Morphological changes in the fetal kidney induced by exposure to fluoride during pregnancy.

To determine if fluoride's established negative impact on adult kidney health begins during gestation, an intergenerational model of Wistar rats was exposed to two doses of fluoride (2.5 or 5.0 mg/kg/day via gavage) 20 days before mating and during gestation (20 days). The results revealed that fluoride was distributed to the amniotic fluid and fetus, resulting in lower weight, more pronounced fetal restriction, and decreased creatinine, osmolarity, and amniotic fluid volume. At the kidney level, less development in the nephrogenic and cortical zones was observed in the fluoride treatment groups, with an imbalance in the number of glomeruli and "S" shaped bodies, an increase in the immunoexpression of the marker of proliferation Ki-67 in the nephrogenic zone, an increase in the expression of Wnt4 and more maturation of the renal tubules, indicating that fluoride exposure during pregnancy alters kidney development and promotes early maturation of tubular segments.

Effect of IL-17A on the immune response to pulmonary tuberculosis induced by high- and low-virulence strains of Mycobacterium bovis.

Tuberculosis (TB) is an infectious, chronic, and progressive disease occurring globally. Human TB is caused mainly by Mycobacterium tuberculosis (M. tuberculosis), while the main causative agent of bovine TB is Mycobacterium bovis (M. bovis). The latter is one of the most important cattle pathogens and is considered the main cause of zoonotic TB worldwide. The mechanisms responsible for tissue damage (necrosis) during post-primary TB remain elusive. Recently, IL-17A was reported to be important for protection against M. tuberculosis infection, but it is also related to the production of an intense inflammatory response associated with necrosis. We used two M. bovis isolates with different levels of virulence and high IL-17A production to study this important cytokine's contrasting functions in a BALB/c mouse model of pulmonary TB. In the first part of the study, the gene expression kinetics and cellular sources of IL-17A were determined by real time PCR and immunohistochemistry respectively. Non-infected lungs showed low production of IL-17A, particularly by the bronchial epithelium, while lungs infected with the low-virulence 534 strain showed high IL-17A expression on Day 3 post-infection, followed by a decrease in expression in the early stage of the infection and another increase during late infection, on Day 60, when very low bacillary burdens were found. In contrast, infection with the highly virulent strain 04-303 induced a peak of IL-17A expression on Day 14 of infection, 1 week before extensive pulmonary necrosis was seen, being lymphocytes and macrophages the most important sources. In the second part of the study, the contribution of IL-17A to immune protection and pulmonary necrosis was evaluated by suppressing IL-17A via the administration of specific blocking antibodies. Infection with M. bovis strain 534 and treatment with IL-17A neutralizing antibodies did not affect mouse survival but produced a significant increase in bacillary load and a non-significant decrease in inflammatory infiltrate and granuloma area. In contrast, mice infected with the highly virulent 04-303 strain and treated with IL-17A blocking antibodies showed a significant decrease in survival, an increase in bacillary loads on Day 24 post-infection, and significantly more and earlier necrosis. Our results suggest that high expression of IL-17A is more related to protection than necrosis in a mouse model of pulmonary TB induced by M. bovis strains.

In Vitro Human Endometrial Cells and In Vivo Rat Model Studies Suggest That Ulipristal Acetate Impacts Endometrial Compatibility for Embryo Implantation.

BACKGROUND: Ulipristal acetate (UPA) and levonorgestrel are used as emergency hormonal contraceptives. Although both are highly effective in preventing pregnancy, UPA shows efficacy even when taken up to 120 h after unprotected sexual intercourse. AIMS: To investigate whether the mechanism of UPA's contraceptive action involves post-fertilization effects. METHODS: In vitro and in vivo studies using cultured human endometrial cells and a pre-clinical rat model. RESULTS: Endometrial cells treated with UPA showed changes in the expression of receptivity gene markers and a significant decrease in trophoblast spheroids attached to the cultured cells. In addition, administration of UPA to female unmated rats decreased the expression of implantation-related genes in the endometrium and inhibited the number of implantation sites in the mated group compared to the non-treated group. CONCLUSIONS: These results support that UPA as an emergency contraceptive might have post-fertilization effects that may affect embryo implantation.

Acute lung injury is prevented by monocyte locomotion inhibitory factor in an experimental severe malaria mouse model.

Acute lung injury caused by severe malaria (SM) is triggered by a dysregulated immune response towards the infection with Plasmodium parasites. Postmortem analysis of human lungs shows diffuse alveolar damage (DAD), the presence of CD8 lymphocytes, neutrophils, and increased expression of Intercellular Adhesion Molecule 1 (ICAM-1). P. berghei ANKA (PbA) infection in C57BL/6 mice reproduces many SM features, including acute lung injury characterized by DAD, CD8+ T lymphocytes and neutrophils in the lung parenchyma, and tissular expression of proinflammatory cytokines and adhesion molecules, such as IFNγ, TNFα, ICAM, and VCAM. Since this is related to a dysregulated immune response, immunomodulatory agents are proposed to reduce the complications of SM. The monocyte locomotion inhibitory factor (MLIF) is an immunomodulatory pentapeptide isolated from axenic cultures of Entamoeba hystolitica. Thus, we evaluated if the MLIF intraperitoneal (i.p.) treatment prevented SM-induced acute lung injury. The peptide prevented SM without a parasiticidal effect, indicating that its protective effect was related to modifications in the immune response. Furthermore, peripheral CD8+ leukocytes and neutrophil proportions were higher in infected treated mice. However, the treatment prevented DAD, CD8+ cell infiltration into the pulmonary tissue and downregulated IFNγ. Moreover, VCAM-1 expression was abrogated. These results indicate that the MLIF treatment downregulated adhesion molecule expression, impeding cell migration and proinflammatory cytokine tissular production, preventing acute lung injury induced by SM. Our findings represent a potential novel strategy to avoid this complication in various events where a dysregulated immune response triggers lung injury.

Comparison of the transcriptome, lipidome, and c-di-GMP production between BCGΔBCG1419c and BCG, with Mincle- and Myd88-dependent induction of proinflammatory cytokines in murine macrophages.

We have previously reported the transcriptomic and lipidomic profile of the first-generation, hygromycin-resistant (HygR) version of the BCGΔBCG1419c vaccine candidate, under biofilm conditions. We recently constructed and characterized the efficacy, safety, whole genome sequence, and proteomic profile of a second-generation version of BCGΔBCG1419c, a strain lacking the BCG1419c gene and devoid of antibiotic markers. Here, we compared the antibiotic-less BCGΔBCG1419c with BCG. We assessed their colonial and ultrastructural morphology, biofilm, c-di-GMP production in vitro, as well as their transcriptomic and lipidomic profiles, including their capacity to activate macrophages via Mincle and Myd88. Our results show that BCGΔBCG1419c colonial and ultrastructural morphology, c-di-GMP, and biofilm production differed from parental BCG, whereas we found no significant changes in its lipidomic profile either in biofilm or planktonic growth conditions. Transcriptomic profiling suggests changes in BCGΔBCG1419c cell wall and showed reduced transcription of some members of the DosR, MtrA, and ArgR regulons. Finally, induction of TNF-α, IL-6 or G-CSF by bone-marrow derived macrophages infected with either BCGΔBCG1419c or BCG required Mincle and Myd88. Our results confirm that some differences already found to occur in HygR BCGΔBCG1419c compared with BCG are maintained in the antibiotic-less version of this vaccine candidate except changes in production of PDIM. Comparison with previous characterizations conducted by OMICs show that some differences observed in BCGΔBCG1419c compared with BCG are maintained whereas others are dependent on the growth condition employed to culture them.

Negative Regulation of Autophagy during Macrophage Infection by Mycobacterium bovis BCG via Protein Kinase C Activation.

Mycobacterium tuberculosis (Mtb) employs various strategies to manipulate the host's cellular machinery, overriding critical molecular mechanisms such as phagosome-lysosome fusion, which are crucial for its destruction. The Protein Kinase C (PKC) signaling pathways play a key role in regulating phagocytosis. Recent research in Interferon-activated macrophages has unveiled that PKC phosphorylates Coronin-1, leading to a shift from phagocytosis to micropinocytosis, ultimately resulting in Mtb destruction. Therefore, this study aims to identify additional PKC targets that may facilitate Mycobacterium bovis (M. bovis) infection in macrophages. Protein extracts were obtained from THP-1 cells, both unstimulated and mycobacterial-stimulated, in the presence or absence of a general PKC inhibitor. We conducted an enrichment of phosphorylated peptides, followed by their identification through mass spectrometry (LC-MS/MS). Our analysis revealed 736 phosphorylated proteins, among which 153 exhibited alterations in their phosphorylation profiles in response to infection in a PKC-dependent manner. Among these 153 proteins, 55 are involved in various cellular processes, including endocytosis, vesicular traffic, autophagy, and programmed cell death. Importantly, our findings suggest that PKC may negatively regulate autophagy by phosphorylating proteins within the mTORC1 pathway (mTOR2/PKC/Raf-1/Tsc2/Raptor/Sequestosome-1) in response to M. bovis BCG infection, thereby promoting macrophage infection.

Oral exposure to food grade titanium dioxide (E171) induces intestinal and behavioural alterations in adult mice but limited effects in young mice.

BACKGROUND: Food-grade titanium dioxide (E171), a white colourant widely used in ultra-processed food products, has been banned in the European Union. However, its usage is still permitted in medicines, and in several other countries. The estimated intake of E171 in children is higher than in adults, which led us to hypothesise that E171 induces differential effects depending on age, with adult mice being the most susceptible due to age, despite the lower dose. AIM: To evaluate the effects of oral administration of E171 on intestinal permeability, ileum, and colon histology, and how these effects impact anxious and depressive behaviour in young and adult mice of both sexes. METHODS: Young and adult mice of both sexes C57BL/6 mice received 10 mg/kgbw E171/3 times per week for 3 months. E171 was administered orally in water by pipetting, while control groups only received drinking water, then intestinal permeability, histology and animal behaviour were analysed. RESULTS: E171 showed an amorphous shape, primary particles sized below 1 µm and anatase crystalline structure. Oral administration of E171 disrupted the intestinal permeability in adult male and female mice, but no effects were observed in young mice of both sexes. E171 promoted ileal adenoma formation in half of the adult female population, moreover hyperplastic crypts, and hyperplastic goblet cells at histological level in adult mice of both sexes. The colon presented hyperplastic goblet cells, hyperchromatic nuclei, increased proliferation and DNA damage in adult mice of both sexes. The anxiety and depressive behaviour were only altered in adult mice treated with E171, but no changes were detected in young animals of both sexes. CONCLUSIONS: Adult mice displayed higher susceptibility in all parameters analysed in this study compared to young mice of both sexes.

Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): Role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Releasing unilateral ureteral obstruction (RUUO) is the gold standard for decreasing renal damage induced during unilateral ureteral obstruction (UUO); however, the complete recovery after RUUO depends on factors such as the time and severity of obstruction and kidney contralateral compensatory mechanisms. Interestingly, previous studies have shown that kidney damage markers such as oxidative stress, inflammation, and apoptosis are present and even increase after removal obstruction. To date, previous therapeutic strategies have been used to potentiate the recovery of renal function after RUUO; however, the mechanisms involving renal damage reduction are poorly described and sometimes focus on the recovery of renal functionality. Furthermore, using natural antioxidants has not been completely studied in the RUUO model. In this study, we selected sulforaphane (SFN) because it activates the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that induces an antioxidant response, decreasing oxidative stress and inflammation, preventing apoptosis. Thus, we pre-administrated SFN on the second day after UUO until day five, where we released the obstruction on the three days after UUO. Then, we assessed oxidative stress, inflammation, and apoptosis markers. Interestingly, we found that SFN administration in the RUUO model activated Nrf2, inducing its translocation to the nucleus to activate its target proteins. Thus, the Nrf2 activation upregulated glutathione (GSH) content and the antioxidant enzymes catalase, glutathione peroxidase (GPx), and glutathione reductase (GR), which reduced the oxidative stress markers. Moreover, the improvement of antioxidant response by SFN restored S-glutathionylation in the mitochondrial fraction. Activated Nrf2 also reduced inflammation by lessening the nucleotide-binding domain-like receptor family pyrin domain containing 3 and interleukin 1ß (IL-1ß) production. Reducing oxidative stress and inflammation prevented apoptosis by avoiding caspase 3 cleavage and increasing B-cell lymphoma 2 (Bcl2) levels. Taken together, the obtained results in our study showed that the upregulation of Nrf2 by SFN decreases oxidative stress, preventing inflammation and apoptosis cell death during the release of UUO.

Adenoviral Vector Codifying for TNF as a Co-Adjuvant Therapy against Multi-Drug-Resistant Tuberculosis.

Mycobacterium tuberculosis is the main causal agent of pulmonary tuberculosis (TB); the treatment of this disease is long and involves a mix of at least four different antibiotics that frequently lead to abandonment, favoring the surge of drug-resistant mycobacteria (MDR-TB), whose treatment becomes more aggressive, being longer and more toxic. Thus, the search for novel strategies for treatment that improves time or efficiency is of relevance. In this work, we used a murine model of pulmonary TB produced by the MDR-TB strain to test the efficiency of gene therapy with adenoviral vectors codifying TNF (AdTNF), a pro-inflammatory cytokine that has protective functions in TB by inducing apoptosis, granuloma formation and expression of other Th1-like cytokines. When compared to the control group that received an adenoviral vector that codifies for the green fluorescent protein (AdGFP), a single dose of AdTNF at the chronic active stage of the disease produced total survival, decreasing bacterial load and tissue damage (pneumonia), which correlated with an increase in cells expressing IFN-γ, iNOS and TNF in pneumonic areas and larger granulomas that efficiently contain and eliminate mycobacteria. Second-line antibiotic treatment against MDR-TB plus AdTNF gene therapy reduced bacterial load faster within a week of treatment compared to empty vector plus antibiotics or antibiotics alone, suggesting that AdTNF is a new potential type of treatment against MDR-TB that can shorten second-line chemotherapy but which requires further experimentation in other animal models (non-human primates) that develop a more similar disease to human pulmonary TB.

The role of TNF receptors as mediators of chronic vasculitis in possible milder forms of the CNS tuberculosis.

INTRODUCTION: Central nervous system (CNS) tuberculosis (TB) is the most severe form of TB due to its high mortality and functional sequelae. There are several differential diagnoses for TB; and, it can also cause secondary conditions, such as vasculitis. METHODOLOGY: 155 biopsies, corresponding to 155 different patients out of 5,386 registered biopsies from 2008-2013, met the criteria of unknown etiology vasculitis and evidence of cerebral vascular disease. These were analyzed to assess the presence of central nervous system TB. The selected cases were assessed with Suzaan Marais (SM) criteria for clinical tuberculosis. After that, Ziehl-Neelsen (ZN) staining and polymerase chain reaction (PCR) were performed to amplify a fragment of the insertion sequence IS6110 of M. tuberculosis. 21 patients met the criteria for definitive tuberculosis by ZN staining and PCR, and 2 met the criteria for possible tuberculosis. Tumor necrosis factor (TNF)-α, TNF-R1, and TNF-R2 were determined by immunohistochemistry in histological sections from formalin-fixed paraffin-embedded (FF-PE) tissues in the 23 selected patients. RESULTS: Granulomatous TB was present in almost half of the cases. TNF-R1 and TNF-R2 were expressed mainly in blood vessels, histiocytes, and macrophages. TNF-R2 expression was higher than the other markers, which suggests an anti-inflammatory response against M. tuberculosis. CONCLUSIONS: The histopathological presentation of TB is not always limited to granulomas, abscesses, or meningitis; there are also clinical presentations characterized only with chronic inflammation of nervous and vascular tissue.

Active tuberculosis patients have high systemic IgG levels and B-cell fingerprinting, characterized by a reduced capacity to produce IFN-γ or IL-10 as a response to M.tb antigens.

Introduction: Tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis (M.tb). B cells are the central mediator of the humoral response; they are responsible for producing antibodies in addition to mediating other functions. The role of the cellular response during the TB spectrum by B cells is still controversial. Methods: In this study, we evaluated the distribution of the circulating B cell subsets in patients with active and latent TB (ATB and LTB, respectively) and how they respond to stimuli of protein or lipid from M.tb. Results: Here, we show that ATB patients show an immune fingerprinting. However, patients with drug-sensitive- (DS-TB) or drug-resistant- (DR-TB) TB have altered frequencies of circulating B cells. DS-TB and DR-TB display a unique profile characterized by high systemic levels of IFN-γ, IL-10, IgG, IgG/IgM ratio, and total B cells. Moreover, B cells from DR-TB are less efficient in producing IL-10, and both DS-TB and DR-TB produce less IFN-γ in response to M.tb antigens. Conclusion: These results provide new insights into the population dynamics of the cellular immune response by B cells against M.tb and suggest a fingerprinting to characterize the B-cell response on DR-TB.

Two murine models of sepsis: immunopathological differences between the sexes-possible role of TGFß1 in female resistance to endotoxemia.

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFß1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFß1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1ß increased at 1.5-6 h and TGFß1 at 12 h; in females, TNF decrease at 6 h and TGFß1 increased from 6 h; in CLP females, TNF and IL-1ß decreased at 12 h and 1.5 h, respectively, and TGFß1 increased from 6 h; in males, TGFß1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFß1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFß1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFß1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice.

Bifurcation analysis of a tuberculosis progression model for drug target identification.

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. The emergence and rapid spread of drug-resistant M. tuberculosis strains urge us to develop novel treatments. Experimental trials are constrained by laboratory capacity, insufficient funds, low number of laboratory animals and obsolete technology. Systems-level approaches to quantitatively study TB can overcome these limitations. Previously, we proposed a mathematical model describing the key regulatory mechanisms underlying the pathological progression of TB. Here, we systematically explore the effect of parameter variations on disease outcome. We find five bifurcation parameters that steer the clinical outcome of TB: number of bacteria phagocytosed per macrophage, macrophages death, macrophage killing by bacteria, macrophage recruitment, and phagocytosis of bacteria. The corresponding bifurcation diagrams show all-or-nothing dose-response curves with parameter regions mapping onto bacterial clearance, persistent infection, or history-dependent clearance or infection. Importantly, the pathogenic stage strongly affects the sensitivity of the host to these parameter variations. We identify parameter values corresponding to a latent-infection model of TB, where disease progression occurs significantly slower than in progressive TB. Two-dimensional bifurcation analyses uncovered synergistic parameter pairs that could act as efficient compound therapeutic approaches. Through bifurcation analysis, we reveal how modulation of specific regulatory mechanisms could steer the clinical outcome of TB.

The Use of Viral Vectors for Gene Therapy and Vaccination in Tuberculosis.

Tuberculosis (TB), an infection caused by Mycobacterium tuberculosis (Mtb), is one of the primary causes of death globally. The treatment of TB is long and based on several drugs, producing problems in compliance and toxicity, increasing Mtb resistance to first-line antibiotics that result in multidrug-resistant TB and extensively drug-resistant TB. Thus, the need for new anti-TB treatments has increased. Here, we review some model strategies to study gene therapy based on the administration of a recombinant adenovirus that encodes diverse cytokines, such as IFNγ, IL12, GM/CSF, OPN, TNFα, and antimicrobial peptides to enhance the protective immune response against Mtb. These models include a model of progressive pulmonary TB, a model of chronic infection similar to latent TB, and a murine model of pulmonary Mtb transmission to close contacts. We also review new vaccines that deliver Mtb antigens via particle- or virus-based vectors and trigger protective immune responses. The results obtained in this type of research suggest that this is an alternative therapy that has the potential to treat active TB as an adjuvant to conventional antibiotics and a promising preventive treatment for latent TB reactivation and Mtb transmission. Moreover, Ad vector vaccines are adequate for preventing infectious diseases, including TB.

Gene Expression Changes in the Ovary Mediate Non-Anovulatory Mechanisms of Contraception with Levonorgestrel.

BACKGROUND: Emergency contraception with levonorgestrel (LNG) is a viable option to prevent unintended pregnancies. Although the efficacy of LNG as an anovulatory agent decreases as treatment approaches ovulation, it still provides some contraceptive benefits. AIM: To better understand the contraceptive mechanisms of LNG in ovulatory subjects. METHODS: We conducted a study on Wistar rats that received a single dose of LNG (0.01 or 0.05 mg/kg) on the morning of proestrus before ovulation and evaluated its effects on ovarian gene expression, ovulation, and implantation. RESULTS: Our findings showed changes in the expression of genes involved in follicular development and oocyte quality. Pregnancy rates - as an indicator of ovulation - and embryo implantation were significantly lower than those in the control group. CONCLUSIONS: This study suggests that LNG alters regulatory factors in the ovary that are essential for the development of competent fertilizable oocytes, highlighting the non-anovulatory mechanisms by which levonorgestrel may regulate fertility and suggesting that it could be a novel observation that contributes to the understanding of emergency contraception in humans.

Allicin, an Emerging Treatment for Pulmonary Arterial Hypertension: An Experimental Study.

We assessed whether allicin, through its antihypertensive and antioxidant effects, relieves vascular remodeling, endothelial function, and oxidative stress (OS), thereby improving experimental pulmonary arterial hypertension (PAH). Allicin (16 mg/kg) was administered to rats with PAH (monocrotaline 60 mg/kg). Allicin encouraged body weight gain and survival rate, and medial wall thickness and the right ventricle (RV) hypertrophy were prevented. Also, angiotensin II concentrations in the lung (0.37 ± 0.01 vs. 0.47 ± 0.06 pmoles/mL, allicin and control, respectively) and plasma (0.57 ± 0.05 vs. 0.75 ± 0.064, allicin and control respectively) and the expressions of angiotensin-converting enzyme II and angiotensin II type 1 receptor in lung tissue were maintained at normal control levels with allicin. In PAH rats treated with allicin, nitric oxide (NO) (31.72 ± 1.22 and 51.4 ± 3.45 pmoles/mL), tetrahydrobiopterin (8.43 ± 0.33 and 10.14 ± 0.70 pmoles/mL), cyclic guanosine monophosphate (5.54 ± 0.42 and 5.64 ± 0.73 pmoles/mL), and Ang-(1-7) (0.88 ± 0.23 and 0.83 ± 0.056 pmoles/mL) concentrations increased in lung tissue and plasma, respectively. In contrast, dihydrobiopterin increase was prevented in both lung tissue and plasma (5.75 ± 0.3 and 5.64 ± 0.73 pmoles/mL); meanwhile, phosphodiesterase-5 was maintained at normal levels in lung tissue. OS in PAH was prevented with allicin through the increased expression of Nrf2 in the lung. Allicin prevented the lung response to hypoxia, preventing the overexpression of HIF-1α and VEGF. Allicin attenuated the vascular remodeling and RV hypertrophy in PAH through its effects on NO-dependent vasodilation, modulation of RAS, and amelioration of OS. Also, these effects could be associated with the modulation of HIF-1α and improved lung oxygenation. The global effects of allicin contribute to preventing endothelial dysfunction, remodeling of the pulmonary arteries, and RV hypertrophy, preventing heart failure, thus favoring survival. Although human studies are needed, the data suggest that, alone or in combination therapy, allicin may be an alternative in treating PAH if we consider that, similarly to current treatments, it improves lung vasodilation and increase survival. Allicin may be considered an option when there is a lack of efficacy, and where drug intolerance is observed, to enhance the efficacy of drugs, or when more than one pathogenic mechanism must be addressed.

The Use of Particulate Systems for Tuberculosis Prophylaxis and Treatment: Opportunities and Challenges.

The use of particles to develop vaccines and treatments for a wide variety of diseases has increased, and their success has been demonstrated in preclinical investigations. Accurately targeting cells and minimizing doses and adverse side effects, while inducing an adequate biological response, are important advantages that particulate systems offer. The most used particulate systems are liposomes and their derivatives, immunostimulatory complexes, virus-like particles, and organic or inorganic nano- and microparticles. Most of these systems have been proven using therapeutic or prophylactic approaches to control tuberculosis, one of the most important infectious diseases worldwide. This article reviews the progress and current state of the use of particles for the administration of TB vaccines and treatments in vitro and in vivo, with a special emphasis on polymeric particles. In addition, we discuss the challenges and benefits of using these particulate systems to provide researchers with an overview of the most promising strategies in current preclinical trials, offering a perspective on their progress to clinical trials.

Combined Inhibition of Indolamine-2,3-Dioxygenase 1 and C-X-C Chemokine Receptor Type 2 Exerts Antitumor Effects in a Preclinical Model of Cervical Cancer.

Cervical cancer is a public health problem diagnosed in advanced stages, and its main risk factor is persistent high-risk human papillomavirus infection. Today, it is necessary to study new treatment strategies, such as immunotherapy, that use different targets of the tumor microenvironment. In this study, the K14E7E2 mouse was used as a cervical cancer model to evaluate the inhibition of indolamine-2,3-dioxygenase 1 (IDO-1) and C-X-C chemokine receptor type 2 (CXCR-2) as potential anti-tumor targets. DL-1MT and SB225002 were administered for 30 days in two regimens (R1 and R2) based on combination and single therapy approaches to inhibit IDO-1 and CXCR-2, respectively. Subsequently, the reproductive tracts were resected and analyzed to determine the tumor areas, and IHCs were performed to assess proliferation, apoptosis, and CD8 cellular infiltration. Our results revealed that combined inhibition of IDO-1 and CXCR-2 significantly reduces the areas of cervical tumors (from 196.0 mm2 to 58.24 mm2 in R1 and 149.6 mm2 to 52.65 mm2 in R2), accompanied by regions of moderate dysplasia, decreased papillae, and reduced inflammation. Furthermore, the proliferation diminished, and apoptosis and intra-tumoral CD8 T cells increased. In conclusion, the combined inhibition of IDO-1 and CXCR-2 is helpful in the antitumor response against preclinical cervical cancer.