressors in the western honey bee (Apis mellifera). Here we describe another shared stress responsive gene, Glycine N-methyl transferase (Gnmt), which is known as a key metabolic switch controlling cellular methylation reactions. We observed Gnmt induction by both abiotic and biotic stressors. We also found increased levels of the GNMT reaction product sarcosine in the midgut after stress linking metabolic changes with the observed changes in gene regulation. Prior to this study, Gnmt upregulation has not previously been associated with cellular stress responses in other organisms. To determine whether this novel stress-responsive gene would behave similarly in other bee species, we first characterized the cellular response to ER stress in lab-reared adults of the solitary alfalfa leafcutting bee (Megachile rotundata) and compared with age-matched honey bees. The novel stress gene Gnmt was induced in addition to a number of canonical gene targets induced in both bee species upon UPR activation, suggesting that stress-induced regulation of cellular methylation reactions is a common feature of bees. Therefore, this study suggests that honey bee can serve as an important model for bee biology more broadly, although studies on diverse bee species will be required to fully understand global declines in bee populations.

Stretch Causes cffDNA and HMGB1-Mediated Inflammation and Cellular Stress in Human Fetal Membranes.

Danger-associated molecular patterns (DAMPs) are elevated within the amniotic cavity, and their increases correlate with advancing gestational age, chorioamnionitis, and labor. Although the specific triggers for their release in utero remain unclear, it is thought that they may contribute to the initiation of parturition by influencing cellular stress mechanisms that make the fetal membranes (FMs) more susceptible to rupture. DAMPs induce inflammation in many different tissue types. Indeed, they precipitate the subsequent release of several proinflammatory cytokines that are known to be key for the weakening of FMs. Previously, we have shown that in vitro stretch of human amnion epithelial cells (hAECs) induces a cellular stress response that increases high-mobility group box-1 (HMGB1) secretion. We have also shown that cell-free fetal DNA (cffDNA) induces a cytokine response in FM explants that is fetal sex-specific. Therefore, the aim of this work was to further investigate the link between stretch and the DAMPs HMGB1 and cffDNA in the FM. These data show that stretch increases the level of cffDNA released from hAECs. It also confirms the importance of the sex of the fetus by demonstrating that female cffDNA induced more cellular stress than male fetuses. Our data treating hAECs and human amnion mesenchymal cells with HMGB1 show that it has a differential effect on the ability of the cells of the amnion to upregulate the proinflammatory cytokines and propagate a proinflammatory signal through the FM that may weaken it. Finally, our data show that sulforaphane (SFN), a potent activator of Nrf2, is able to mitigate the proinflammatory effects of stretch by decreasing the levels of HMGB1 release and ROS generation after stretch and modulating the increase of key cytokines after cell stress. HMGB1 and cffDNA are two of the few DAMPs that are known to induce cytokine release and matrix metalloproteinase (MMP) activation in the FMs; thus, these data support the general thesis that they can function as potential central players in the normal mechanisms of FM weakening during the normal distension of this tissue at the end of a normal pregnancy.

Acute lung injury: a view from the perspective of necroptosis.

ALI/ARDS is a syndrome of acute onset characterized by progressive hypoxemia and noncardiogenic pulmonary edema as the primary clinical manifestations. Necroptosis is a form of programmed cell necrosis that is precisely regulated by molecular signals. This process is characterized by organelle swelling and membrane rupture, is highly immunogenic, involves extensive crosstalk with various cellular stress mechanisms, and is significantly implicated in the onset and progression of ALI/ARDS. The current body of literature on necroptosis and ALI/ARDS was thoroughly reviewed. Initially, an overview of the molecular mechanism of necroptosis was provided, followed by an examination of its interactions with apoptosis, pyroptosis, autophagy, ferroptosis, PANOptosis, and NETosis. Subsequently, the involvement of necroptosis in various stages of ALI/ARDS progression was delineated. Lastly, drugs targeting necroptosis, biomarkers, and current obstacles were presented. Necroptosis plays an important role in the progression of ALI/ARDS. However, since ALI/ARDS is a clinical syndrome caused by a variety of mechanisms, we emphasize that while focusing on necroptosis, it may be more beneficial to treat ALI/ARDS by collaborating with other mechanisms.

Impaired autophagy following ex vivo cooling of simulated hypothermic temperatures in peripheral blood mononuclear cells from young and older adults

Hypothermia is a critical consequence of extreme cold exposure that increases the risk of cold-related injury and death in humans. While the initiation of cytoprotective mechanisms including the process of autophagy and the heat shock response (HSR) is crucial to cellular survival during periods of stress, age-related decrements in these systems may underlie cold-induced cellular vulnerability in older adults. Moreover, whether potential sex-related differences in autophagic regulation influence the human cold stress response remain unknown. We evaluated the effect of age and sex on mechanisms of cytoprotection (autophagy and the HSR) and cellular stress (apoptotic signaling and the acute inflammatory response) during ex vivo hypothermic cooling. Venous blood samples from 20 healthy young (10 females; mean [SD]: 22 [2] years) and 20 healthy older (10 females; 66 [5] years) adults were either isolated immediately (baseline) for peripheral blood mononuclear cells (PBMCs) or exposed to water bath temperatures maintained at 37, 35, 33, 31, or 4 °C for 90 min before PBMC isolation. Proteins associated with autophagy, apoptosis, the HSR, and inflammation were analyzed via Western blotting. Indicators of autophagic initiation and signaling (LC3, ULK1, and beclin-2) and the HSR (HSP90 and HSP70) increased when exposed to hypothermic temperatures in young and older adults (all p ≤ 0.007). Sex-related differences were only observed with autophagic initiation (ULK1; p = 0.015). However, despite increases in autophagic initiators ULK1 and beclin-2 (all p < 0.001), this was paralleled by autophagic dysfunction (increased p62) in all groups (all p < 0.001). Further, apoptotic (cleaved-caspase-3) and inflammatory (IL-6 and TNF-α) signaling increased in all groups (all p < 0.001). We demonstrated that exposure to hypothermic conditions is associated with autophagic dysfunction, irrespective of age or sex, although there may exist innate sex-related differences in cytoprotection in response to cold exposure as evidenced through altered autophagic initiation.

Assessing Combined Metal Exposure: Insights into Cellular Bioavailability, Oxidative Stress, and Toxicity Mechanisms of Co(II) and Ni(II) in HepG2 Cells

Assessing Combined Metal Exposure: Insights into Cellular Bioavailability, Oxidative Stress, and Toxicity Mechanisms of Co(II) and Ni(II) in HepG2 Cells

The role of different antioxidant pathways like AKT, SIRT-1, NRF2 and HO-1 in cardiac damage after subarachnoid hemorrhage.

The aim of this study was to explore the pathophysiological mechanism of subarachnoid haemorrhage (SAH) using cellular oxidative stress mechanisms and inflammation. A total of 20 Wistar Albino rats were divided into two groups, namely sham and SAH. On day 0, 0.3 mL of saline in the sham group and 0.3 ml of autologous blood in the SAH group were applied in the cisterna magna of the animals. After scarification on the 7th day of the procedure, brain, blood and heart tissues were collected. In different tissues, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI), creatin kinase MB (CKMB) and lactate dehydrogenase (LDH) levels were detected biochemically. AKT, sirtuin-1 (SIRT-1), NF-E2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) genes and glutathione peroxidase-4 expression were examined genetically. Moreover, histopathological analyses were conducted both in heart and brain tissues. Enhanced TOS, OSI levels in all tissues and glial fibrillary acidic protein (GFAP) expressions in brain tissue and NFkβ, IL-6 and Cox-1 expressions in heart tissues; it was observed that levels of TAS in blood and AKT, SIRT-1, NRF2 and HO-1 gene expressions in brain tissue were decreased. In the oxidative stress and inflammation situation that takes place following SAH, AKT, SIRT-1, NRF2 and HO-1 pathways, which are antioxidant mechanisms, are suppressed and GFAP, NFkβ, IL-6, Cox-1 expressions, which trigger inflammation, are enhanced. Treatment of SAH necessitates studies on the inhibition or activation of such pathways.

Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells

Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell's need for protein synthesis surpasses the ER's capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors. ObjectiveTo identify the role of ER-stress and lipid metabolism in mediating drug response in HCC. MethodsBy using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4μ8C and/or doxorubicin (DOX) twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4μ8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate. ResultsWe reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4μ8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells. ConclusionsThis study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients.

Effects of Chromium Exposure on the Gene Expression of the Midgut in Silkworms, Bombyx mori.

Chromium is a severe heavy metal pollutant with significant environmental risks. The effects of Chromium on the digestion of Bombyx mori (silkworms) are of particular importance due to their ecological and economic significance. Herein, RNA sequencing was conducted on nine midgut samples from silkworms exposed to control, 12 g/kg and 24 g/kg Chromium chemical diets. Comparative transcriptomics revealed that under moderate Chromium exposure, there was a significant increase in up-regulated genes (1268 up-regulated to 857 down-regulated), indicating a stimulation response. At higher stress levels, a weakened survival response was observed, with a decrease in up-regulated genes and an increase in down-regulated genes (374 up-regulated to 399 down-regulated). A notable shift in cellular responses under medium chromium exposure was exposed, signifying the activation of crucial metabolic and transport systems and an elevation in cellular stress and toxicity mechanisms. The observation of up-regulated gene expression within xenobiotic metabolism pathways suggests a heightened defense against Chromium-induced oxidative stress, which was primarily through the involvement of antioxidant enzymes. Conversely, high-dose Chromium exposure down-regulates the folate biosynthesis pathway, indicating biological toxicity. Two novel genes responsive to pressure were identified, which could facilitate future stress adaptation understanding. The findings provide insights into the molecular mechanisms underlying silkworms' digestion response to Chromium exposure and could inform its biological toxicity.

Pulsed field ablation as a precise approach for cardiac arrhythmia treatment via cardiac microenvironment remodeling

PFA uses short-duration, high-voltage electrical pulses to induce transient or irreversible electroporation on cell membranes, causing cell death. Selective inhibition of chaotic electrical signals in morbid cardiomyocytes significantly aids the treatment of atrial fibrillation, ventricular tachycardia, and other heart arrhythmias. Recent preclinical and clinical studies have only investigated physical changes, such as lesion size and myocardial scar. Compared to radiofrequency ablation and cryoballoon ablation, PFA causes less postoperative myocardial cell fibrosis and inflammatory reaction and does not result in myocardial necrosis or tissue scar formation. However, the regulatory mechanism of cellular stress following PFA treatment remains unknown. This study aimed to analyze the transcriptome of the mouse ventricle after PFA treatment. The animals were subjected to a 225-V electric pulse with a 1.5-mm gap between the positive and negative electrodes. Hearts were harvested at 3, 6, 12, 24 h, and 2, 5 days for myocardial zymogram testing. PFA-treated ventricular regions were selected for single-nucleus sequencing. We discovered that PFA remodeled the cardiac microenvironment as a whole. Further, we discussed the possible stress response and wound-healing mechanism in non-targeted cells. In conclusion, PFA allowed effective and selective ventricular myocardium ablation with controllable inflammation.

Discovery of oxindole-based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a-c inhibited 68%-73% and 83%-91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%-2% and 27%-39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Therapeutic Potential for Targeting Autophagy in ER+ Breast Cancer.

Simple SummaryWhile ER+ breast cancer is generally considered to have a better prognosis than other breast cancer subtypes, relapse may nevertheless occur years after diagnosis and treatment. Despite initially responding to treatment, 30–40% of tumors acquire resistance to treatment that contributes to disease recurrence, metastasis, and ultimately, death. In the case of the individual estrogen antagonists or aromatase inhibitors, the autophagy induced by these agents is largely cytoprotective. However, whether autophagy inhibition will prove to be a useful strategy for improving outcomes for current combination therapeutic strategies awaits further studies.While endocrine therapy remains the mainstay of treatment for ER-positive, HER2-negative breast cancer, tumor progression and disease recurrence limit the utility of current standards of care. While existing therapies may allow for a prolonged progression-free survival, however, the growth-arrested (essentially dormant) state of residual tumor cells is not permanent and is frequently a precursor to disease relapse. Tumor cells that escape dormancy and regain proliferative capacity also tend to acquire resistance to further therapies. The cellular process of autophagy has been implicated in the adaptation, survival, and reactivation of dormant cells. Autophagy is a cellular stress mechanism induced to maintain cellular homeostasis. Tumor cells often undergo therapy-induced autophagy which, in most contexts, is cytoprotective in function; however, depending on how the autophagy is regulated, it can also be non-protective, cytostatic, or cytotoxic. In this review, we explore the literature on the relationship(s) between endocrine therapies and autophagy. Moreover, we address the different functional roles of autophagy in response to these treatments, exploring the possibility of targeting autophagy as an adjuvant therapeutic modality together with endocrine therapies.

The influence of stochastic temperature fluctuations in shaping the physiological performance of the California mussel, Mytilus californianus.

Climate change is forecasted to increase temperature variability and stochasticity. Most of our understanding of thermal physiology of intertidal organisms has come from laboratory experiments that acclimate organisms to submerged conditions and steady-state increases in temperatures. For organisms experiencing the ebb and flow of tides with unpredictable low tide aerial temperatures, the reliability of reported tolerances and thus predicted responses to climate change requires incorporation of environmental complexity into empirical studies. Using the mussel Mytilus californianus, our study examined how stochasticity of the thermal regime influences physiological performance. Mussels were acclimated to either submerged conditions or a tidal cycle that included either predictable, unpredictable or no thermal stress during daytime low tide. Physiological performance was measured through anaerobic metabolism, energy stores and cellular stress mechanisms just before low tide, and cardiac responses during a thermal ramp. Both air exposure and stochasticity of temperature change were important in determining thermal performance. Glycogen content was highest in the mussels from the unpredictable treatment, but there was no difference in the expression of heat shock proteins between thermal treatments, suggesting that mussels prioritise energy reserves to deal with unpredictable low tide conditions. Mussels exposed to fluctuating thermal regimes had lower gill anaerobic metabolism, which could reflect increased metabolic capacity. Our results suggest that although thermal magnitude plays an important role in shaping physiological performance, other key elements of the intertidal environment complexity such as stochasticity, thermal variability and thermal history are also important considerations for determining how species will respond to climate warming.

Hypo-osmotic stress induces the epithelial alarmin IL-33 in the colonic barrier of ulcerative colitis

Epithelial alarmins are gaining interest as therapeutic targets for chronic inflammation. The nuclear alarmin interleukin-33 (IL-33) is upregulated in the colonic mucosa of acute ulcerative colitis (UC) and may represent an early instigator of the inflammatory cascade. However, it is not clear what signals drive the expression of IL-33 in the colonic mucosa, nor is the exact role of IL-33 elucidated. We established an ex vivo model using endoscopic colonic biopsies from healthy controls and UC patients. Colonic biopsies exposed to hypo-osmotic medium induced a strong nuclear IL-33 expression in colonic crypts in both healthy controls and UC biopsies. Mucosal IL33 mRNA was also significantly increased following hypo-osmotic stress in healthy controls compared to non-stimulated biopsies (fold change 3.9, p-value < 0.02). We observed a modest induction of IL-33 in response to TGF-beta-1 stimulation, whereas responsiveness to inflammatory cytokines TNF and IFN-gamma was negligible. In conclusion our findings indicate that epithelial IL-33 is induced by hypo-osmotic stress, rather than prototypic proinflammatory cytokines in colonic ex vivo biopsies. This is a novel finding, linking a potent cytokine and alarmin of the innate immune system with cellular stress mechanisms and mucosal inflammation.

Assess heavy metals-induced oxidative stress of microalgae by Electro-Raman combined technique

Oxidative stress of aquatic microorganisms under heavy metal stress is closely reflected by metabolite changes in cells but it is very difficult to study due to the fast metabolism process and severe in-situ measurements hurdle. Herein, the oxidative stress of cadmium on Euglena gracilis was systematically studied through multi-combined techniques. In particular, for the first time electrochemical approach was associated with Raman spectroscopy imaging to vividly to investigate temporal-spatially varied oxidative stress and its effects on cells metabolism, in which former real-time measured a volcanic relation of extracellular hydrogen peroxide versus the increase of cadmium stress, while the latter shows the corresponding metabolic changes by Raman imaging of single cells. This work builds a bridge to unravel the mechanism of cellular oxidative stress under harsh conditions in a more systematic and holistic approach, while holding a great promise to construct heavy metal biosensors precisely monitoring high heavy metal tolerance strains for environmental modification.

Inflammation: A New Look at an Old Problem.

Pro-inflammatory stress is inherent in any cells that are subject to damage or threat of damage. It is defined by a number of universal components, including oxidative stress, cellular response to DNA damage, unfolded protein response to mitochondrial and endoplasmic reticulum stress, changes in autophagy, inflammasome formation, non-coding RNA response, formation of an inducible network of signaling pathways, and epigenetic changes. The presence of an inducible receptor and secretory phenotype in many cells is the cause of tissue pro-inflammatory stress. The key phenomenon determining the occurrence of a classical inflammatory focus is the microvascular inflammatory response (exudation, leukocyte migration to the alteration zone). This same reaction at the systemic level leads to the development of life-critical systemic inflammation. From this standpoint, we can characterize the common mechanisms of pathologies that differ in their clinical appearance. The division of inflammation into alternative variants has deep evolutionary roots. Evolutionary aspects of inflammation are also described in the review. The aim of the review is to provide theoretical arguments for the need for an up-to-date theory of the relationship between key human pathological processes based on the integrative role of the molecular mechanisms of cellular and tissue pro-inflammatory stress.

Response mechanisms of different antibiotic-resistant bacteria with different resistance action targets to the stress from photocatalytic oxidation

The stress response of antibiotic-resistant bacteria (ARB) and the spread of antibiotic resistance genes (ARGs) pose a serious threat to the aquatic environment and human beings. This study mainly explored the effect of the heterogeneous photocatalytic oxidation (UVA-TiO2 system) on the stress response mechanism of ARB with different antibiotic resistance action targets, including the cell wall, proteins, DNA, RNA, folate and the cell membrane. Results indicate that the stress response mechanism of tetracycline- and sulfamethoxazole-resistant E. coli DH5α, which targets the synthesis of protein and folate, could rapidly induce global regulators by the overexpression of relative antibiotic resistance action target genes. Different stress response systems were mediated via cross-protection mechanism, causing stronger tolerance to an adverse environment than other ARB. Moreover, the photocatalytic inactivation mechanism of bacterial cells and a graded response of cellular stress mechanism caused differences in the intensity of the stress mechanism of antibiotic resistance action targets. E. coli DH5α resistant to cefotaxime and polymyxin, targeting synthesis of the cell wall and cell membrane, respectively, could confer greater advantages to bacterial survival and higher conjugative transfer frequency than E. coli DH5α resistant to nalidixic acid and rifampicin, which target the synthesis of DNA and RNA, respectively. This new perspective provides detailed information on the practical application of photocatalytic oxidation for inactivating ARB and hampering the spreading of ARGs in the aquatic environment.

Sensing Mechanisms of Cellular Stress and Related Disease- Osmotic Stress Sensing by Molecular Crowding and LLPS

Sensing Mechanisms of Cellular Stress and Related Disease- Osmotic Stress Sensing by Molecular Crowding and LLPS

Escherichia coli cryptic prophages sense nutrients to influence persister cell resuscitation.

Cryptic prophages are not genomic junk but instead enable cells to combat myriad stresses as an active stress response. How these phage fossils affect persister cell resuscitation has, however, not been explored. Persister cells form as a result of stresses such as starvation, antibiotics and oxidative conditions, and resuscitation of these persister cells likely causes recurring infections such as those associated with tuberculosis, cystic fibrosis and Lyme disease. Deletion of each of the nine Escherichia coli cryptic prophages has no effect on persister cell formation. Strikingly, elimination of each cryptic prophage results in an increase in persister cell resuscitation with a dramatic increase in resuscitation upon deleting all nine prophages. This increased resuscitation includes eliminating the need for a carbon source and is due to activation of the phosphate import system resulting from inactivating the transcriptional regulator AlpA of the CP4-57 cryptic prophage. Deletion of alpA increases persister resuscitation, and AlpA represses phosphate regulator PhoR. Both phosphate regulators PhoP and PhoB stimulate resuscitation. This suggests a novel cellular stress mechanism controlled by cryptic prophages: regulation of phosphate uptake which controls the exit of the cell from dormancy and prevents premature resuscitation in the absence of nutrients.

Transcriptome-based analysis of blood samples reveals elevation of DNA damage response, neutrophil degranulation, cancer and neurodegenerative pathways in Plasmodium falciparum patients

BackgroundMalaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children. While the majority of falciparum malaria survivors make a full recovery, there are reports of some patients ending up with neurological sequelae or cognitive deficit.MethodsAn analysis of pooled transcriptome data of whole blood samples derived from two studies involving various P. falciparum infections, comprising mild malaria (MM), non-cerebral severe malaria (NCM) and CM was performed. Pathways and gene ontologies (GOs) elevated in the distinct P. falciparum infections were determined.ResultsIn all, 2876 genes were expressed in common between the 3 forms of falciparum malaria, with CM having the least number of expressed genes. In contrast to other research findings, the analysis from this study showed MM share similar biological processes with cancer and neurodegenerative diseases, NCM is associated with drug resistance and glutathione metabolism and CM is correlated with endocannabinoid signalling and non-alcoholic fatty liver disease (NAFLD). GO revealed the terms biogenesis, DNA damage response and IL-10 production in MM, down-regulation of cytoskeletal organization and amyloid-beta clearance in NCM and aberrant signalling, neutrophil degranulation and gene repression in CM. Differential gene expression analysis between CM and NCM showed the up-regulation of neutrophil activation and response to herbicides, while regulation of axon diameter was down-regulated in CM.ConclusionsResults from this study reveal that P. falciparum-mediated inflammatory and cellular stress mechanisms may impair brain function in MM, NCM and CM. However, the neurological deficits predominantly reported in CM cases could be attributed to the down-regulation of various genes involved in cellular function through transcriptional repression, axonal dysfunction, dysregulation of signalling pathways and neurodegeneration. It is anticipated that the data from this study, might form the basis for future hypothesis-driven malaria research.