In vitro and computational investigation of antioxidant and anticancer properties of Streptomyces coeruleofuscus SCJ extract on MDA-MB-468 triple-negative breast cancer cells.

This study aimed to explore the antioxidant potential of the ethyl acetate extract of Streptomyces coeruleofuscus SCJ strain, along with its inhibitory effects on the triple-negative human breast carcinoma cell line (MDA-MB-468). The ethyl acetate extract's total phenolic and flavonoid contents were quantified, and its antioxidant activity was investigated using DPPH (1,1-Diphenyl-2-picrylhydrazyl), ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid), and FRAP (Ferric Reducing Antioxidant Power) assays. Furthermore, the cytotoxic effect of the organic extract from Streptomyces coeruleofuscus SCJ on MDA-MB-468 cancer cells was assessed via the crystal violet assay. In tandem, a thorough computational investigation was conducted to explore the pharmacokinetic properties of the identified components of the extract, utilizing the SwissADME and pKCSM web servers. Additionally, the molecular interactions between these components and Estrogen Receptor Beta, identified as a potential target, were probed through molecular docking studies. The results revealed that ethyl acetate extract of SCJ strain exhibited remarkable antioxidant activity, with 39.899 ± 1.56% and 35.798 ± 0.082% scavenging activities against DPPH and ABTS, respectively, at 1 mg/mL. The extract also displayed significant ferric reducing power, with a concentration of 1.087 ± 0.026 mg ascorbic acid equivalents per mg of dry extract. Furthermore, a strong positive correlation (p < 0.0001) between the antioxidant activity, the polyphenol and the flavonoid contents. Regarding anticancer activity, the SCJ strain extract demonstrated significant anticancer activity against TNBC MDA-MB-468 cancer cells, with an inhibition percentage of 62.76 ± 0.62%, 62.67 ± 0.93%, and 58.07 ± 4.82% at 25, 50, and 100 µg/mL of the extract, respectively. The HPLC-UV/vis analysis revealed nine phenolic compounds: gallic acid, sinapic acid, p-coumaric acid, cinnamic acid, trans-fereulic acid, syringic acid, chloroqenic acid, ellagic acid, epicatechin. Streptomyces coeruleofuscus SCJ showed promise for drug discovery, exhibiting antioxidant and anticancer effects.

Exploring the antimicrobial and antioxidant properties of Lentzea flaviverrucosa strain E25-2 isolated from Moroccan forest soil.

The alarming rise in antimicrobial resistance (AMR) has created a significant public health challenge, necessitating the discovery of new therapeutic agents to combat infectious diseases and oxidative stress-related disorders. The Lentzea flaviverrucosa strain E25-2, isolated from Moroccan forest soil, represents a potential avenue for such research. This study aimed to identify the isolate E25-2, obtained from soil in a cold Moroccan ecosystem, and further investigate its antimicrobial and antioxidant activities. Phylogenetic analysis based on 16S rRNA gene sequences revealed the strain's classification within the Lentzea genus, with a sequence closely resembling that of Lentzea flaviverrucosa AS4.0578 (96.10% similarity). Antimicrobial activity in solid media showed moderate to strong activity against Staphylococcus aureus ATCC 25923, Bacillus cereus strain ATCC 14579, Escherichia coli strain ATCC 25922, Candida albicans strain ATCC 60193 and 4 phytopathogenic fungi. In addition, ethyl acetate extract of this isolate demonstrated potent antimicrobial activity against 7 clinically multi-drug resistant bacteria. Furthermore, it demonstrated antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radicals, as well as a significant increase in ferric reducing antioxidant power. A significant positive correlation was observed between antioxidant activities and total content of phenolic compounds (p < 0.0001), along with flavonoids (p < 0.0001). Furthermore, gas chromatography-mass spectrometry (GC-MS) analysis revealed the presence of amines, hydroxyl groups, pyridopyrazinone rings, esters and pyrrolopyrazines. The Lentzea genus could offer promising prospects in the fight against antibiotic resistance and in the prevention against oxidative stress related diseases.

Exploring Symptom Overlaps: Post-COVID-19 Neurological Syndrome and Post-Concussion Syndrome in Athletes.

The COVID-19 pandemic has introduced new challenges in managing neurological conditions, particularly among athletes. This paper explores the intersection of post-COVID-19 neurological syndrome (PCNS/PASC) and post-concussion syndrome (PCS), focusing on their implications in sports medicine. Our analysis covers the symptomatology, pathophysiology, and management strategies for PCNS/PASC and PPCS, with special attention paid to the unique challenges faced by athletes recovering from these conditions, including the risk of symptom exacerbation and prolonged recovery. Key findings reveal that both PCNS/PASC and PPCS present with overlapping symptoms such as cognitive difficulties, exercise intolerance, and mental health issues, but differ in specific manifestations like anosmia and ageusia, unique to COVID-19. Pathophysiological analysis reveals similarities in blood-brain barrier disruption (BBB) but differences in the extent of immune activation. Management strategies emphasize a gradual increase in physical activity, close symptom monitoring, and psychological support, with a tailored approach for athletes. Specific interventions include progressive aerobic exercises, resistance training, and cognitive rehabilitation. Furthermore, our study highlights the importance of integrating neurology, psychiatry, physical therapy, and sports medicine to develop comprehensive care strategies. Our findings underscore the dual challenge of COVID-19 and concussion in athletes, necessitating a nuanced, interdisciplinary approach to effective management. Future research should focus on the long-term neurological effects of both conditions and optimizing treatment protocols to improve patient outcomes. This comprehensive understanding is crucial for advancing the management of athletes affected by these overlapping conditions and ensuring their safe return to sports.

Predictive factors for recurrence and outcomes in T1a renal cell carcinoma: Analysis of the INMARC (International Marker Consortium for Renal Cancer) database.

OBJECTIVE: Stage migration in renal cell carcinoma (RCC) has led to an increasing proportion of diagnosed small renal masses. Emerging knowledge regarding heterogeneity of RCC histologies and consequent impact on prognosis led us to further explore outcomes and predictive factors in surgically-treated T1a RCC. METHODS: The INMARC database was queried for T1aN0M0 RCC. Patients were stratified into groups based on recurrence. Primary outcome was overall survival (OS). Multivariable analyses (MVA) were performed for factors associated with recurrence, cancer-specific (CSM), and all-cause mortality (ACM). Kaplan-Meier analyses (KMA) assessed survival by histology and grade. Subset analysis for time to recurrence was conducted for grade and histologic groups and compared with recent AUA follow-up guidelines [low-risk (AUA-LR), intermediate-risk (AUA-IR), high-risk (AUA-HR), and very-high risk (AUA-VHR) groups]. RESULTS: We analyzed 1,878 patients (median follow-up 35.2 months); 101 (5.4%) developed recurrence. MVA for recurrence demonstrated increasing age (P = 0.026), male sex (P = 0.043), diabetes (P = 0.007), high/unclassified grade (P < 0.001-0.007), and variant histology (P = 0.017) as independent risk factors for increased risk, while papillary (P = 0.016) and chromophobe (P = 0.049) were associated with decreased risk. MVA identified high/unclassified grade (P = 0.003-0.004) and pT3a upstaging (P = 0.043) as predictive factors for worsened risk of CSM while papillary (P = 0.034) was associated with improved risk. MVA for ACM demonstrated increasing age (P < 0.001), non-white (P < 0.001), high-grade (P = 0.022), variant histology (P = 0.049), recurrence (P = 0.004), and eGFR<45 at last follow-up (P < 0.001) to be independent risk factors. KMA comparing clear cell, chromophobe, papillary, and variant RCC revealed significant differences for 5-year CSS (P = 0.018) and RFS (P < 0.001), but not OS (P = 0.34). Median time to recurrence was 23.8 months for low-grade (AUA-LR), 17.3 months for high-grade (AUA-IR), 18 months for pT3a upstaging (AUA-HR), and 12 months for variant histology (AUA-VHR; P < 0.001). CONCLUSION: We noted differential outcomes in T1a RCC based on histology and grade for recurrence and CSM, while renal functional decline in addition to pathological factors and recurrence were predictive for ACM. Our findings support recently promulgated AUA follow-up guidelines for low-grade and variant histology pT1a RCC, but call for consolidation of follow-up protocols for high-grade pT1a and pT3a upstaged patients, with intensification of frequency of imaging follow-up in pT1a high-grade RCC.

Oxidative Stress in the Pathogenesis of Oral Cancer.

Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) and antioxidants, contributes significantly to oral cancer such as oral squamous cell carcinoma (OSCC) initiation, promotion, and progression. ROS, generated both internally and externally, induce cellular damage including DNA mutations and lipid peroxidation, fostering oncogene activation and carcinogenesis. The objective of this review was to cover and analyze the interplay between ROS and antioxidants, influencing the key processes such as cell proliferation, apoptosis, and angiogenesis, shaping the trajectory of OSCC development. Despite the promise of antioxidants to halt cancer progression and mitigate oxidative damage, their therapeutic efficacy remains debated. The conducted literature search highlighted potential biomarkers that indicate levels of oxidative stress, showing promise for the early detection and monitoring of OSCC. Furthermore, melatonin has emerged as a promising adjunct therapy for OSCC, exerting antioxidant and oncostatic effects by modulating tumor-associated neutrophils and inhibiting cancer cell survival and migration. In addition, this review aims to shed light on developing personalized therapeutic strategies for patients with OSCC such as melatonin therapy, which will be discussed. Research is needed to elucidate the underlying mechanisms and clinical implications of oxidative stress modulation in the context of oral cancer.

Understanding Functional Neurological Disorder: Recent Insights and Diagnostic Challenges.

Functional neurological disorder (FND), formerly called conversion disorder, is a condition characterized by neurological symptoms that lack an identifiable organic purpose. These signs, which can consist of motor, sensory, or cognitive disturbances, are not deliberately produced and often vary in severity. Its diagnosis is predicated on clinical evaluation and the exclusion of other medical or psychiatric situations. Its treatment typically involves a multidisciplinary technique addressing each of the neurological symptoms and underlying psychological factors via a mixture of medical management, psychotherapy, and supportive interventions. Recent advances in neuroimaging and a deeper exploration of its epidemiology, pathophysiology, and clinical presentation have shed new light on this disorder. This paper synthesizes the current knowledge on FND, focusing on its epidemiology and underlying mechanisms, neuroimaging insights, and the differentiation of FND from feigning or malingering. This review highlights the phenotypic heterogeneity of FND and the diagnostic challenges it presents. It also discusses the significant role of neuroimaging in unraveling the complex neural underpinnings of FND and its potential in predicting treatment response. This paper underscores the importance of a nuanced understanding of FND in informing clinical practice and guiding future research. With advancements in neuroimaging techniques and growing recognition of the disorder's multifaceted nature, the paper suggests a promising trajectory toward more effective, personalized treatment strategies and a better overall understanding of the disorder.

Nutritional Deficiencies Before and After Bariatric Surgery in Low- and High-Income Countries: Prevention and Treatment.

Nutritional deficiencies represent a prevalent concern among individuals with obesity, stemming from suboptimal dietary habits, chronic inflammation, and preoperative weight reduction efforts. Bariatric surgical interventions, employing either restrictive, malabsorptive or a combination of the two methods, further compound these deficiencies. Commonly observed nutritional deficits following bariatric surgeries include vitamin B12, vitamin D, thiamine, folate, iron, and protein deficiencies. These deficiencies are further complicated by disparities in healthcare resources and income that distinguish low, medium, and high-income countries. The escalating rates of obesity in low- and medium-income countries are primarily attributed to the increasing availability of cheap, nutritionally depleted, and processed foods, coupled with limited access to healthcare. The provision of bariatric surgical interventions in such regions is hindered by the lack of appropriately trained medical personnel and adequate infrastructure. Additionally, the crucial facets of postoperative care, including diligent follow-up, precise weight loss monitoring, and the administration of appropriate nutritional supplements, often remain lacking. This narrative review provides a comprehensive examination of the prevention and treatment of nutritional deficiencies before and after bariatric surgery in the context of varying healthcare resources and income levels. Bariatric procedures and their global prevalence are discussed, and the prevalence, symptoms, and management strategies of specific nutritional deficiencies are explained. This review also outlines practical strategies for providing more equitable care in low- and medium-income countries.

Epidemiology, Risk Factors, and Biomarkers of Post-Traumatic Epilepsy: A Comprehensive Overview.

This paper presents an in-depth exploration of Post-Traumatic Epilepsy (PTE), a complex neurological disorder following traumatic brain injury (TBI), characterized by recurrent, unprovoked seizures. With TBI being a global health concern, understanding PTE is crucial for effective diagnosis, management, and prognosis. This study aims to provide a comprehensive overview of the epidemiology, risk factors, and emerging biomarkers of PTE, thereby informing clinical practice and guiding future research. The epidemiological aspect of the study reveals PTE as a significant contributor to acquired epilepsies, with varying incidence influenced by injury severity, age, and intracranial pathologies. The paper delves into the multifactorial nature of PTE risk factors, encompassing clinical, demographic, and genetic elements. Key insights include the association of injury severity, intracranial hemorrhages, and early seizures with increased PTE risk, and the roles of age, gender, and genetic predispositions. Advancements in neuroimaging, electroencephalography, and molecular biology are presented, highlighting their roles in identifying potential PTE biomarkers. These biomarkers, ranging from radiological signs to electroencephalography EEG patterns and molecular indicators, hold promise for enhancing PTE pathogenesis understanding, early diagnosis, and therapeutic guidance. The paper also discusses the critical roles of astrocytes and microglia in PTE, emphasizing the significance of neuroinflammation in PTE development. The insights from this review suggest potential therapeutic targets in neuroinflammation pathways. In conclusion, this paper synthesizes current knowledge in the field, emphasizing the need for continued research and a multidisciplinary approach to effectively manage PTE. Future research directions include longitudinal studies for a better understanding of TBI and PTE outcomes, and the development of targeted interventions based on individualized risk profiles. This research contributes significantly to the broader understanding of epilepsy and TBI.

Cashew (Anacardium occidentale) Extract: Possible Effects on Hypothalamic-Pituitary-Adrenal (HPA) Axis in Modulating Chronic Stress.

Depression presents a significant global health burden, necessitating the search for effective and safe treatments. This investigation aims to assess the antidepressant effect of the hydroethanolic extract of Anacardium occidentale (AO) on depression-related behaviors in rats. The depression model involved 42 days of unpredictable chronic mild stress (UCMS) exposure and was assessed using the sucrose preference and the forced swimming (FST) test. Additionally, memory-related aspects were examined using the tests Y-maze and Morris water maze (MWM), following 21 days of treatment with varying doses of the AO extract (150, 300, and 450 mg/kg) and Imipramine (20 mg/kg), commencing on day 21. The monoamines (norepinephrine, serotonin, and dopamine), oxidative stress markers (MDA and SOD), and cytokines levels (IL-1ß, IL-6, and TNF-α) within the brain were evaluated. Additionally, the concentration of blood corticosterone was measured. Treatment with AO significantly alleviated UCMS-induced and depressive-like behaviors in rats. This was evidenced by the ability of the extract to prevent further decreases in body mass, increase sucrose consumption, reduce immobility time in the test Forced Swimming, improve cognitive performance in both tests Y-maze and the Morris water maze by increasing the target quadrant dwelling time and spontaneous alternation percentage, and promote faster feeding behavior in the novelty-suppressed feeding test. It also decreased pro-inflammatory cytokines, corticosterone, and MDA levels, and increased monoamine levels and SOD activity. HPLC-MS analysis revealed the presence of triterpenoid compounds (ursolic acid, oleanolic acid, and lupane) and polyphenols (catechin quercetin and kaempferol). These results evidenced the antidepressant effects of the AO, which might involve corticosterone and monoaminergic regulation as antioxidant and anti-inflammatory activities.

The Role of Potential Oxidative Biomarkers in the Prognosis of Acute Ischemic Stroke and the Exploration of Antioxidants as Possible Preventive and Treatment Options.

Ischemic strokes occur when the blood supply to a part of the brain is interrupted or reduced due to arterial blockage, and it often leads to damage to brain cells or death. According to a myriad of experimental studies, oxidative stress is an important pathophysiological mechanism of ischemic stroke. In this narrative review, we aimed to identify how the alterations of oxidative stress biomarkers could suggest a severity-reflecting diagnosis of ischemic stroke and how these interactions may provide new molecular targets for neuroprotective therapies. We performed an eligibility criteria-based search on three main scientific databases. We found that patients with acute ischemic stroke are characterized by increased oxidative stress markers levels, such as the total antioxidant capacity, F2-isoprostanes, hydroxynonenal, total and perchloric acid oxygen radical absorbance capacity (ORACTOT and ORACPCA), malondialdehyde (MDA), myeloperoxidase, and urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine. Thus, acute ischemic stroke is causing significant oxidative stress and associated molecular and cellular damage. The assessment of these molecular markers could be useful in diagnosing ischemic stroke, finding its causes, predicting its severity and outcomes, reducing its impact on the cellular structures of the brain, and guiding preventive treatment towards antioxidant-based therapy as novel therapeutic alternatives.

Mild Traumatic Brain Injury as a Risk Factor for Parkinsonism, Tics, and Akathisia: A Systematic Review and Meta-Analysis.

This meta-analysis aimed to assess the association between mild traumatic brain injury (mTBI) and the risk of developing Parkinsonism. A systematic literature review was conducted using PubMed, Embase, and Cochrane Library databases. Studies were eligible if they reported on the association between MTBI and Parkinsonism. Pooled odds ratios (ORs) were calculated using a random-effects model. Publication bias was assessed using Egger's and Begg's tests. A total of 18 studies were included in this meta-analysis, with 1,484,752 participants. The overall OR for Parkinsonism in individuals with a history of mTBI was 1.637 (95% CI, 1.203-2.230; p = 0.01), indicating a significant association. The OR for Parkinson's disease (PD) specifically was 1.717 (95% CI, 1.206-2.447; p = 0.01). However, insufficient data on tics and akathisia limited a meta-analysis. There was no evidence of publication bias according to Egger's (p = 0.8107) and Begg's (p = 0.4717) tests. This meta-analysis provides evidence that mTBI is a significant risk factor for Parkinsonism, particularly PD. However, the findings should be interpreted with caution due to the heterogeneity among the studies included and the study's limitations. Further research is needed to confirm these findings and to investigate the underlying mechanisms of the mTBI-Parkinsonism association.

Epidemiologic risk factors for patients admitted with chronic pancreatitis and pancreatic ductal adenocarcinoma in the United States.

BACKGROUND: Epidemiological studies of chronic pancreatitis (CP) and its association with pancreatic ductal adenocarcinoma (PDAC) are limited. Understanding demographic and ethno-racial factors may help identify patients at the highest risk for CP and PDAC. AIM: To evaluate the ethno-racial risk factors for CP and its association with PDAC. The secondary aim was to evaluate hospitalization outcomes in patients admitted with CP and PDAC. METHODS: This retrospective cohort study used the 2016 and 2017 National Inpatient Sample databases. Patients included in the study had ICD-10 codes for CP and PDAC. The ethnic, socioeconomic, and racial backgrounds of patients with CP and PDAC were analyzed. RESULTS: Hospital admissions for CP was 29 per 100000, and 2890 (0.78%) had PDAC. Blacks [adjusted odds ratio (aOR) 1.13], men (aOR 1.35), age 40 to 59 (aOR 2.60), and being overweight (aOR 1.34) were significantly associated with CP (all with P < 0.01). In patients with CP, Whites (aOR 1.23), higher income, older age (aOR 1.05), and being overweight (aOR 2.40) were all significantly associated with PDAC (all with P < 0.01). Men (aOR 1.81) and Asians (aOR 15.19) had significantly increased mortality (P < 0.05). Hispanics had significantly increased hospital length of stay (aOR 5.24) (P < 0.05). CONCLUSION: Based on this large, nationwide analysis, black men between 40-59 years old and overweight are at significantly increased risk for admission with CP. White men older than 40 years old and overweight with higher income were found to have significant associations with CP and PDAC. This discrepancy may reflect underlying differences in healthcare access and utilization among different socioeconomic and ethno-racial groups.

Chemical Composition, Antioxidant and Antiproliferative Activities of Taraxacum officinale Essential Oil.

Taraxacum officinale (TO) has been historically used for medicinal purposes due to its biological activity against specific disorders. To investigate the antioxidant and the antiproliferativepotential of TO essential oil in vitro and in vivo, the chemical composition of the essential oil was analyzed by GC-MS. The in vivo antioxidant capacity was assessed on liver and kidney homogenate samples from mice subjected to acetaminophen-induced oxidative stress and treated with TO essential oil (600 and 12,000 mg/kg BW) for 14 days. The in vitro scavenging activity was assayed using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and the reducing power methods. The cytotoxic effects against the HeLa cancer cell line were analyzed. The GC-MS analysis showed the presence of 34 compounds, 8 of which were identified as major constituents. The TO essential oil protected mice's liver and kidneys from acetaminophen-induced oxidative stress by enhancing antioxidant enzymes (catalase, superoxide dismutase, and glutathione) and lowering malondialdehyde levels. In vitro, the TO essential oil demonstrated low scavenging activity against DPPH (IC50 = 2.00 ± 0.05 mg/mL) and modest reducing power (EC50 = 0.963 ± 0.006 mg/mL). The growth of the HeLa cells was also reduced by the TO essential oil with an inhibition rate of 83.58% at 95 µg/mL. Current results reveal significant antioxidant and antiproliferative effects in a dose-dependent manner and suggest that Taraxacum officinale essential oil could be useful in formulations for cancer therapy.

A Rare Case of Aggressive Metastatic Laryngeal Chondrosarcoma Presenting as Bilateral Necrotizing Pneumonia.

Laryngeal chondrosarcomas are rare tumors that account for only 0.2% of malignant tumors of the larynx. Approximately 80% of these tumors are low grade and well differentiated and are associated with a good long-term prognosis. Herein, we report a case of a 77-year-old male presenting with acute hypoxic respiratory failure that required intubation and mechanical ventilation. Chest CT showed multiple pulmonary nodules and cavities. He then required a tracheostomy, and a soft tissue mass in the subglottic mass was discovered. A laryngoscopy-guided excisional biopsy of the mass was performed. Histopathological examination confirmed the diagnosis of laryngeal chondrosarcoma. Clinicians should consider metastatic laryngeal chondrosarcoma as a differential diagnosis for lung cavities. Overall, we believe this to be the first case of aggressive laryngeal chondrosarcoma with mediastinal and pulmonary metastasis mimicking necrotizing pneumonia.

Chemical Composition and Antioxidant Activity of Ammi visnaga L. Essential Oil.

The present study evaluated the chemical composition and the in vitro and in vivo antioxidant potential of Ammi visnaga L. essential oil to provide a scientific basis for the use of this plant in the traditional pharmacopoeia. Gas chromatography-mass spectrometry was used to identify the volatile constituents present of the oil. The in vitro antioxidant capacity was evaluated by the DPPH and the reducing power assays. For the in vivo tests, oral administration of Ammi visnaga L. oil (600 and 1200 mg/kg body weight) was performed in Swiss albino mice treated with acetaminophen (400 mg/kg). The toxic effect of acetaminophen and the action of the essential oil were measured by determining the levels of lipid peroxidation and antioxidant enzymes in liver and kidneys homogenates. The major components identified were butanoic acid, 2-methyl-, pentyl ester, (Z)-ß-ocimene, D-limonene, linalool, pulegone and lavandulyl-butyrate. The in vitro DPPH and reducing power assays showed moderate to low free radical scavenging activity and the antioxidant power was positively correlated with the polyphenols' concentration. In vivo, the Ammi visnaga L. essential oil showed a high antioxidant capacity at both concentrations (600 and 1200 mg/kg), effectively increasing the levels of reduced glutathione, superoxide dismutase, and catalase and significantly reducing the lipid peroxidation. The results obtained from this study suggest that Ammi visnaga L. could represent a source of molecules with antioxidant potential in the prevention of free radical-related diseases.

Essential functions of chaperones and adaptors of protein secretion systems in Gram-negative bacteria.

Equipped with a plethora of secreted toxic effectors, protein secretion systems are essential for bacteria to interact with and manipulate their neighboring environment to survive in host microbiota and other highly competitive communities. While effectors have received spotlight attention in secretion system studies, many require accessory chaperone and adaptor proteins for proper folding/unfolding and stability throughout the secretion process. Here, we review the functions of chaperones and adaptors of three protein secretions systems, type 3 secretion system (T3SS), type 4 secretion system (T4SS), and type 6 secretion system (T6SS), which are employed by many Gram-negative bacterial pathogens to deliver toxins to bacterial, plant, and mammalian host cells through direct contact. Since chaperone and adaptor functions of the T3SS and the T4SS are relatively well studied, we discuss in detail the methods of chaperone-facilitated effector secretion by the T6SS and highlight commonalities between the effector chaperone/adaptor proteins of these diverse secretion systems. While the chaperones and adaptors are generally referred to as accessory proteins as they are not directly involved in toxicities to target cells, they are nonetheless vital for the biological functions of the secretion systems. Future research on biochemical and structural properties of these chaperones will not only elucidate the mechanisms of chaperone-effector binding and release process but also facilitate custom design of cargo effectors to be translocated by these widespread secretion systems for biotechnological applications.

The Involvement of the Oxidative Stress Status in Cancer Pathology: A Double View on the Role of the Antioxidants.

Oxygen-free radicals, reactive oxygen species (ROS) or reactive nitrogen species (RNS), are known by their "double-sided" nature in biological systems. The beneficial effects of ROS involve physiological roles as weapons in the arsenal of the immune system (destroying bacteria within phagocytic cells) and role in programmed cell death (apoptosis). On the other hand, the redox imbalance in favor of the prooxidants results in an overproduction of the ROS/RNS leading to oxidative stress. This imbalance can, therefore, be related to oncogenic stimulation. High levels of ROS disrupt cellular processes by nonspecifically attacking proteins, lipids, and DNA. It appears that DNA damage is the key player in cancer initiation and the formation of 8-OH-G, a potential biomarker for carcinogenesis. The harmful effect of ROS is neutralized by an antioxidant protection treatment as they convert ROS into less reactive species. However, contradictory epidemiological results show that supplementation above physiological doses recommended for antioxidants and taken over a long period can lead to harmful effects and even increase the risk of cancer. Thus, we are describing here some of the latest updates on the involvement of oxidative stress in cancer pathology and a double view on the role of the antioxidants in this context and how this could be relevant in the management and pathology of cancer.

Differential Cellular Response to Translocated Toxic Effectors and Physical Penetration by the Type VI Secretion System.

The type VI secretion system (T6SS) is a lethal microbial weapon that injects a large needle-like structure carrying toxic effectors into recipient cells through physical penetration. How recipients respond to physical force and effectors remains elusive. Here, we use a series of effector mutants of Vibrio cholerae to determine how T6SS elicits response in Pseudomonas aeruginosa and Escherichia coli. We show that TseL, but no other effectors or physical puncture, triggers the tit-for-tat response of P. aeruginosa H1-T6SS. Although E. coli is sensitive to all periplasmically expressed effectors, P. aeruginosa is most sensitive to TseL alone. We identify a number of stress response pathways that confer protection against TseL. Physical puncture of T6SS has a moderate inhibitory effect only on envelope-impaired tolB and rseA mutants. Our data reveal that recipient cells primarily respond to effector toxicity but not to physical contact, and they rely on the stress response for immunity-independent protection.

Envelope stress responses defend against type six secretion system attacks independently of immunity proteins.

The arms race among microorganisms is a key driver in the evolution of not only the weapons but also defence mechanisms. Many Gram-negative bacteria use the type six secretion system (T6SS) to deliver toxic effectors directly into neighbouring cells. Defence against effectors requires cognate immunity proteins. However, here we show immunity-independent protection mediated by envelope stress responses in Escherichia coli and Vibrio cholerae against a V. cholerae T6SS effector, TseH. We demonstrate that TseH is a PAAR-dependent species-specific effector highly potent against Aeromonas species but not against its V. cholerae immunity mutant or E. coli. A structural analysis reveals TseH is probably a NlpC/P60-family cysteine endopeptidase. We determine that two envelope stress-response pathways, Rcs and BaeSR, protect E. coli from TseH toxicity by mechanisms including capsule synthesis. The two-component system WigKR (VxrAB) is critical for protecting V. cholerae from its own T6SS despite expressing immunity genes. WigR also regulates T6SS expression, suggesting a dual role in attack and defence. This deepens our understanding of how bacteria survive T6SS attacks and suggests that defence against the T6SS represents a major selective pressure driving the evolution of species-specific effectors and protective mechanisms mediated by envelope stress responses and capsule synthesis.

An onboard checking mechanism ensures effector delivery of the type VI secretion system in Vibrio cholerae.

The type VI secretion system (T6SS) is a lethal yet energetically costly weapon in gram-negative bacteria. Through contraction of a long sheath, the T6SS ejects a few copies of effectors accompanied by hundreds of structural carrier proteins per delivery. The few ejected effectors, however, dictate T6SS functions. It remains elusive how the T6SS ensures effector loading and avoids futile ejection. Here, by systemically mutating the active sites of 3 Vibrio cholerae effectors, TseL, VasX, and VgrG3, we show that the physical presence but not their activities is crucial for T6SS assembly. We constructed catalytic mutants of TseL and VgrG3 and truncated VasX mutants. These mutations abolished the killing of the effector-cognate immunity mutants. We determined that the VasX-mediated antimicrobial activity is solely dependent on the C-terminal colicin domain. Removal of the colicin domain abolished VasX secretion and reduced T6SS assembly, while deletion of the colicin internal loop abolished its toxicity but had little effect on secretion and assembly. The triple effector-inactive mutant maintains an active T6SS that is capable of delivering chimeric VgrG, PAAR, and TseL proteins fused with a cargo nuclease, indicating effector activities are not required for T6SS assembly or penetration into the cytosol of recipient cells. Therefore, by recruiting effectors as critical components for T6SS assembly, it represents an effective onboard checking mechanism that ensures effectors are loaded in place to prevent futile secretion. Our study also demonstrates a detoxified secretion platform by inactivating native effector activities that could translocate engineered cargo proteins via multiple routes.