Targeting programmed cell death protein 1 (PD-1) for treatment of non-small-cell lung carcinoma (NSCLC); the recent advances.

The immune system uses various immune checkpoint axes to adjust responses, support homeostasis, and deter self-reactivity and autoimmunity. Nevertheless, non-small-cell lung carcinoma (NSCLC) can use protective mechanisms to facilitate immune evasion, which leads to potentiated cancer survival and proliferation. In this light, many blocking anti-bodies have been developed to negatively regulate checkpoint molecules, in particular, programmed cell death protein 1 (PD-1) / PD-ligand 1 (L1), and bypass these immune suppressive mechanisms. Meanwhile, anti-PD-1 anti-bodies such as nivolumab, pembrolizumab, cemiplimab, and sintilimab have shown excellent competence in successfully inspiring immune responses versus NSCLC. Accordingly, the United States Food and Drug Administration (FDA) has recently approved nivolumab (alone or in combination with ipilimumab) and pembrolizumab (alone or in combination with chemotherapy) as first-line treatment for advanced NSCLC patients. However, PD-1 blockade monotherapy remains inefficient in more than 60% of NSCLC patients, and many patients don't respond or acquire resistance to this modality. Also, toxicities related to anti-PD-1 anti-body have been progressively identified in clinical trials and oncology practice. Herein, we will outline the clinical benefits of PD-1 blockade therapy alone or in combination with other treatments (e.g., chemotherapy, radiotherapy, anti-angiogenic therapy) in NSCLC patients. Moreover, we will take a glimpse into the recently identified predictive biomarkers to determine patients most likely to suffer serious adverse events to decrease untoward toxicity risk and diminish treatment costs.

Emerging role of human microbiome in cancer development and response to therapy: special focus on intestinal microflora.

In recent years, there has been a greater emphasis on the impact of microbial populations inhabiting the gastrointestinal tract on human health and disease. According to the involvement of microbiota in modulating physiological processes (such as immune system development, vitamins synthesis, pathogen displacement, and nutrient uptake), any alteration in its composition and diversity (i.e., dysbiosis) has been linked to a variety of pathologies, including cancer. In this bidirectional relationship, colonization with various bacterial species is correlated with a reduced or elevated risk of certain cancers. Notably, the gut microflora could potentially play a direct or indirect role in tumor initiation and progression by inducing chronic inflammation and producing toxins and metabolites. Therefore, identifying the bacterial species involved and their mechanism of action could be beneficial in preventing the onset of tumors or controlling their advancement. Likewise, the microbial community affects anti-cancer approaches' therapeutic potential and adverse effects (such as immunotherapy and chemotherapy). Hence, their efficiency should be evaluated in the context of the microbiome, underlining the importance of personalized medicine. In this review, we summarized the evidence revealing the microbiota's involvement in cancer and its mechanism. We also delineated how microbiota could predict colon carcinoma development or response to current treatments to improve clinical outcomes.

Human amniotic membrane mesenchymal stem cell-conditioned medium reduces inflammatory factors and fibrosis in ovalbumin-induced asthma in mice.

NEW FINDINGS: What is the central question of this study? Is mesenchymal stem cell-conditioned medium capable of improving the pathological alterations of ovalbumin-induced asthma in mice? What is the main finding and its importance? Our study indicated that human amniotic membrane mesenchymal stem cell-conditioned medium is capable of modulating inflammation, fibrosis, oxidative stress and the pathological consequences of ovalbumin-induced allergic asthma in mice. ABSTRACT: Paracrine factors secreted by mesenchymal stem cells (MSCs) have immunomodulatory, anti-inflammatory and antifibrotic properties, and the conditioned medium (CM) of these cells might have functional capabilities. We examined the effects of human amniotic membrane MSC-CM (hAM-MSC-CM) on ovalbumin (OVA)-induced asthma. Forty male Balb/c mice were randomly divided into the following four groups: control; OVA (sensitized and challenged with OVA); OVA+CM (sensitized and challenged with OVA and treated with hAM-MSC-CM); and OVA+Placebo (sensitized and challenged with OVA and treated with placebo). Forty-eight hours after the last challenge, serum and bronchoalveolar lavage fluid samples were collected and used for evaluation of inflammatory factors and cells, respectively. Lung tissue sections were stained with Haematoxylin and Eosin or Masson's Trichrome to evaluate pathological changes, and oxidative stress was assessed in fresh lung tissues. Treatment with hAM-MSC-CM significantly hindered histopathological changes and fibrosis and reduced the total cell count and the percentage of eosinophils and neutrophils in bronchoalveolar lavage fluid. Furthermore, it reduced serum levels of immunoglobulin E, interleukin-4, transforming growth factor-ß and lung malondialdehyde. It also increased serum levels of interferon-γ and interleukin-10, in addition to the enzymatic activity of glutathione peroxidase, catalase and superoxide dismutase in lung tissue in comparison to the OVA and OVA+Placebo groups. This study showed that administration of hAM-MSC-CM can improve pathological conditions, such as inflammation, fibrosis and oxidative stress, in OVA-induced allergic asthma.

Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats.

AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin. MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured. KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2). In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups. SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.

Muscarinic receptors, nitric oxide formation and cyclooxygenase pathway involved in tracheal smooth muscle relaxant effect of hydro-ethanolic extract of Lavandula angustifolia flowers.

BACKGROUND: Lavandula angustifolia (L. angustifolia) Mill. (Common name Lavender) is used in traditional and folk medicines for the treatment of various diseases including respiratory disorders worldwide. The relaxant effect of the plant on the smooth muscle of some tissues was shown previously. The present study has investigated the role of different receptors and pathways in the relaxant effect of L. angustifolia on tracheal smooth muscle. METHODS: Cumulative concentrations of the hydro-ethanolic extract of L. angustifolia flowers (0.5, 1, 2 and 4 mg/ml) were added on pre-contracted tracheal smooth muscle by methacholine (10 µM) or KCl (60 mM) on non-preincubated or preincubated tissues with atropine, chlorpheniramine, propranolol, diltiazem, glibenclamide, indomethacin, ω-nitro-L-arginine methyl ester (L-NAME) and papaverine. The results compared with of theophylline (0.2, 0.4, 0.6 and 0.8 mM) as positive control and saline (1 ml) as negative control. RESULTS: The extract showed concentration-dependent relaxant effects in non-preincubated tracheal smooth muscle contracted by KCl and methacholine (p < 0.05 to p < 0.001). The relaxant effect ofL. angustifolia was not significantly different between non-preincubated and preincubated tissues with chlorpheniramine, propranolol, diltiazem, glibenclamide, and papaverine. However, two higher concentrations of L. angustifolia in preincubated tissues with L-NAME (p < 0.01), indomethacin (p < 0.05 to p < 0.001) and atropine (p < 0.05) showed significantly lower relaxant effects than non-preincubated tissues. The EC50 values of L. angustifolia in tissues preincubated with indomethacin was significantly higher than non-preincubated trachea (p < 0.05). The effects of three first concentrations of the extract on KCl and methacholine-induced muscle contraction were significantly lower than those of theophylline (p < 0.05 to p < 0.001). CONCLUSIONS: These results indicated a relatively potent relaxant effect ofL. angustifolia that was lower than the effect of theophylline. The possible mechanisms of relaxant effect of this plant on tracheal smooth muscle are muscarinic receptors blockade, inhibition of cyclooxygenase pathways and/or involvement of nitric oxide production. Its clinical applications should be investigated in further studies.

Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet: an additional mechanism for the hypolipidemic effects of berberine.

OBJECTIVE: To evaluate the effects of berberine (BBR) on the liver phosphatidate phosphohydrolase (PAP) and plasma lipids in rats fed on high lipogenic and normal diet. METHODS: Forty rats were randomly divided into 5 groups. Group I (control) received standard diet. Group II received standard diet plus 90 mg/kg BBR and Groups IV received lipogenic diet (containing sunflower oil, cholesterol and ethanol) without treatment. Groups III and V received lipogenic diet plus 90 mg/kg BBR and 30 mg/kg gemfibrozil, respectively. On Day 60 of the experiment, blood samples were collected and PAP, total cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, very low density lipoprotein, malondialdehyde, plasma antioxidant, and liver histopathology assessments were conducted. RESULTS: PAP, plasma triglyceride, total cholesterol, very low density lipoprotein, and malondialdehyde levels decreased significantly (P<0.05) in Group III compared to Group IV (24.94%, 36.11%, 21.18%, 36.86% and 19.59%, respectively). The liver triglyceride and cholesterol in Groups III and V had a remarkable decrease (P<0.001) compared with Group IV (24.94% and 49.13%, respectively). There was a significant reduction (P<0.05) in atherogenic index in Groups III compared with Group IV. CONCLUSIONS: These results clearly suggested that BBR could be effective in reducing liver PAP, lipid abnormality, liver triglyceride and lateral side effects of hyperlipidemia.

Detection of airway partitioning following unilateral nasal stimulations by the forced oscillation technique in rats.

Nasal mucosa has an extraordinary nerve supply with unique geometry that encompasses complex physiology. Among these, side-specific predilections to the respiratory and autonomic centers are the interesting issues that have been raised about the consequences of the nasal irritations. The aim of the study was an evaluation of how intranasal stimulation influences lung mechanics and determines whether unilateral stimulation produces side-specific partitioning responses. Tracheotomized-paralyzed rats received unilateral air-puff stimulation. Inspiratory pressure- volume (P-V) curve was obtained. Low frequency forced oscillation technique (FOT) was used to detect changes in central and peripheral airways. Mean airway pressure significantly increased to >10 cmH2O in the presence of 5cmH2O of positive end-expiratory pressure. Elastance was significantly changed, and significant higher airway resistance (Raw) and lower reactance (Xrs) were noticed in peripheral airways following different side of stimulation. Calculated inspiratory P-V curve showed significant deviations in transitional, rising and maximal pressures following stimulations. Transitional left-side shifting was observed following right side stimulation, whereas left side stimulation shifted the curve to the right. May be altered respiratory mechanics is the consequences of bimodal pressure-volume relationships observed in central and peripheral airways following nasal stimulation.

Metabolic effects of berberine on liver phosphatidate phosphohydrolase in rats fed on high lipogenic diet：an additional mechanism for the hypolipidemic effects of berberine

Objective: To evaluate the effects of berberine (BBR) on the liver phosphatidate phosphohydrolase (PAP) and plasma lipids in rats fed on high lipogenic and normal diet.Methods:diet. Group II received standard diet plus 90 mg/kg BBR and Groups IV received lipogenic diet (containing sunflower oil, cholesterol and ethanol) without treatment. Groups III and V received lipogenic diet plus 90 mg/kg BBR and 30 mg/kg gemfibrozil, respectively. On Day 60 of the experiment, blood samples were collected and PAP, total cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, very low density lipoprotein, malondialdehyde, plasma antioxidant, and liver histopathology assessments were conducted.Results:Forty rats were randomly divided into 5 groups. Group I (control) received standard malondialdehyde levels decreased significantly (P<0.05) in Group III compared to Group IV (24.94%, 36.11%, 21.18%, 36.86% and 19.59%, respectively). The liver triglyceride and cholesterol in Groups III and V had a remarkable decrease (P<0.001) compared with Group IV (24.94% and 49.13%, respectively). There was a significant reduction (P<0.05) in atherogenic index in Groups III compared with Group IV. PAP, plasma triglyceride, total cholesterol, very low density lipoprotein, and Conclusions: These results clearly suggested that BBR could be effective in reducing liver PAP, lipid abnormality, liver triglyceride and lateral side effects of hyperlipidemia.

Differential consequences of unilateral nasal air-puff stimulation on breathing pattern and respiratory system mechanics in tracheotomized rats.

OBJECTIVE(S): Reflexes that rose from mechanoreceptors in nasal cavities have extensive neuro-regulatory effects on respiratory system. Because of side specific geometry and dual innervations of the nasal mucosa, we investigated the consequences of unilateral nasal stimulations on respiratory mechanics and breathing patterns. MATERIALS AND METHODS: Unilateral nasal air-puff stimulation (30 min) in the presence of propranolol (25 mg/kg) and atropine (5 mg/kg) were applied on tracheotomized spontaneously breathing rats. Breathing rate and pattern monitored. Peak inspiratory pressure (PIP) and flow (PIF) were exploited for calculation of resistance, dynamic compliance (Cdyn), and estimation of respiratory system impedance (Zrs). RESULTS: During right-side stimulation, in propranolol (P<0.05) and atropine groups (P<0.01) PIP significantly decreased in comparison to the control group. Alternatively, it significantly increased in left-side and propranolol-left groups (P<0.05) than control group. Mean Cdyn following left-side stimulation and propranolol, revealed significant decrements (P<0.05) than control group. In the case of atropine-right and atropine-left groups, mean Cdyn had significantly decreased in comparison with atropine alone (P<0.05). Airway resistance (R) did not reveal significant difference during nasal stimulations whereas least square approximation revealed a significant side-specific frequency dependent deviation of imaginary part of impedance (X). An inverse correlation was determined for Cdyn versus frequency following right side (R=-0.76) and left side (R=-0.53) stimulations. CONCLUSION: For the reason that lower airways mechanics changed in a way independent from smooth muscle, it may be concluded from our data that unilateral nasal stimulations exert their different controls through higher regulatory centers.