Ambient air pollutants, diabetes and risk of newly diagnosed drug-resistant tuberculosis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB), diabetes and exposure to air pollution are thought to be important threat to human health, but no studies have explored the effects of ambient air pollutants on DR-TB when adjusting diabetes status so far. METHODS: We performed a study among 3759 newly diagnosed TB cases with drug-susceptibility testing results, diabetes status, and individual air pollution data in Shandong from 2015 to 2019. Generalized linear mixed models (GLMM) including three models (Model 1: without covariates, Model 2: adjusted by diabetes status only, Model 3: with all covariates) were applied. RESULTS: Of 3759 TB patients enrolled, 716 (19.05%) were DR-TB, and 333 (8.86%) had diabetes. High exposure to O3 was associated with an increased risk of RFP-resistance (Model 2 or 3: odds ratio (OR) = 1.008, 95% confidence intervals (CI): 1.002-1.014), ethambutol-resistance (Model 3: OR = 1.015, 95%CI: 1.004-1.027) and any rifampicin+streptomycin resistance (Model 1,2,3: OR = 1.01, 95%CI: 1.002-1.018) at 90 days. In contrast, NO2 was associated with a reduced risk of DR-TB (Model 3: OR = 0.99, 95%CI: 0.981-0.999) and multidrug-resistant TB (MDR-TB) (Model 3: OR = 0.977, 95%CI: 0.96-0.994) at 360 days. Additionally, SO2 (Model 1, 2, 3: OR = 0.987, 95%CI: 0.977-0.998) showed a protective effect on MDR-TB at 90 days. PM2.5 (90 days, Model 2: OR = 0.991, 95%CI: 0.983-0.999), PM10 (360 days, Model 2: OR = 0.992, 95%CI: 0.985-0.999) had protective effects on any RFP+SM resistance. CONCLUSIONS: O3 contributed to an elevated risk of TB resistance but PM2.5, PM10, SO2, NO2 showed an inverse effect. Air pollutants may affect the development of drug resistance among TB cases by adjusting the status of diabetes.

The miR-599 promotes non-small cell lung cancer cell invasion via SATB2.

MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. Here, we identified that miR-599 is up-regulated in non-small cell lung cancer (NSCLC) patients. It promoted NSCLC cell proliferation by negatively regulating SATB2. In NSCLC cell lines, CCK-8 proliferation assay indicated that the cell proliferation is promoted by miR-599 mimics. Transwell assay showed that miR-599 mimics promoted the invasion and migration of NSCLC cells. Luciferase assays confirmed that miR-599 directly binds to the 3'untranslated region of SATB2, and western blotting showed that miR-599 suppresses the expression of SATB2 at the protein level. This study indicates that miR-599 promotes proliferation and invasion of NSCLC cell lines via SATB2. The miR-599 may represent a potential therapeutic target for NSCLC treatment.

Effect of ambient air pollution on tuberculosis risks and mortality in Shandong, China: a multi-city modeling study of the short- and long-term effects of pollutants.

Few studies conducted in China have assessed the effects of ambient air pollution exposure on tuberculosis (TB) risk and mortality, especially with a multicity setting. We evaluated the effect of short- and long-term ambient sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and particulate matter≤2.5 µm in aerodynamic diameter (PM2.5) exposures on development and mortality of active TB in 7 Chinese cities in Shandong province from January 1, 2013, to December 31, 2017. We estimated the pollution-associated risk to new infection TB, recurrent TB, and mortality in relation to 1-µg/m3 increases in air pollutants using the penalized multivariate Poisson regression models. A total of 83,555 new infective TB and 3060 recurrent TB including 997 deaths were recorded. Short- and long-term exposures to outdoor air pollutants (SO2, NO2, CO, O3, and PM2.5) were significantly associated with new infection TB, recurrent TB risk, and mortality. The dominant positive effects of SO2, NO2, CO, and PM2.5 for new infection and recurrent TB risk were observed at long-term (>30 days) exposure, whereas the dominant effects of SO2, CO, and PM2.5 for mortality were observed at short-term (≤30 days) exposures. Of the 5 air pollutants we assessed, SO2 and PM2.5 exhibited more consistent and strong associations with TB-related outcomes. We estimated an increase of 1.33% (95% CI 1.29%, 1.37%) and 3.04% (95% CI 2.98%, 3.11%) in new infection TB count for each 1-µg/m3 increase of SO2 at lag 0-180 days and PM2.5 at lag 0-365 days, respectively. This epidemiologic study in China shows that air pollution exposure is associated with increased risk of active TB development and mortality. The control of ambient air pollution may benefit the control and decrease the mortality of TB disease.

An increasing public health burden arising from children infected with SARS-CoV2: A systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is spreading all over the world and poses a great threat to humans. This study aimed to systematically review the current situation and public health burden associated with children infected with SARS-CoV2. METHODS: We searched four electronic databases without language limitations. The pooled proportion or odds ratio (OR) and 95% CI confidence interval (CI) were calculated for each analysis to explore the prevalence of asymptomatic infection and coinfection, as well as to assess the sex of SARS-CoV-2-infected children. RESULTS: We obtained data from 14 eligible studies with 410 patients for the meta-analysis. The pooled proportion of asymptomatic infection was 40.45% (95% CI, 24.04-56.85), while coinfection was 10.14% (95% CI, 3.97-16.30), of which Mycoplasma pneumonia (50%; 95% CI, 28.24-71.76) and influenza virus or parainfluenza virus (22.76%; 95% CI, 4.76-40.77) were the most common pathogens. Both male and female children were susceptible to SARS-CoV2 infection. And the pooled proportion of family clustering infection was 83.63% (95% CI, 77.54-89.72). CONCLUSION: A high proportion of asymptomatic infections occurs in children infected with SARS-CoV2, who are also susceptible to coinfection regardless of sex. These data affirm the increasing public health burden arising from infected children regarding the causation of asymptomatic infection or misdiagnosis and as a significant contributor to virus spread. The public should pay more attention to children during epidemics and conduct multimethod detection to further effectively identify infected children and control the source of infection.

Proton pump inhibitors act synergistically with fluconazole against resistant Candida albicans.

The incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 µg/mL to 1-4 µg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by two-fold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans.

Drug resistance of previously treated tuberculosis patients with diabetes mellitus in Shandong, China.

BACKGROUND: Although the association between diabetes mellitus (DM) and tuberculosis (TB) has been well-documented for centuries, evidence of the link between diabetes and drug resistance among previously treated TB patients remains limited and inconsistent. METHODS: An observational study was performed that involved 1791 retreated TB-no DM patients (refers to TB cases without diabetes) and 93 retreated TB-DM patients (refers to TB cases with diabetes) in Shandong, China from 2004 to 2017. Baseline data including demographic and clinical characteristics, drug susceptibility test (DST) results, and diabetes status were collected. Categorical baseline characteristics were compared by Fisher's exact or Pearson Chi-square test. Univariable analysis and multivariable logistic models were used to estimate the association between diabetes and different drug resistance profiles. RESULTS: Retreated TB-DM patients have a higher rate of drug resistance than TB-no DM patients (34.41% vs 25.00%, P < 0.01). Diabetes co-morbidity was significantly associated with any drug-resistant tuberculosis (DR-TB, odds ratio (OR):1.56, 95% confidence interval (CI): 1.01-2.43), multidrug resistant tuberculosis (MDR-TB, OR: 2.48, 95%CI:1.39-4.41; adjusted OR (aOR):2.94, 95%CI:1.57-5.48), isoniazid-related resistance (OR:1.71, 95%CI:1.04-2.81), rifampin-related resistance (OR:2.56, 0.54, 95%CI: 1.54-4.26; aOR:2.69, 95%CI:1.524-4.74), isoniazid + rifampin resistance (OR: 3.55, 95%CI:1.33-9.44; aOR:4.13, 95%CI:1.46-11.66), any resistance to isoniazid + streptomycin (OR:2.34, 95%CI:1.41-3.89; aOR:2.22, 95%CI:1.26-3.94), and any resistance to rifampin + isoniazid (OR:2.48, 95%CI:1.39-4.41; aOR:2.94, 95%CI: 1.57-5.48), compared with pan susceptible TB cases, P < 0.05. CONCLUSIONS: The risk of acquired drug resistance increased significantly among retreated TB-DM patients compared with retreated TB-no DM patients, underlining the necessity of more interventions during the clinical management of TB-DM cases.

In vivo activity of fluconazole/tetracycline combinations in Galleria mellonella with resistant Candida albicans infection.

OBJECTIVES: Treatment of azole-resistant Candida albicans infections continues to pose significant challenges. With limited options of licensed agents, drug combinations may be a practical treatment alternative. In our previous studies, the combinations minocycline/fluconazole (MINO/FLC) and doxycycline/fluconazole (DOXY/FLC) shown synergistic effects in vitro. It is necessary to explore their appropriate dosage, potential toxicity and in vivo efficacy. METHODS: The Galleria mellonella infection model was employed to study the in vivo efficacy of MINO/FLC and DOXY/FLC by survival analysis, quantification of C. albicans fungal burden and histological studies. RESULTS: The survival rates of G. mellonella larvae infected with lethal doses of resistant C. albicans CA10 increased significantly when treated with the drug combinations compared with FLC treatment alone, and the fungal burden was reduced by almost four-fold. The histopathological study showed that fewer infected areas in larvae were observed and the destructive degree was less when larvae were exposed to the drug combinations. CONCLUSIONS: These findings suggest that combination of a tetracycline antibiotic (MINO or DOXY) with FLC has antifungal activity against azole-resistant C. albicans in vivo. This is in agreement with several previous in vitro studies and provides preliminary in vivo evidence that such a combination might be useful therapeutically.

Gentamicin synergises with azoles against drug-resistant Candida albicans.

Candida spp. are the primary opportunistic pathogens of nosocomial fungal infections, causing both superficial and life-threatening systemic infections. Combination therapy for fungal infections has attracted considerable attention, especially for those caused by drug-resistant fungi. Gentamicin (GM), an aminoglycoside antibiotic, has weak antifungal activity against Fusarium spp. The aim of this study was to investigate the interactions of GM with azoles against Candida spp. and the underlying mechanisms. In a chequerboard assay, GM was found not only to work synergistically with azoles against planktonic cells of drug-resistant Candida albicans with a fractional inhibitory concentration index (FICI) of 0.13-0.14, but also synergised with fluconazole (FLC) against C. albicans biofilms pre-formed in <12 h. Synergism of GM with FLC was also confirmed in vivo in a Galleria mellonella infection model. In addition, mechanism studies showed that GM not only suppressed the efflux pump of resistant C. albicans in a dose-dependent manner but also inhibited extracellular phospholipase activity of resistant C. albicans when combined with FLC. These findings suggest that GM enhances the efficacy of azoles against resistant C. albicans via efflux inhibition and decreased activity of extracellular phospholipase.

Linezolid in Combination With Azoles Induced Synergistic Effects Against Candida albicans and Protected Galleria mellonella Against Experimental Candidiasis.

The incidence of resistant Candida isolates has increased continuously in recent decades, especially Candida albicans. To overcome this resistance, research on antifungal sensitizers has attracted considerable attention. Linezolid was found to inhibit the growth of Pythium insidiosum and synergize with amphotericin B against Cryptococcus neoformans. The objective of this study was to determine the interactions of linezolid and azoles against C. albicans in vitro and in vivo. In vitro, linezolid combined with azoles induced synergistic effects not only against some susceptible C. albicans isolates, but also against all tested resistant C. albicans isolates. For all resistant isolates, exposure to the combination of linezolid with azoles induced a significant decrease in the minimum inhibitory concentrations (MIC) of azoles, from >512 to 0.5-1 µg/mL for fluconazole, from >16 to 0.25-1 µg/mL for itraconazole, and from >16 to 0.03-0.25 µg/mL for voriconazole. Additionally, linezolid synergized with fluconazole against biofilms that were preformed for ≤ 12 h from both susceptible and resistant C. albicans, and the sessile MIC of fluconazole decreased from >1024 to 1-4 µg/mL. In vivo, linezolid plus azoles prolonged the survival rate of infected Galleria mellonella larvae twofold compared with the azole monotherapy group, significantly decreased the fungal burden of the infected larvae, and reduced the damage of resistant C. albicans to the larval tissue. These findings will contribute to antifungal agent discovery and new approaches for the treatment of candidiasis caused by C. albicans.

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets.

In recent decades, the incidence of invasive fungal infections has increased notably. Candida albicans (C. albicans), a common opportunistic fungal pathogen that dwells on human mucosal surfaces, can cause fungal infections, especially in immunocompromised and high-risk surgical patients. In addition, the wide use of antifungal agents has likely contributed to resistance of C. albicans to traditional antifungal drugs, increasing the difficulty of treatment. Thus, it is urgent to identify novel antifungal drugs to cope with C. albicans infections. Heat shock proteins (Hsps) exist in most organisms and are expressed in response to thermal stress. In C. albicans, Hsps control basic physiological activities or virulence via interaction with a variety of diverse regulators of cellular signaling pathways. Moreover, it has been demonstrated that Hsps confer drug resistance to C. albicans. Many studies have shown that disrupting the normal functions of C. albicans Hsps inhibits fungal growth or reverses the tolerance of C. albicans to traditional antifungal drugs. Here, we review known functions of the diverse Hsp family, Hsp-associated intracellular signaling pathways and potential antifungal targets based on these pathways in C. albicans. We hope this review will aid in revealing potential new roles of C. albicans Hsps in addition to canonical heat stress adaptions and provide more insight into identifying potential novel antifungal targets.

Ambroxol Hydrochloride Combined with Fluconazole Reverses the Resistance of Candida albicans to Fluconazole.

In this study, we found that ambroxol hydrochloride (128 µg/mL) exhibits synergistic antifungal effects in combination with fluconazole (2 µg/mL) against resistant planktonic Candida albicans (C. albicans) cells. This combination also exhibited synergistic effects against resistant C. albicans biofilms in different stages (4, 8, and 12 h) according to the microdilution method. In vitro data were further confirmed by the success of this combination in treating Galleria mellonella infected by resistant C. albicans. With respect to the synergistic mechanism, our result revealed that ambroxol hydrochloride has an effect on the drug transporters of resistant C. albicans, increasing the uptake and decreasing the efflux of rhodamine 6G, a fluorescent alternate of fluconazole. This is the first study to investigate the in vitro and in vivo antifungal effects, as well as the possible synergistic mechanism of ambroxol hydrochloride in combination with fluconazole against resistant C. albicans. The results show the potential role for this drug combination as a therapeutic alternative to treat resistant C. albicans and provide insights into the development of antifungal targets and new antifungal agents.

Strong synergism of dexamethasone in combination with fluconazole against resistant Candida albicans mediated by inhibiting drug efflux and reducing virulence.

Candida albicans is the most commonly isolated Candida spp. in the clinic and its resistance to fluconazole (FLC) has been emerging rapidly. Combination therapy may be a potentially effective approach to combat drug resistance. In this study, the combination antifungal effects of dexamethasone (DXM) and FLC against resistant C. albicans in vitro were assayed using minimum inhibitory concentrations (MICs), sessile MICs and time-kill curves. The in vivo efficacy of this drug combination was evaluated using a Galleria mellonella model by determining survival rate, fungal burden and histological damage. In addition, the impact of DXM on efflux pump activity was investigated using a rhodamine 6G assay. Expression of CDR1, CDR2 and MDR1 was determined by real-time quantitative PCR, and extracellular phospholipase activity was detected by the egg yolk agar method to reveal the potential synergistic mechanism. The results showed that DXM potentiates the antifungal effect of FLC against resistant C. albicans strains both in vitro and in vivo, and the synergistic mechanism is related to inhibiting the efflux of drugs and reducing the virulence of C. albicans.

Synergistic Effects and Mechanisms of Budesonide in Combination with Fluconazole against Resistant Candida albicans.

Candida albicans is an important opportunistic pathogen, causing both superficial mucosal infections and life-threatening systemic diseases in the clinic. The emergence of drug resistance in Candida albicans has become a noteworthy phenomenon due to the extensive use of antifungal agents and the development of biofilms. This study showed that budesonide potentiates the antifungal effect of fluconazole against fluconazole-resistant Candida albicans strains both in vitro and in vivo. In addition, our results demonstrated, for the first time, that the combination of fluconazole and budesonide can reverse the resistance of Candida albicans by inhibiting the function of drug transporters, reducing the formation of biofilms, promoting apoptosis and inhibiting the activity of extracellular phospholipases. This is the first study implicating the effects and mechanisms of budesonide against Candida albicans alone or in combination with fluconazole, which may ultimately lead to the identification of new potential antifungal targets.

Potential Antifungal Targets against a Candida Biofilm Based on an Enzyme in the Arachidonic Acid Cascade-A Review.

Candida is an important opportunistic fungal pathogen, especially in biofilm associated infections. The formation of a Candida biofilm can decrease Candida sensitivity to antifungal drugs and cause drug resistance. Although many effective antifungal drugs are available, their applications are limited due to their high toxicity and cost. Seeking new antifungal agents that are effective against biofilm-associated infection is an urgent need. Many research efforts are underway, and some progress has been made in this field. It has been shown that the arachidonic acid cascade plays an important role in fungal morphogenesis and pathogenicity. Notably, prostaglandin E2 (PGE2) can promote the formation of a Candida biofilm. Recently, the inhibition of PGE2 has received much attention. Studies have shown that cyclooxygenase (COX) inhibitors, such as aspirin, ibuprofen, and indomethacin, combined with fluconazole can significantly reduce Candida adhesion and biofilm development and increase fluconazole susceptibility; the MIC of fluconazole can be decrease from 64 to 2 µg/ml when used in combination with ibuprofen. In addition, in vivo studies have also confirmed the antifungal activities of these inhibitors. In this article, we mainly review the relationship between PGE2 and Candida biofilm, summarize the antifungal activities of COX inhibitors and analyze the possible antifungal activity of microsomal prostaglandin E synthase-1 (MPGES-1) inhibitors; additionally, other factors that influence PGE2 production are also discussed. Hopefully this review can disclose potential antifungal targets based on the arachidonic acid cascade and provide a prevailing strategy to alleviate Candida albicans biofilm formation.

[Roles of Th17 lymphocytes and inflammatory cytokines in airway inflammation exacerbation of murine asthmatic model].

AIM: To investigate the roles of Th17 lymphocytes and its inflammatory cytokines in airway inflammation exacerbation of murine asthmatic model. METHODS: Twenty mice were randomized into control group and asthma group. For the murine asthma model, the mice were sensitized and challenged with ovalbumin (OVA). The control mice were given normal saline alone under the same conditions as the asthma group. We observed the changes in cellular proportions in the bronchoalveolar lavage fluid (BALF) under a light microscope and the histological changes in lung tissue by HE staining. The levels of IL-4, IFN-γ and IL-17 were detected by ELISA. Th1, Th2 and Th17 cells in the peripheral blood were detected by flow cytometry. We did a correlation analysis between Th1, Th2 and Th17 cells in the peripheral blood and neutrophils in BALF. RESULTS: The total cell number and the percentages of neutrophils, eosinophils and lymphocytes in BALF of the asthmatic mice were significantly higher than those in the control mice (P<0.05). The neutrophils and eosinophils infiltration in pulmonary tissue was also dramatically detected in asthmatic mice. The levels of IL-4 and IL-17 were significantly higher than those in the control mice (P<0.05), while the level of IFN-γ was much lower than in the control mice (P<0.05). Besides, the percentages of Th2 and Th17 cells in peripheral blood were significantly higher in the asthmatic mice than in the control mice (P<0.05). The expression of Th17 was positively correlated with the levels of neutrophils in BALF(r(Th17);=0.394, P<0.05), and the expression of Th1 was negatively correlated with the level of neutrophils in BALF (r(Th1);=-0.446, P<0.05). CONCLUSION: Th17 cells could induce the recruitment of inflammatory cytokines and neutrophils into airways, which might aggravate the asthmatic inflammation and be related with asthma exacerbation.