Alginate/gum arabic-based biomimetic hydrogel enriched with immobilized nerve growth factor and carnosine improves diabetic wound regeneration.

Diabetic foot ulcers (DFUs) often remain untreated because they are difficult to heal, caused by reduced skin sensitivity and impaired blood vessel formation. In this study, we propose a novel approach to manage DFUs using a multifunctional hydrogel made from a combination of alginate and gum arabic. To enhance the healing properties of the hydrogel, we immobilized nerve growth factor (NGF), within specially designed mesoporous silica nanoparticles (MSN). The MSNs were then incorporated into the hydrogel along with carnosine (Car), which further improves the hydrogel's therapeutic properties. The hydrogel containing the immobilized NGF (SiNGF) could control the sustain release of NGF for >21 days, indicating that the target hydrogel (AG-Car/SiNGF) can serve as a suitable reservoir managing diabetic wound regeneration. In addition, Car was able to effectively reduce inflammation and significantly increase angiogenesis compared to the control group. Based on the histological results obtained from diabetic rats, the target hydrogel (AG-Car/SiNGF) reduced inflammation and improved re-epithelialization, angiogenesis, and collagen deposition. Specific staining also confirmed that AG-Car/SiNGF exhibited improved tissue neovascularization, transforming growth factor-beta (TGFß) expression, and nerve neurofilament. Overall, our research suggests that this newly developed composite system holds promise as a potential treatment for non-healing diabetic wounds.

Catalase-gold nanoaggregates manipulate the tumor microenvironment and enhance the effect of low-dose radiation therapy by reducing hypoxia.

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC.

Hypoxia effects on oncolytic virotherapy in Cancer: Friend or Foe?

Researchers have tried to find novel strategies for cancer treatment in the past decades. Among the utilized methods, administering oncolytic viruses (OVs) alone or combined with other anticancer therapeutic approaches has had promising outcomes, especially in solid tumors. Infecting the tumor cells by these viruses can lead to direct lysis or induction of immune responses. However, the immunosuppressive tumor microenvironment (TME) is considered a significant challenge for oncolytic virotherapy in treating cancer. Based on OV type, hypoxic conditions in the TME can accelerate or repress virus replication. Therefore, genetic manipulation of OVs or other molecular modifications to reduce hypoxia can induce antitumor responses. Moreover, using OVs with tumor lysis capability in the hypoxic TME may be an attractive strategy to overcome the limitations of the therapy. This review summarizes the latest information available in the field of cancer virotherapy and discusses the dual effect of hypoxia on different types of OVs to optimize available related therapeutic methods.

Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango?

Tumor-infiltrating lymphocytes (TILs), frontline soldiers of the adaptive immune system, are recruited into the tumor site to fight against tumors. However, their small number and reduced activity limit their ability to overcome the tumor. Enhancement of TILs number and activity against tumors has been of interest for a long time. A lack of knowledge about the tumor microenvironment (TME) has limited success in primary TIL therapies. Although the advent of engineered T cells has revolutionized the immunotherapy methods of hematologic cancers, the heterogeneity of solid tumors warrants the application of TILs with a wide range of specificity. Recent advances in understanding TME, immune exhaustion, and immune checkpoints have paved the way for TIL therapy regimens. Nowadays, TIL therapy has regained attention as a safe personalized immunotherapy, and currently, several clinical trials are evaluating the efficacy of TIL therapy in patients who have failed conventional immunotherapies. Gaining favorable outcomes following TIL therapy of patients with metastatic melanoma, cervical cancer, ovarian cancer, and breast cancer has raised hope in patients with refractory solid tumors, too. Nevertheless, TIL therapy procedures face several challenges, such as high cost, timely expansion, and technical challenges in selecting and activating the cells. Herein, we reviewed the recent advances in the TIL therapy of solid tumors and discussed the challenges and perspectives.

Catalase application in cancer therapy: Simultaneous focusing on hypoxia attenuation and macrophage reprogramming.

The tumor microenvironment (TME), as an immunosuppressive milieu, has a critical role in tumor progression and increases resistance to the conventional treatments. Among the abundant immunosuppressive cells in the TME, tumor-associated macrophages (TAMs) could be a promising target for reprogramming and potentiating the local anti-tumor response. On the other hand, hypoxia is a major barrier in treating solid tumors, which aggravates the situation and alleviates the anti-tumor immune responses. Moreover, catalase and catalase-mimicking compounds can efficiently participate in the TAMs polarization and hypoxia attenuation in the TME. In this review, we will introduce a practical and novel approach which can simultaneously reduce hypoxia and polarize TAMs in the TME. Furthermore, catalase therapeutic effects in combination with cancer therapy methods will be fully discussed. This work aims to inspire readers to explore new avenues for designing and development of next-generation catalase-based formulations for cancer therapy.

The Situation of Small Molecules Targeting Key Proteins in combatting SARS-CoV-2: Synthesis, Metabolic Pathway, Mechanism of Action, and Potential Therapeutic Applications.

Due to the high mortality rate of the 2019 coronavirus disease (COVID-19) pandemic, there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, and mechanism of action of the existing drugs with potential therapeutic applications for COVID-19. Furthermore, we summarized the molecular docking stimulation of the medications related to key protein targets. These already established drugs could be further developed, and after their testing through clinical trials, they could be used as suitable therapeutic options for patients suffering from COVID-19.

Immune and metabolic checkpoints blockade: Dual wielding against tumors.

Recent advances in cancer immunotherapy have raised hopes for treating cancers that are resistant to conventional therapies. Among the various immunotherapy methods, the immune checkpoint (IC) blockers were more promising and have paved their way to the clinic. Tumor cells induce the expression of ICs on the immune cells and derive them to a hyporesponsive exhausted phenotype. IC blockers could hinder immune exhaustion in the tumor microenvironment and reinvigorate immune cells for an efficient antitumor response. Despite the primary success of IC blockers in the clinic, the growing numbers of refractory cases require an in-depth study of the cellular and molecular mechanisms underlying IC expression and function. Immunometabolism is recently found to be a key factor in the regulation of immune responses. Activated or exhausted immune cells exploit different metabolic pathways. Tumor cells can suppress antitumor responses via immunometabolism alteration. Therefore, it is expected that concurrent targeting of ICs and immunometabolism pathways can cause immune cells to restore their antitumor activity. In this review, we dissected the reciprocal interactions of immune cell metabolism with expression and signaling of ICs in the tumor microenvironment. Recent findings on dual targeting of ICs and metabolic checkpoints have also been discussed.

A biocompatible theranostic nanoplatform based on magnetic gadolinium-chelated polycyclodextrin: in vitro and in vivo studies.

A novel theranostic nanoplatform was prepared based on Fe3O4 nanoparticles (NPs) coated with gadolinium ions decorated-polycyclodextrin (PCD) layer (Fe3O4@PCD-Gd) and employed for Curcumin (CUR) loading. The dissolution profile of CUR indicated a pH sensitive release manner. Fe3O4@PCD-Gd NPs exhibited no significant toxicity against both normal and cancerous cell lines (MCF 10A and 4T1, respectively); while the CUR-free NPs showed more toxicity against 4T1 than MCF 10A cells. In vivo anticancer study revealed appropriate capability of the system in tumor shrinking with no tissue toxicity and adverse effect on body weight. In vivo MR imaging of BALB/c mouse showed both T1 and T2 contrast enhancement on the tumor cells. Fe3O4@PCD-Gd/CUR NPs showed significant features as a promising multifunctional system having appropriate T1-T2 dual contrast enhancement and therapeutic efficacy in cancer theranostics.

Immunopathological similarities between COVID-19 and influenza: Investigating the consequences of Co-infection.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a global public health emergency since December 2019, and so far, more than 980,000 people (until September 24, 2020) around the world have died. SARS-CoV-2 mimics the influenza virus regarding methods and modes of transmission, clinical features, related immune responses, and seasonal coincidence. Accordingly, co-infection by these viruses is imaginable because some studies have reported several cases with SARS-CoV-2 and influenza virus co-infection. Given the importance of the mentioned co-infection and the coming influenza season, it is essential to recognize the similarities and differences between the symptoms, immunopathogenesis and treatment of SARS-CoV-2 and influenza virus. Therefore, we reviewed the virology, clinical features, and immunopathogenesis of both influenza virus and SARS-CoV-2 and evaluated outcomes in cases with SARS-CoV-2 and influenza virus co-infection.

Detection of HCV genome in peripheral blood mononuclear cells of Iranian seropositive and HCV RNA negative in plasma of patients with beta-thalassemia major: Occult HCV infection.

Beta (ß) thalassemia major is a genetic blood disorder with a deficiency in the hemoglobin beta chain, requiring blood transfusion therapy. Multiple blood transfusions increase the risk of transmitting blood-borne infections. The aim of this study is to determine the frequency of hepatitis C virus (HCV) infection in Iranian individuals with ß-thalassemia major. A total of 164 patients with ß-thalassemia major were recruited for this study. HCV RNA testing was done on plasma and peripheral blood mononuclear cells (PBMCs) from the HCV seropositive samples (with reverse transcriptase-nested polymerase chain reaction [PCR] method using primers from the 5'-untranslated region [UTR]), and all HCV RNA positive samples were genotyped by the restriction fragment length polymorphism assay. For confirmation of the HCV genotyping in PBMCs of occult HCV infection [OCI]-positive patients, the PCR products of two different regions of HCV (5'-UTR and nonstructural protein 5B [NS5B]) were sequenced. Of 164 patients, 29.3% were positive for anti-HCV antibodies, and HCV RNA was detected in the plasma specimens of 13.4% patients and in the PBMC samples of 15.2% participants. The genomic HCV-RNA was detected in PBMC samples in 3 (6.3%) of the total 48 individuals who were HCV seropositive, and plasma HCV-RNA negative (occult HCV infection). The subtypes of HCV in the plasma and PBMC samples of three participants were not identical. This study shows that among this group of Iranian patients with ß-thalassemia major, 13.4% had active HCV infection and 6.3% had occult HCV infection as evidenced by HCV RNA detected in PBMC specimens. Therefore, the design of a prospective study that focuses on the diagnosis of OCI can be very valuable and provide more information.

Relationship between behavioral indices of pain during labor pain with pain intensity and duration of delivery.

BACKGROUND: Certain behaviors can be adopted by women to cope with labor pain according to their individual characteristics, which are currently called behavioral indicators during labor pain, and include facial expressions, verbal expressions, tone of voice, body movements, degree of relaxation, and respiratory system functioning during delivery. Moreover, severity of pain and duration of labor can vary due to several factors including individual characteristics. OBJECTIVE: The purpose of the present study was to determine the relationship between behavioral indicators during labor pain, severity of pain, and delivery duration. METHODS: In this cross-sectional study, 120 low risk pregnant women who referred to Omolbanin (AS) Hospital in the city of Mashhad (Iran) for delivery in 2014, were selected via convenience sampling method, which was then followed by completion of demographic information forms. From cervical dilatation of 3-5 centimeters until delivery, the Labor Pain Coping Behavior Observation Form (comprised of 6 sub-groups of facial expressions, verbal expressions, tone of voice, body movements, degree of relaxation, and respiratory function and severity and duration of pain) was completed during uterine contractions and every half an hour. Using the Inventory of Labor Information; vital signs, frequency of contractions, and duration of the first and second stages of labor were measured. Furthermore, the content validity of the questionnaire was determined and its reliability was confirmed by Cronbach's alpha method. Then, the data were analyzed using the SPSS version 16, through Pearson Product-Moment Correlation and Spearman's Rank-Order Correlation, Kruskal-Wallis test, and ANOVA. RESULTS: According to the results, 16.2% of the individuals had undesirable behavioral indicators during labor pain, 50% of them were endowed with acceptable behaviors, and 33.8% of these women had desirable behaviors. The findings also revealed that the duration of the active phase of the first stage of labor (p<0.001 and r=-0.453), the duration of the second stage of labor (p<0.012 and r=-0.146), and the severity of pain (p<0.001 and r=-0.450) were significantly and inversely correlated with behavioral indicators during labor pain; i.e. an increase in the mean score of behavioral indicators during labor pain could lead to a decline in the duration of stages of labor and severity of pain. CONCLUSION: It was concluded that behaviors demonstrated by women in labor had effects on their pains in the course of delivery, and there was also a relationship between the duration of stages of labor and its severity of pain. Therefore, it was recommended to turn attention to behaviors by women in labor in order to achieve a desirable clinical management.

Investigation of the effects of a prevention of mother-to-child HIV transmission program among Iranian neonates.

Human immunodeficiency virus (HIV) infection is mostly spreading in developing countries. One of the most important pathways of HIV infection in these nations is the vertical route, from mother to infant. Therefore, this study evaluated the effectiveness of the prevention of mother-to-child transmission (PMTCT) program for HIV among Iranian neonates born to HIV-positive mothers. A total of 54 neonates born to HIV-1 positive mothers, all of whom were in a PMTCT program for HIV, as per the Iranian guidelines, were enrolled in this descriptive cross sectional study from March 2014 to July 2017. After RNA extraction of a plasma specimen, HIV-1 viral load was tested by an Artus HIV-1 RG RT-PCR Kit. Out of 54 evaluated neonates, 32 (59.3%) were male. The mean age of the HIV-infected mothers was 30.1 ± 5.4 (range: 19-47) years, and 36 (66.7%) of the mothers were in the age group 26-34 years. In the present study, it was found that none of the neonates whose mothers had previously entered PMTCT programs had HIV. 15 children were found who were born to HIV-positive mothers who had not entered the PMTCT program. Three of these children were infected with HIV (CRF35_AD), and none of them carried HIV-1 variants with SDRMs. The results of this study indicate that if HIV-positive pregnant women enter the PMTCT program for HIV, they can realistically hope to give birth to a non-infected child.

Association between matrix metaloproteinases 2-1306C/T polymorphism and the risk of coronary artery disease in Iranian population.

BACKGROUND: Coronary Artery Disease (CAD) represents the most important cause of sudden cardiac death. Interaction between genetic and environmental factors, individual susceptibility of the development of CAD is one of the MMP2 genes. Genetic variants' dysfunction of the MMP2 gene associated with the risk of CAD. The aim of the present study is to assess possible association between risk of Coronary Artery Disease and MMP2-1306C/T polymorphism. METHODS: This case-control study contains a total number of 344 subjects, including 215 patients with CAD and 129 of controls. Genomic DNA was isolated from whole blood and genotyping was performed by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR- RFLP) method. RESULTS: This study reveals the result that about 3.5% of CAD patients had TT genotype while 30.4% of them had CT genotype. Corresponding figures for subjects without CAD were zero and 52.6% respectively. These differences were statistically significant (P=0.002). Frequencies of T allele among patients with and without CAD were 18.71% and 26.28% respectively (p=0.04). The odds ratio between T allele and CAD was 0.64 (p=0.055). we couldn't trace significant differences among alleles in Gensini score, Gesnsini score's median among patients carried out TT, CT and CC genotypes were 4, 2 and 2 respectively (p=0.3). CONCLUSIONS: Result of this study provides some evidences that the MMP2-1306 polymorphism can be associated with coronary artery disease. Further longitudinal studies including more sample sizes are required to confirm this protective effect.

Development of an immune function assay by measuring intracellular adenosine triphosphate (iATP) levels in mitogen-stimulated CD4+ T lymphocytes.

We developed an immune function assay for monitoring CD4+ T cells activity based on changes in intracellular adenosine triphosphate (iATP) levels after phytohemagglutinin (PHA) stimulation. Blood samples were obtained from 40 healthy subjects and 30 RTRs and incubated with 5 µg/mL of PHA for 15-18 hr at 37°C and 5% CO2. Afterward, the CD4+ T cells were separated by antibody-coated magnetic beads and lysed. Then, iATP content in unstimulated and stimulated conditions was measured by luciferin-luciferase reaction using a log-log standard curve. The iATP levels showed significant increase in CD4+ T cells in both healthy persons (mean: 550 ± 142 ng/mL vs. 109 ± 54 ng/mL) and RTRs (mean: 394 ± 160 ng/mL vs. 52 ± 37 ng/mL) after PHA stimulation (P < 0.001). However, the iATP production in RTRs was significantly lower than that in healthy individuals; both prior to and after stimulation with PHA (P < 0.001). No gender-specific difference in iATP production was observed between women and men subjects. This rapid and low-cost assay reflects the degree of immune cell function through assessment of CD4+ T cells activation. Thus, it can be used for evaluation of immune system status in immunodeficient individuals as well as in immunosuppressed transplant recipients who needs drug adjustment.

Prevalence of human herpesvirus-8 among HIV-infected patients, intravenous drug users and the general population in Iran.

Studies looking at the frequency of human herpesvirus-8 (HHV-8) among Iranian blood donors have produced conflicting results. The aim of this study was to investigate the prevalence of HHV-8 DNA by using polymerase chain reaction methods among 168 healthy individuals, 60 intravenous drug users and 100 HIV-infected patients from Iran. The prevalence of HHV-8 was significantly higher among intravenous drug users (13.3%) compared with the general population (3.6%; P=0.017). The HHV-8 genome was mostly detected among intravenous drug users who displayed high-risk sexual behaviours. Moreover, the HHV-8 genome was also detected in 8% of HIV-infected patients. The present study findings support the likelihood that the transmission of HHV-8 is via a sexual route in the Iranian population.

First report of human parvovirus 4 detection in Iran.

Parvovirus 4 (PARV4) is an emerging and intriguing virus that currently received many attentions. High prevalence of PARV4 infection in high-risk groups such as HIV infected patients highlights the potential clinical outcomes that this virus might have. Molecular techniques were used to determine both the presence and the genotype of circulating PARV4 on previously collected serum samples from 133 HIV infected patients and 120 healthy blood donors. Nested PCR was applied to assess the presence of PARV4 DNA genome in both groups. PARV4 DNA was detected in 35.3% of HIV infected patients compared to 16.6% healthy donors. To genetically characterize the PARV4 genotype in these groups, positive samples were randomly selected and subjected for sequencing and phylogenetic analysis. All PARV4 sequences were found to be genotype 1 and clustered with the reference sequences of PARV4 genotype 1. J. Med. Virol. 88:1314-1318, 2016. © 2016 Wiley Periodicals, Inc.

NMR investigation of methyl-2,4-dimethoxysalicylate: effect of solvent and temperature.

(1)H NMR and (13)C NMR of methyl-2,4-dimethoxysalicylate 2 was measured in chloroform-d at the temperature range of 220-330 K, in dimethyl sulfoxide-d(6) at the temperature range of 300-400 K and in a polar protic solvent (CD(3)OD) at 300 K. The structure of 2 in liquid phase (solvent) is compared with those in solid phase (X-ray) and in the gas phase (quantum mechanical calculations). The relationship between molecular geometry, (1)H NMR chemical shift and W coupling of involved protons has a complex nature, but hydrogen bonds [C=O...H-O and C=O...H-CH(2)O] strength is the principle factor.