Integration of phytotherapy and chemotherapy: Recent advances in anticancer molecular pathways.

Cancer is a disease characterized by abnormal and uncontrolled growth of cells, leading to invasion and metastasis to other tissues. Chemotherapy drugs are some of the primary treatments for cancer, which could detrimentally affect the cancer cells by various molecular mechanisms like apoptosis and cell cycle arrest. These treatment lines have always aligned with side effects and drug resistance. Due to their anticancer effects, medicinal herbs and their active derivative compounds are being profoundly used as complementary treatments for cancer. Many studies have shown that herbal ingredients exert antitumor activities and immune-modulation effects and have fewer side effects. On the other hand, combining phytotherapy and chemotherapy, with their synergistic effects, has gained much attention across the medical community. This review article discussed the therapeutic effects of essential herbal active ingredients combined with chemotherapeutic drugs in cancer therapy. To write this article, PubMed and Scopus database were searched with the keywords "Cancer," "Combination," "Herbal," "Traditional," and "Natural." After applying inclusion/exclusion criteria, 110 articles were considered. The study shows the anticancer effects of the active herbal ingredients by inducing apoptosis and cell cycle arrest in cancer cells, especially with a chemotherapeutic agent. This study also indicates that herbal compounds can reduce side effects and dosage, potentiate anticancer responses, and sensitize cancer cells to chemotherapy drugs.

Mesenchymal Stem Cell-derived Exosome; An Interesting Nanocarrier to Improve Allergen-specific Intranasal Immunotherapy.

Increasing the efficacy of allergen-specific intranasal immunotherapy (INIT) has recently been the main goal of several studies to establish this route as a safe delivery method through mucosal pathways. In this case, the present study evaluated the potential of INIT using ovalbumin (OVA)-loaded mesenchymal stromal/stem cell (MSC)-derived exosomes (Exo-OVA) in an allergic asthma mouse model. Together with control groups, sensitized Balb/c mice underwent intranasal immunotherapy with Exo-OVA (10 µg OVA per dose) for three consecutive weeks. Serum-specific immunoglobulin E (IgE) levels, transforming growth factor-beta (TGF-ß), interleukin (IL)-4, and interferon-gamma (IFN-γ) production by cultured spleen cells, lung histopathologic analysis, and nasopharyngeal lavage fluid cellular examinations were then conducted. The results showed that INIT using Exo-OVA significantly increased IFN-γ and TGF-ß secretion, while allergen-specific IgE and IL-4 production were dramatically decreased compared to the control group receiving phosphate-buffered saline. In addition, the eosinophil and total cell counts in the nasopharyngeal lavage fluid were reduced, and inflammatory conditions and cell accumulation in lung tissue were ameliorated. In conclusion, the Exo-OVA improved the INIT efficacy compared to free OVA. Therefore, this formulation could be introduced as an effective approach for immunomodulatory purposes with a shorter treatment duration and reduced side effects.

Combined training improves the diagnostic measures of sarcopenia and decreases the inflammation in HIV-infected individuals.

BACKGROUND: HIV-related sarcopenia is an emerging health issue that often remains undiagnosed and can lead to reduced quality of life, independence, and premature death if untreated. This study investigated the effects of a 6 month combined training (resistance plus aerobic exercise) (CT) intervention on diagnostic measures of sarcopenia, including grip strength, appendicular lean mass index (ALMI), and gait speed. METHODS: Forty participants were randomized into either a CT group (n = 20; age = 38.3 ± 4.9 years) or a control group (CON; n = 20; age = 37.9 ± 5.1 years). Participants in the CT group performed three supervised sessions per week for 6 months, consisting of weekly reverse linear periodized resistance training followed by 20 min aerobic training. Participants in the CON group were instructed to continue with their current lifestyle habits. Assessments were completed at baseline and after 6 months. Statistical analyses were performed using a two-way analysis of covariance (ANCOVA) adjusted for sex and preintervention values. Primary outcomes included grip strength, ALMI, and gait speed. Secondary outcomes were changes in levels of pro-inflammatory cytokines (IL-6 and TNF-α), IGF-1, and myostatin. Associations were explored between changes in inflammatory markers (IL-6 and TNF-α), gait speed, and ALMI with grip strength. RESULTS: A significant increase in ALMI was found for CT compared with CON (0.29 ± 0.13 kg/m2 vs. -0.11 ± 0.14 kg/m2 , respectively; P < 0.001). Significant improvements in grip strength (7.86 ± 8.50 kg for CT vs. -1.58 ± 2.47 kg for CON) and gait speed (0.16 ± 0.07 m/s2 for CT vs. -0.06 ± 0.52 m/s2 for CON; both P < 0.001) were also observed in CT compared with CON. Reduction in inflammatory biomarkers was found in CT compared with CON (IL-6; TNF-α, both P < 0.001). An increase in IGF-1 (74.36 ± 56.64 pg/mm3 for CT vs. 7.19 ± 99 pg/mm3 for CON; P < 0.001) and a decrease in myostatin (-158.90 ± 62.03 pg/mm3 for CT vs. -43.33 ± 146.60 pg/mm3 for CON; P < 0.001) was found following CT compared with the CON group. Change in grip strength was correlated with changes in IL-6 (r = -0.65, P < 0.001), TNF-α (r = -0.63, P < 0.001), gait speed (r = 0.63, P < 0.001), and ALMI (r = 0.54, P = 0.001), but not IGF-1 and myostatin. No adverse events were recorded, and compliance with the CT exercise sessions was high (>85%). CONCLUSIONS: Combined training appears to be an effective means to counteract sarcopenia and improve various inflammatory markers and growth hormones in people living with HIV.

ß-D-mannuronic Acid (M2000) and Inflammatory Cytokines in COVID-19; An In vitro Study.

coronavirus disease of 2019 (COVID-19) can be complicated by acute respiratory distress syndrome (ARDS) and may be associated with cytokine storm and multiorgan failure. Anti-inflammatory agents, such as systemic corticosteroids, monoclonal antibodies, and nonsteroidal anti-inflammatory drugs (NSAIDs) can be used for this purpose. In this study, we evaluated the immunomodulatory effect of mannuronic acid (M2000), which is a novel NSAID, on COVID-19-related cytokine storms. This study was conducted in vitro on blood samples of 30 COVID-19 patients who presented with ARDS to a referral center. Peripheral blood mononuclear cells (PBMCs) were isolated from blood samples and incubated with phorbol myristate acetate for 24 hours. M2000 was administered with the dosages of 25 µg/well and 50 µg/well after 4 hours of incubation at 37°C. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to assess mRNA gene expression. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the supernatant PBMC levels of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. Both mRNA expression and the supernatant PBMC levels of IL-17, TNF-α, IL­6, and IFN­Î³ were decreased in PBMCs of COVID-19 patients treated with M2000 compared with the control  group. For the first time, it was observed that M2000 could be effective in alleviating the inflammatory cascade of COVID-19 patients based on an in vitro model. After further studies in vitro and in animal models, M2000 could be considered a novel NSAID drug in COVID-19 patients.

Combination of resistance and aerobic exercise for six months improves bone mass and physical function in HIV infected individuals: A randomized controlled trial.

To evaluate the effect of combined resistance and aerobic training (RT+AT) on regional bone mineral density (BMD) and physical performance in people living with HIV (PLWH). Forty PLWH (20 men and 20 women) were randomized into RT+AT group (n = 20; age = 38.3 ± 4.9) or non-exercise control group (n = 20; age = 37.9 ± 5.1). The RT+AT group was required to perform a nonlinear periodized resistance training program targeting large muscle groups followed by 20 min aerobic exercise at 65-80% of maximal heart rate. Participants in RT+AT performed three supervised sessions per week for 6-months, whereas participants in the control group were instructed to continue with their current lifestyle habits. The primary outcome was bone mineral density (lumbar spine (L2-L4), femoral neck, and distal 1/3 radius). Secondary outcomes included physical function, anthropometry, inflammatory markers, and growth factors. The RT+AT group demonstrated a significant increase in BMD at follow-up for the Lumbar spine (L2-L4), femoral neck, and 1/3 radius (all, P < .05), and There were no gender differences in the training response between men and women for any of the BMD regions. Similar findings were also observed for lean body mass, IGF1and Adiponectin (P < .001). We observed a decrease in percent body fat, fat mass, IL-6, TNF-α, and myostatin in the RT+AT group (P < .001). Finally, there was a significant increase in handgrip strength and gait speed for both women and men in the RT+AT group (P < .001). A combination of resistance and aerobic training appears to be a feasible and effective means for counteracting bone loss and improving various inflammatory markers, physical function, and growth hormones in PLWH.

Generation of CCR5-ablated Human Induced Pluripotent Stem Cells as a Therapeutic Approach for Immune-mediated Diseases.

C-C chemokine receptor type 5 (CCR5) is a receptor for some pro-inflammatory chemokines which plays important roles in immunological disorder and host responses to infectious agents. Additionally, the prognosis of some immune-mediated diseases in the people who are naturally carrying the CCR5 32bp deletions is optimistic. However, the clinical application of CCR5 32bp mutant cells is very limited due to the rare availability of donors who are homozygous for CCR5 D32. The transfection efficiency of nucleofected placental mesenchymal stem cells derived - human induced pluripotent stem cells (PMSC-hiPSCs) was examined through the evaluation of green fluorescent protein (GFP) expression using flow cytometry. The nucleofected clonal populations were selected using colony picking. The CCR5 gene disrupted clonal populations were evaluated and confirmed by PCR and Sanger sequencing methods. Also, off-target sites were evaluated by the "Loss of a primer binding site" technique. The results of the flow cytometry revealed that among the six applied nucleofection programs for PMSC-iPSCs, the program of A-033 has achieved the best transfection efficiency (27.7%). PCR and then sequencing results confirmed the CCR5 gene was disrupted in two clonal populations of 16 (D6) and 62 (D20) by the Clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease 9 (CRISPR/Cas9) system. The "Loss of a primer binding site" technique showed that no exonic off-target mutations were induced in both CCR5 gene disrupted clonal populations. We establish a CRISPR/Cas9 mediated CCR5 ablated PMSC-hiPSCs without detectable off-target damage. This approach can provide a stable supply of autologous/allogeneic CCR5-disrupted PMSC-hiPSCs that might be a feasible approach for the treatment of immune-mediated diseases.

HIV Prevalence and Sexual Behaviors Among Transgender Women in Tehran, Iran.

To date, no study has looked at the prevalence of HIV and the high-risk behaviors among transgender women in Iran. Between May 2013 and February 2014, 104 transgender women were recruited for participation in this study. Inclusion criteria consisted of having an official letter from the Tehran Psychiatric Institute, or a well-known psychiatrist, that showed a diagnosis of gender dysphoria and/or completed Gender-Affirming Surgery at least 6 months prior to this study. Of the 104 participants, 2 were diagnosed with HIV, which translates to a HIV prevalence of 1.9%. Condom use with a non-paying partner, casual partner, and paying partner was respectively 39.7%, 34.6%, and 53.3%. A high percentage of transgender women in Tehran engage in high-risk sexual behaviors including condomless receptive anal sex, which is of particular concern given the low rates of HIV testing. Targeted public intervention programs and research are desperately needed for this high-risk group.

Enhanced Immune Responses against HIV-1 with Adenovector (Gag and Tat) Prime/Protein Boost Regimen and GM-CSF Injection.

Vaccines against the HIV-1 virus offers the best hope for eliminating HIV-associated mortality. Recombinant adenovector type 5 (rAd5) vaccine is a potential candidate for preventive vaccine strategies. In this study, we evaluated the rAd5 prime/protein boost strategy in a murine model. We used rAd5 harboring single HIV-1 genes. These genes, including gag (p24) and exon1 of tat, were amplified from HIV-1 (clade A) RNA using nested PCR. Recombinant vectors were constructed, purified and then injected at 1012 viral particles into four groups, each comprising five mice. The groups were each assigned to receive one of rAd5 prime/protein boost Gag, Tat with and without recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and rAd5 with and without genes. The humoral responses were evaluated using ELISA and cellular immune responses checked by cell proliferation and ELISpot assays (IL-2, IL-4 and IFN-γ). It was shown that compared with the rAd5 injection alone, the rAd5 prime/protein boost plan increased cellular immunity (p= 0.009) as well as humoral immunity (p= 0.009). Moreover, rGM-CSF as an adjuvant enhanced cell-mediated immunity and increased IL-4 expression (p=0.032). The results revealed that the simultaneous use of multiple antigens and heterologous prime/boost strategy can enhance both humoral and cellular immune systems. Moreover, subcutaneous injection of rGM-CSF increases IL-4 production and shifts the immune pattern to Th2. These strategies can potentially be used to develop an efficient HIV-1 vaccine.

Assessment of the Effects of a Novel Herbal Immunomodulator Drug (IMOD) on Cytokine Profiles in Experimental Canine Visceral Leishmaniasis: a Preliminary Survey.

BACKGROUND: Cytokines play a fundamental role in the regulation of immune responses in remission and/or relapsing of leishmaniasis. Therefore, immunotherapy for the treatment of canine visceral leishmaniasis (CVL) has represented a principle approach in control of the infection. The present research aimed to evaluating the immunotherapeutic potential of a novel herbal immunomodulator drug (IMOD) on CVL. METHODS: Twelve mongrel dogs were intravenously infected with Iranian strain of L. infantum and randomly divided into three groups; 1: negative control (non-infected), 2: immunotherapy with IMOD and 3: positive control (non-treated). Cell proliferation and Th1-/Th2-type cytokines were measured in peripheral blood mononuclear cell (PBMC) by cell proliferation kit I (MTT) and enzyme-linked immunospot (ELISpot) assays, respectively. RESULTS: At the 60 days follow-up assessment, no adverse effects were observed in treated interventional group. Cellular proliferation assay indicated that PBMCs of IMOD group had higher stimulation index (SI) than positive control group (p < 0.05). Enhancement of CD4+T cells such as IL-2, IL-4 & IL-10 were detected in negative control group due to in vitro IMOD stimulation 30 days post-treatment. In accordance to decreasing trends of Th1 & Th2 cytokines in positive control group, the mean number of IFN-γ IL-2, IL-4 and IL-10 spot forming cells (SFCs) down regulated for IMOD group during the study. CONCLUSION: These data indicate that IMOD had immunomodulatory potential but is not sufficient for total parasitic cure due to balance of Th1/Th2 cytokines. This is a preliminary study and we propose to undertake a series of experiments to evaluate the CVL due to in vitro modulatory effects of IMOD.