Targeting Solute Carrier Transporters (SLCs) as a Therapeutic Target in Different Cancers.

Solute carrier (SLC) transporters constitute a vast superfamily of transmembrane proteins tasked with regulating the transport of various substances such as metabolites, nutrients, ions, and drugs across cellular membranes. SLC transporters exhibit coordinated expression patterns across normal tissues, suggesting a tightly regulated regulatory network governing normal cellular functions. These transporters are crucial for the transport of various metabolites, including carbohydrates, proteins, lipids, and nucleic acids. However, during tumor development, metabolic changes drive an increased demand for energy and nutrients. Consequently, tumor cells alter the expression of SLC transporters to meet their heightened nutrient requirements. Targeting SLCs through inhibition or activation presents a promising therapeutic approach in cancer treatment. Certain SLCs also serve as intriguing chemo-sensitizing targets, as modulating their activity can potentially alter the response to chemotherapy. This review underscores the significance of various SLCs in tumor progression and underscores their potential as both direct and indirect targets for cancer therapy.

Exploring the role of the protein tyrosine kinase a (PtkA) in mycobacterial intracellular survival.

Mycobacterium tuberculosis (Mtb) continues to define new paradigms of host-pathogen interaction. There are several host proteins known which are regulated by Mtb infection. The proteins which regulate host biological processes like apoptosis, cell processes, stress proteins, metabolic enzymes, etc. are targeted by the pathogens. Mtb proteins interact directly or indirectly with host proteins and play an important role in their persistence and intracellular growth. Mtb is an intracellular pathogen. It remains dormant for years within the host without activating its immune system. Mtb Protein tyrosine kinase (PtkA) regulates host anti-apoptotic protein, metabolic enzymes, and several other proteins that are involved in stress regulation, cell proliferation, protein folding, DNA repair, etc. PtkA regulates other mycobacterial proteins and plays an important role in its growth and survival. Here we summarized the current knowledge of PtkA and reviewed its role in mycobacterial intracellular survival as it regulates several other mycobacterial proteins and host proteins. PtkA regulates PtpA secretion which is essential for mycobacterial virulence and could be used as an attractive drug target.

Oral Vaccination Approaches for Anti-SHIV Immunity.

We modified a Sabin Oral Poliovirus Vaccine (OPV) vector to permit secretion of the antigens of interest with the goal of improving anti-HIV Env humoral responses in a SHIV mucosal immunization composed of DNA and recombinant OPVs. We evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in Rhesus macaques by two regimens, both involving a prime with a SHIVBG505 DNA construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral cavity, and two different viral vector boostings, administered in the oral cavity and intestinally. Group 1 was boosted with rMVA-SHIVBG505, expressing SIV Gag/Pol and HIVBG505 Env. Group 2 was boosted with a SHIVBG505-OPV vaccine including a non-secreting SIVmac239CA-p6-OPV, expressing Gag CA, NC and p6 proteins, and a HIVBG505C1-V2-OPV, secreting the C1-V2 fragment of HIV EnvBG505, recognized by the broadly neutralizing antibody PG16. A time course analysis of anti-SHIV Gag and Env CD4+ and CD8+ T-cell responses in PBMC and in lymph node, rectal, and vaginal MNC was carried out. Both regimens stimulated significant cell-mediated responses in all compartments, with SHIVBG505-OPV immunization stimulating more significant levels of responses than rMVA- SHIVBG505. Boolean analysis of these responses revealed predominantly monofunctional responses with multifunctional responses also present in all tissues. Stimulation of antibody responses was disappointing in both groups with negative anti-SHIV IgG in plasma, and IgA in salivary, rectal and vaginal secretions being restricted to a few animals. After repeated rectal challenge with SHIVBG505, two Group 1 animals remained uninfected at challenge termination. No significant differences were observed in post-infection viral loads between groups. After the acute phase decline, CD4+ T cell percentages returned to normal levels in vaccinated as well as control animals. However, when compared to controls, vaccinate groups had more significant preservation of PBMC and rectal MNC Th17/Treg ratios, considered the strongest surrogate marker of progression to AIDS. We conclude that the vaccine platforms used in this study are insufficient to stimulate significant humoral immunity at the tested doses and schedule but sufficient to stimulate significant mucosal and systemic cell-mediated immunity, impacting the preservation of key Th17 CD4+ T cells in blood and rectal mucosa.

Diversity of KIR/HLA Genotypes and Their Association with Psoriasis Vulgaris in the Western Mexican Population.

NK and some T cell functions are regulated by the interaction between KIR and HLA molecules. Several studies have shown an association between activating KIR genes and the development of autoimmune diseases, including psoriasis vulgaris (PsV). Our objective was to determine the association between KIR/HLA genes and genotypes with PsV in the Western mestizo Mexican population. One hundred subjects diagnosed with PsV (SP) and 108 healthy subjects (HS) were genotyped for 14 KIR genes, HLA-Bw4, HLA-C1, and HLA-C2 by PCR-single specific primer (SSP). Positive associations of the KIR3DS1 gene (odds ratio (OR) 1.959, p = 0.021), G11 genotype (OR 19.940, p = 0.008), and KIR3DS1/HLA-ABw4 (OR 2.265, p = 0.009) were found with susceptibility to PsV. In contrast, the G1 genotype (OR 0.448, p = 0.031) and KIR3DL1/HLA-Bw4Ile80 (OR 0.522, p = 0.022) were negatively associated with susceptibility to this disease. These results suggest an implication of the KIR3DS1/HLA-ABw4 genotype in PsV pathology.

Distribution of KIR genes and KIR2DS4 gene variants in two Mexican Mestizo populations.

Killer immunoglobulin-like receptors (KIR) are transmembrane proteins that regulate NK and T cell subsets by recognizing HLA-I molecules as ligands. The KIR gene family consists of 16 genes, located at chromosome 19q13.4. KIR gene frequencies vary among populations. In Mexico, HLA and genetic ancestry studies show that Mestizo populations have different genetic backgrounds based on admixture with European, African, and Asian ancestry. This study aimed to evaluate the frequencies of KIR genes and genotypes in Guerrero and Jalisco, two Mexican Mestizo populations located in the south and the west of the country, respectively, and to compare these frequencies with those of other populations. KIR genotyping was performed by SSP-PCR. We observed that KIR gene frequencies were similar in both populations. There were 24 genotypes observed in Guerrero, 38 genotypes observed in Jalisco, 15 genotypes shared in both populations and 32 genotypes unique to one population or the other. In 10 individuals, nine novel genotypes were identified. KIR2DS4 gene variants showed significant differences: The KIR2DS4full gene was more common in Guerrero (p<0.0001), and the KIR2DS4del variant was more common in Jalisco (p<0.05). Differences in KIR2DS4 gene variants and genotypic profiles could be influenced by the genetic admixture in both regions.

KIR2DL2 and KIR2DS2 as genetic markers to the methotrexate response in rheumatoid arthritis patients.

CONTEXT: Disease Modifying Anti-Rheumatic Drugs (DMARDs) are aimed to interfere with rheumatoid arthritis (RA) progression and reduce the joint damage; however, not all patients respond alike. Killer-cell immunoglobulin-like receptors (KIR) and their ligands, human leucocyte antigen class I (HLA-I), have been associated with RA pathology; therefore, KIR and HLA genes may influence the treatment response. MATERIALS AND METHODS: We evaluated the association of KIR genotype and their ligands HLA-C genes with the response to DMARDs in RA patients. We included 69 patients diagnosed with RA and 82 healthy individuals as the reference group. KIR and HLA-C genotyping was performed using SSP-PCR. RA patients were assessed at baseline and under treatment at 6 and 12 months; subsequently classified as responders and non-responders in each time period. We evaluated the association between DMARD response and genes using statistical analysis by using Fisher exact test with Bonferroni correction; results were regarded as statistically significant at p < 0.05. RESULTS: Significant difference was observed in gene frequencies of patients and the reference group, KIR2DL2 was associated with RA (p = 0.031, OR = 2.119). We also observed an association between KIR2DS2 and the response to methotrexate (MTX), moreover, the combination KIR2DL2+/KIR2DS2+ was more frequent in responders to MTX (p = 0.043). DISCUSSION AND CONCLUSIONS: In our results, responders and non-responders to DMARDs showed KIR2DS2 and KIR2DL2 different gene frequencies, therefore, these genes could be used as response predictors to DMARDs treatment. Thus, these genes were also associated with disease severity, as well as the treatment response possibly by the immunoregulatory function of NK cells.

University students' knowledge and attitudes towards leprosy.

INTRODUCTION: Patients with leprosy may be affected psychologically and socially by the negative attitude of society toward leprosy, caused by widespread ignorance and prevailing stereotypes surrounding the disease. This study aimed to determine the knowledge and attitudes toward leprosy among students at the University of Guadalajara. METHODOLOGY: This descriptive cross-sectional study included 1,300 students over 18 years of age from various Thematic University Centres in Guadalajara. Students' degree subjects included the health sciences, humanities, exact sciences (i.e., chemistry, physics), arts, biological-agricultural sciences, and administration. Students were randomly selected regardless of gender and all students were enrolled in either the first, second, or third year of their undergraduate studies. RESULTS: Overall, students showed an intermediate level of knowledge of leprosy. Results showed that 67% correctly responded that leprosy is an infectious disease, 64% knew of the presence of skin lesions, and 60% knew that a microbe causes the disease. Furthermore, 45% correctly responded that leprosy is a disease associated with poverty and 40% responded that leprosy is disabling. Only 31% stated that leprosy is curable. Negative attitudes were evident regarding the question of employing a leprosy patient (57%) and having a leprosy patient as a spouse or partner (30%). DISCUSSION: The results revealed that there is insufficient knowledge of and poor attitudes toward leprosy among students at the University of Guadalajara. It is necessary to improve current health education measures by using updated educational strategies to reduce the stigma of leprosy and the segregation of leprosy patients and their families.