Micronutrient therapy and effective immune response: a promising approach for management of COVID-19.

The escalating prevalence of coronavirus disease 2019 (COVID-19) worldwide, with an increased rate of morbidity and mortality, highlights an urgent need to develop more effective therapeutic interventions. Despite the authorized treatment against COVID-19 by the European Union (EU), the safety and effectiveness of this therapeutic strategy for a wide variety of patients have remained a significant challenge. In this respect, micronutrients such as vitamins and minerals, as essential factors, can be considered for improving the function of the immune system and accelerating the treatment procedure. Dietary supplements can attenuate vascular and inflammatory manifestations related to infectious diseases in large part due to their anti-inflammatory and antioxidant properties. Recently, it has been revealed that poor nutritional status may be one of the notable risk factors in severe COVID-19 infections. In the current review, we focus on the micronutrient therapy of COVID-19 patients and provide a comprehensive insight into the essential vitamins/minerals and their role in controlling the severity of the COVID-19 infection. We also discuss the recent advancements, challenges, negative and positive outcomes in relevance to this approach.

To resist and persist: Important factors in the pathogenesis of Bacteroides fragilis.

Bacteroides fragilis is a most frequent anaerobic pathogen isolated from human infections, particularly found in the abdominal cavity. Different factors contribute to the pathogenesis and persistence of B. fragilis at infection sites. The knowledge of the virulence factors can provide applicable information for finding alternative options for the antibiotic therapy and treatment of B. fragilis caused infections. Herein, a comprehensive review of the important B. fragilis virulence factors was prepared. In addition to B. fragilis toxin (BFT) and its potential role in the diarrhea and cancer development, some other important virulence factors and characteristics of B. fragilis are described including capsular polysaccharides, iron acquisition, resistance to antimicrobial agents, and survival during the prolonged oxidative stress, quorum sensing, and secretion systems.

The relationship between microRNAs and Rab family GTPases in human cancers.

microRNAs (miRNAs), as a group of noncoding RNAs, posttranscriptionally control gene expression by binding to 3'-untranslated region (3'-UTR). Ras-associated binding (Rab) proteins function as molecular switches for regulating vesicular transport, which mainly have oncogenic roles in cancer development and preventing the efficacy of chemotherapies. Increased evidence supported that miRNAs/Rabs interaction have been determined as potential therapeutics for cancer therapy. Nevertheless, instability and cross-targeting of miRNAs are main limitations of using miRNA-based therapeutic. The mutual interplay between Rabs and miRNAs has been poorly understood. In the present review, we focused on the essence and activity of these molecules in cancer pathogenesis. Also, numerous hindrances and potential methods in the expansion of miRNA as an anticancer therapeutics are mentioned.

Current trends in targeted therapy for drug-resistant infections.

Escalating antibiotic resistance is now a serious menace to global public health. It may be led to the emergence of "postantibiotic age" in which most of infections are untreatable. At present, there is an essential need to explore novel therapeutic strategies as a strong and sustainable pipeline to combat antibiotic-resistant infections. This review focuses on recent advances in this area including therapeutic antibodies, antimicrobial peptides, vaccines, gene therapy, genome editing, and phage therapy for tackling drug-resistant infections.

Rhinocerebral mucormycosis, risk factors and the type of oral manifestations in patients referred to a University Hospital in Tabriz, Iran 2007-2017.

Inadequate data are available on the global epidemiology of mucormycosis, mainly derived from the evaluation of specific population groups. Rhinocerebral mucormycosis is an invading and fatal mycosis, particularly among diabetic patients. In the present study, patients hospitalised in Imam Reza Hospital in Tabriz, from 2007 to 2017, were evaluated. The hospital information system (HIS) was used to collect the records of the patients. A total of 42 patients with a diagnosis of mucormycosis were included in the study, 40 cases (95%) of which had a diagnosis of the rhinocerebral form. Of these 40 patients, 21 (52.5%) and 19 (47.5%) were male and female, respectively. Seven cases (17.5%) of rhinocerebral mucormycosis were due to dental procedures. The most predisposing factor in the patients was diabetes with 36 (90%) cases. In our study, the role of tooth extraction in patients with uncontrolled diabetes was identified as an important factor. It may show the important role of dentists in preventing of the disease in diabetic patients.

Protective efficacy of recombinant exotoxin A--flagellin fusion protein against Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa is an opportunistic bacterium that causes serious nosocomial infection in immunocompromised patients. The aim of this study was to prepare a fusion protein consisting of exotoxin A (ExoA) and flagellin (Fla) from P. aeruginosa and to evaluate its potential as a vaccine candidate against P. aeruginosa infection. The genes encoding for ExoA and Fla proteins were cloned in-frame and expressed in Escherichia coli. The recombinant ExoA-Fla fusion protein was purified by Ni-NTA affinity chromatography. Mice were immunized subcutaneously with ExoA, Fla, and ExoA-Fla fusion proteins, and the humoral immune response was evaluated by ELISA method. The immunized and control group mice were challenged with a 2× LD50 (7.5 × 10(7) CFU) of P. aeruginosa for the protection assay. The results indicated that vaccination with Fla, ExoA, and ExoA-Fla fusion proteins produced a significant amount of specific immunoglobulin G antibodies. Immunization of mice with ExoA-Fla fusion protein showed significant protection against intraperitoneal challenge with 7.5 × 10(7) CFU (2× LD50) P. aeruginosa. Results of this study suggest that recombinant ExoA-Fla fusion protein is a highly immunogenic protective protein showing promise as a vaccine candidate against P. aeruginosa.

Profiling mRNA and miRNA expression variations associated with cyclin-dependent kinase pathway in the low-grade luminal early breast cancer.

Luminal A and B subtypes of breast tumors have fluctuated in proliferation rates, which arise from cell cycle dysregulation in cancer. Besides, microRNAs can regulate various cell processes through integration with mRNA. miRNAs that target the cell cycle are significant because of their prediction capability of prognosis. The objective of this study is to discover the integration between miRNA-mRNA and miRNA-miRNA related to cyclin-dependent kinase. Thirty-four pairs of human primary breast cancer and tumor margin samples from luminal breast cancer patients were investigated to assess the expression levels of CCND1, E2F1, miR-124, miR-503, miR-449a, and miR-449b. Afterward, the expression levels of mRNAs and miRNAs were investigated by real-time PCR. Statistical analysis was conducted to compare the expression levels between breast cancer and corresponding normal tissues. The protein expressions of E2F1 and CCND1 were verified by western blotting. Further, the correlation between mRNAs and miRNAs was calculated. E2F1 was significantly increased in both luminal A and B patients, while CCND1 was upregulated only in luminal B. Significant differences in all miRNAs were detected in both luminal A and B biopsy specimens (p < 0.0001). The correlation analysis revealed a positive strong correlation between miR-124 and E2F1 in luminal A patient. Moreover, the correlation test confirmed the ability of miR-449a to increase the CCND1 gene in luminal B subtypes. Also, miRNA correlation exhibited the miRNA-miRNA interaction in luminal breast cancer. This study demonstrated the novel miRNA-mRNA and miRNA-miRNA interactions, providing new insights into the molecular integration in luminal A and B patients. The authors propose that this research could contribute to introducing valuable biomarkers for luminal cancerous cells.

The high cross-transmission in methicillin resistant Staphylococcus aureus between healthy and patient communities.

Background and Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the main causes of high mortality and morbidity in hospitals. This study was aimed to examine virulence factors, molecular typing, and the antibiotic resistance pattern of MRSA isolates in hemodialysis patients and healthy communities. Materials and Methods: Total of 231 and 400 nasal samples were obtained from hemodialysis patients and healthy communities, respectively. Virulence factors profile was examined in two groups by PCR reaction. Enterobacterial Repetitive Intergenic Consensus (ERIC-PCR) was used as a molecular typing approach. Results: Overall, 35.49% (82/231) of hemodialysis patients were positive for S. aureus, and 47.56% (39/82) of isolates were positive for mecA. In a healthy community, 15% (60/400) of samples were positive for S. aureus, and 36.66% (22/60) were positive for mecA. The frequency of MDR was significantly higher in patients group (p-value < 0.00001). The frequency of pvl (p.value = 0.003932, P<0.05) and tsst-1 (p.value = 0.003173, p < .05) were significantly higher in patients group. The highest frequency virulence factors in healthy individuals were related to hla (68.33%, 41/60), hlb (53.33%, 32/60), and Acme/arcA (46.66%) genes. Two groups were clustered by the ERIC-PCR method into 7 clusters and 2 single isolate with a 0.74 similarity index. Based on the results, each cluster was combination with healthy and patient isolates. Conclusion: Our findings indicate a notable variation in the frequency of virulence factors between S. aureus isolates obtained from dialysis patients and the healthy community.

Pulmonary Mucormycosis and hydatid cyst: A case report.

Mucormycosis is a group of life-threatening diseases caused by a fungus of the Mucoraceae family and has a higher mortality rate compared with other known fungal infections. Hydatid cyst, caused by Echinococcus, is a crucial health concern in endemic areas and the disease is characterized by slow-growing cysts in the liver, lungs, or other organs. In this report, a woman with coexistence of hydatid cyst and Mucormycosis is introduced. The patient was a 52-year-old woman with approximately 6 years' history of uncontrolled diabetes mellitus and hypothyroidism, who presented with cough, sputum, and dyspnea 2 months ago. On the initial auscultation of the lungs, there was a decreased sound at the base of the left lung, and she had a fever. In blood tests, she had a high titer of erythrocyte sedimentation rate and 3+ C-Reactive Protein. The symptoms in favor of hydatid cyst were observed in lung computed tomography and in pleural needle biopsy, hydatid cyst was confirmed. With this indication, she underwent wedge resection, and resection of the left lower lung cyst. Two samples are taken from the cyst side and the pathology report was consistent with Mucormycosis (wide filaments with a 90-degree angle). The patient was immediately treated with liposomal amphotericin for 4 weeks. The Lung CT scan was performed before and after treatment. Albendazole was treated to treat hydatid cyst. After discharge, the treatment of the patient continued with oral Posaconazole, and after the treatment finalization, the general condition of the patient was good, and she did not have any complaints. In pulmonary diseases that do not respond significantly to surgical treatment (such as hydatid cyst), fungal disease (mucor) must be considered simultaneously. Mucormycosis is more prevalent in patients with uncontrolled diabetes, and it is necessary to be considered if these patients were infected with pneumonia and their symptoms did not improve with usual treatments.

Post-antifungal effect of the combination of anidulafungin with amphotericin B and fluconazole against fluconazole-susceptible and -resistant Candida albicans.

Background and Purpose: Invasive candidiasis is a life-threatening condition that kills a large number of immunocompromised patients each year worldwide. We used post-antifungal effect studies to analyze the activities of anidulafungin (AFG), as a clinically crucial antifungal drug, amphotericin B (AMB), and fluconazole (alone and in combinations) against FLC-susceptible and -resistant Candida albicans (C. albicans) isolates obtained from the cancer patients. Materials and Methods: We tested the phenomenon of post antifungal effects of FLC, AMB, AFG, and combinations of FLC+AFG, AFG+AMB, and FLC+AMB against 17 C. albicans isolates obtained from the oral cavity of cancer patients. Isolates that had not been exposed to antifungals, served as a control group. Colony counts were performed at 0, 2, 4, 6, and 24 h after a brief (1 h) exposure to antifungal. Results: The FLC had no detectable post-antifungal effect independent of antifungal concentration and resembled drug-free FLC (control). Significant variations in the post-antifungal effect were observed when all AMB and AFG were compared to FLC. The combination of AFG and AMB with FLC resulted in effective activity compared to FLC alone. Combination regimens were rated as indifferent in general. Interestingly, low dosages of the AFG displayed increasing fungistatic action as it approached a fungistatic endpoint against C. albicans isolates (n=17). Conclusion: Our findings suggested that brief exposure to AFG, in combination with FLC and AMB, at low concentrations of the medicines utilized, could be effective in the evaluation and optimization of new dosage regimens to manage candidiasis. However, future studies will determine the clinical utility of our findings.

Antimicrobial Benefits of Flavonoids and their Nanoformulations.

Nowadays, there is an urgent need to discover and develop long-term and effective antimicrobial and biofilm-inhibiting compounds. Employing combination therapies using novel drug delivery systems and also natural antimicrobial substances is a promising strategy in this field. Nanoparticles (NPs)-based materials have become well appreciated in recent times due to their function as antimicrobial agents or carriers for promoting the bioavailability and effectiveness of antibiotics. Flavonoids belong to the promising groups of bioactive compounds abundantly found in fruits, vegetables, spices, and medicinal plants with strong antimicrobial features. Flavonoids and NPs have the potential to work as alternatives to the conventional antimicrobial agents, when used alone as well as in combination. Different classes of flavonoid NPs may be particularly advantageous in treating microbial infections. The most important antimicrobial mechanisms of flavonoid NPs include oxidative stress induction, non-oxidative mechanisms, and metal ion release. However, the efficacy of flavonoid NPs against pathogens and drug-resistant pathogens changes according to their physicochemical characteristics as well as the particular structure of microbial cell wall and enzymatic composition. In this review, we provide an outlook on the antimicrobial mechanism of flavonoid-based NPs and the crucial factors involved in it.

Application of Nano-based Drug Loading Systems in the Treatment of Neurological Infections: An Updated Review.

Infection of the central nervous system (CNS) is a global healthcare concern with high rates of death and disease. CNS infections mainly include meningitis, encephalitis, and brain abscesses. Bacteria, viruses, fungi, protozoa, and parasites are the most common causes of neuroinfections. There are many types of medications used in the treatment of CNS infections, but drug delivery through the blood-brain barrier (BBB) is a major challenge to overcome. The BBB is a specialized multicellular barrier separating the neural tissue from the peripheral blood circulation. Unique characteristics of the BBB allow it to tightly control the movement of ions and molecules. Thus, there is a critical need to deal with these conditions with the aim of improving novel antimicrobial agents. Researchers are still struggling to find effective drugs to treat CNS infections. Nanoparticle (NP)-mediated drug delivery has been considered a profound substitute to solve this problem because NPs can be tailored to facilitate drug transport across the BBB. NPs are colloidal systems with a size range of 1-1000 nm, which can be used to encapsulate therapeutics, improve drug transport across the BBB, and target specific brain areas in CNS infections. A wide variety of NPs has been displayed for the CNS delivery of therapeutics, especially when their surfaces are coated with targeting moieties. This study aimed to review the available literature on the application of NPs in CNS infections.

The molecular characterization of colistin-resistant isolates of Acinetobacter baumannii from patients at intensive care units.

Background and Objectives: The objective of this study was to determine molecular characterization and genetic diversity of colistin-resistant A. baumannii clinical isolates in Intensive Care Unit hospitalized patients. Materials and Methods: A total of 127 A. baumannii clinical isolates were evaluated for antimicrobial susceptibility. PCR reaction and sequencing were performed for the detection of mutations in pmrAB and lpx ACD genes. Results: Based on antimicrobial susceptibility testing, 40.94% and 33.85% of the isolates were MDR and XDR respectively whereas 3.93% of them were found to be PDR. Results of agar dilution MIC and E-test indicated that 76% of the isolates were sensitive to colistin. All of the isolates were positive for bla OXA-51 and 50% of them were positive for both bla OXA-23 -like and bla OXA-143 -like genes while only 25% of the isolates were positive for bla OXA-72 . None of them were positive for the bla OXA-58 -like gene. There is no mutation in pmrA. The V162A substitution for pmrB gene was repeated in two isolates, and E394D and Y292H substitutions in lpxA were observed in two isolates; also, C120R and F165L substitutions in lpxC gene was repeated in two isolates. Analysis of phylogenetic tree based on alterations in lpxACD and pmrB genes indicated the appearance of new isolates compared to the reference strain ATCC17978 A. baumannii isolates. Conclusion: The present study indicated the prevalence of MDR and XDR A. baumannii isolates and the emergence of PDR isolates in the northwest portion of Iran. The appearance of colistin-resistant isolates with new mutations in pmrB, lpxACD genes indicates new resistance mechanisms.

Let-7d and miR-185 Impede Epithelial-Mesenchymal Transition by Downregulating Rab25 in Breast Cancer.

OBJECTIVE: MicroRNAs (miRNAs) expression has deregulated in several cancer types including breast cancer (BC). The present study aims at investigating the role, mechanism, clinical value of let-7d and miR-185 in BC, and the possible correlation these miRNAs with Rab25. MATERIALS AND METHODS: Tumor samples as well adjacent normal tissues (ANT) were acquired from fresh surgical specimens from 110 patients and the expression levels of let-7d, miR-185, Rab25, and snail were evaluated using real-time PCR. The immunohistochemical (IHC) process and western blot were done to detect the level of Rab25 and Snail protein expression in BC samples. RESULTS: By comparing miRNAs expression profiles in clinical tissues of 110 patients using real-time PCR, let-7d, and miR-185 expression were dramatically downregulated in BC tissues (P < 0.05). Tumor size, stage, and lymph node metastasis were significantly related to miRNAs expression. Based on qRT-PCR and bioinformatics database analyses, we also recognized Rab25 as a possible target of miR-185 and let-7d. Rab25 expression was enhanced in BC cells and associated inversely with the expression level of mentioned miRNAs. qRT-PCR, immunohistochemistry, and western blot studies verified that Rab25 upregulation increased the levels of the snail, that key transcription factor of epithelial-mesenchymal transition (EMT). CONCLUSION: These findings demonstrated that let-7d and miR-185 inhibited EMT by targeting Rab25 expression in BC. Therefore, targeting the let-7d and miR-185/Rab25 interaction may offer new therapeutic opportunities for treating BC patients.
.

miR-140 and miR-196a as Potential Biomarkers in Breast Cancer Patients.

OBJECTIVE: MiR-140 and miR-196a were known to be correlated with cancer diagnosis and prognosis. The current study aimed at the analysis of miR-140 and miR-196a expression patterns and their clinical significance for breast cancer (BC) patients. METHODS: Differentially expressed miR-140 and miR-196a were examined via quantitative PCR in 110 cases of BC and their adjacent non-tumor (ANT) tissues. RESULTS: The results indicated that miR-140 and miR-196a, respectively, notably decreased and increased expression in BC samples in comparison with ANT (p<0.001). Reduced miR-140 expression was also related to Lymph node metastasis (LNM, P= 0.023) and stage (P = 0.009). Additionally, Receiver Operating Characteristics (ROC) analysis illustrated that miR-140 had a significant diagnostic accuracy for stage and LNM of BC patients. We also discovered a strong negative correlation between miR-196a expression with histological grade (P = 0.038), LNM (P = 0.012) and stage (P = 0.001). CONCLUSION: Overall, exploring the miR-140 and miR-196a profiles not only can statistically different among BC and ANT samples, but it is also expected to become potential BC biomarkers.
.

A 14-year-old female with fever, rash, lymphadenopathy, and pancytopenia: a case report.

BACKGROUND: Anticonvulsant hypersensitivity syndrome is a rare adverse drug reaction associated with aromatic anticonvulsant drugs. This syndrome can range from mild cutaneous rash to drug reaction with eosinophilia and systemic symptoms that include fever, rash, lymphadenopathy, pancytopenia, and involvement of multiple internal organs. We aimed to report this case in the literature and make physicians aware of the uncommon symptoms of this syndrome when they prescribe antiepileptic medications in particular. CASE PRESENTATION: A 14-year-old Middle Eastern female patient from Iran with free past medical and allergic history was admitted to hospital because of fever, rash, lymphadenopathy, and pancytopenia after taking anticonvulsants due to new-onset seizure. High fever and cutaneous rash along with lymphadenopathy following administration of anticonvulsant medications that could not be explained by other causes alerted the physician to the possibility of this syndrome. Our investigation revealed no further diagnosis and 1 week after discontinuation of the drugs, her symptoms were resolved. Anticonvulsant hypersensitivity syndrome is a diagnosis of exclusion and immediate discontinuation of the suspicious drugs is necessary. Hence, early recognition can prevent permanent multiorgan damage. CONCLUSIONS: Chlorpheniramine as a simple treatment was provided for this syndrome.

Diagnostic value of chest CT in Iranian patients with suspected COVID-19.

BACKGROUND: In the current COVID-19 pandemic, there is a rising need for a rapid and reliable diagnostic tool. We hypothesized that chest computed tomography (CT) can be a potential alternative for reverse transcription-polymerase chain reaction (RT-PCR). The aim of this study was to compare the diagnostic value of chest CT and RT-PCR in Iranian patients with suspected COVID-19. METHODS: In a retrospective, single-center case series, 568 consecutive hospitalized or outpatient patients with suspected COVID-19 underwent chest CT and/or RT-PCR testing at Imam Reza Hospital, the tertiary teaching hospital of Tabriz University of Medical Sciences in Iran, from February 21 and March 28, 2020. RESULTS: The sensitivity of chest CT for signifying COVID-19 was 64% (95% CI: 56%-71%) on the basis of positive RT-PCR results as a standard method. CT imaging also had a specificity of 77% (95% CI: 73%-81%), positive predictive value of 35% (95% CI: 0.31-0.39), negative predictive value of 66% (95% CI: 0.61-0.69), positive likelihood ratio of 2.79 (95% CI: 2.26-3.46), and negative likelihood ratio of 0.47 (95% CI: 0.38-0.57). CONCLUSION: Chest CT had higher specificity in the diagnosis of COVID-19 than that of the previous studies. Therefore, it can play a crucial role in the early diagnosis. Similar to the previous studies, the typical CT features were patchy ground-glass opacities as well as peripheral aspects of the lungs consolidations.

The central role of the SOS DNA repair system in antibiotics resistance: A new target for a new infectious treatment strategy.

Bacteria have a considerable ability and potential to acquire resistance against antimicrobial agents by acting diverse mechanisms such as target modification or overexpression, multidrug transporter systems, and acquisition of drug hydrolyzing enzymes. Studying the mechanisms of bacterial cell physiology is mandatory for the development of novel strategies to control the antimicrobial resistance phenomenon, as well as for the control of infections in clinics. The SOS response is a cellular DNA repair mechanism that has an essential role in the bacterial biologic process involved in resistance to antibiotics. The activation of the SOS network increases the resistance and tolerance of bacteria to stress and, as a consequence, to antimicrobial agents. Therefore, SOS can be an applicable target for the discovery of new antimicrobial drugs. In the present review, we focus on the central role of SOS response in bacterial resistance mechanisms and its potential as a new target for control of resistant pathogens.

Nasal and extra nasal MRSA colonization in hemodialysis patients of north-west of Iran.

OBJECTIVES: Methicillin resistant Staphylococcus (S.) aureus colonization is one of the main causes of serious infections in hemodialysis patients. This cross-sectional study was performed to examine prevalence of MRSA colonization and evaluation of risk factors in hemodialysis patients. A total of 560 swab samples from nasal, the skin around catheter and throat were collected from 231 hemodialysis patients in Tabriz. The standard biochemical tests were used for identification of S. aureus isolates. Antimicrobial susceptibility profile was determined against 11 antibiotics by the disk diffusion method. Phenotypic test of S. aureus was performed using novobiocin 30 µg/disc, and methicillin sensitivity test was performed by cefoxitin 30 µg/disc. RESULTS: Overall, 50.65% (118/231) hemodialysis patients were positive for S. aureus which 34.93% (80/231) of patients were MRSA carriage. The MRSA colonization in patients with a catheter (44.06%) was more than individuals utilizing a fistula (24.57%, p = 0.030). Among sampling sites, the highest MRSA was related to nasal samples (30.70%, p < 0.00001). Extra nasal colonization of S. aureus was observed in 12.71% patients. The highest rates of resistance were observed against ampicillin (93.98%) and the highest sensitivity was against linezolid antibiotic (5.42%). These findings highlight the necessity of prophylaxis against S. aureus in individuals under dialysis.