In silico functional and tumor suppressor role of hypothetical protein PCNXL2 with regulation of the Notch signaling pathway

Since the last decade, various genome sequencing projects have led to the accumulation of an enormous set of genomic data; however, numerous protein-coding genes still need to be functionally characterized. These gene products are called “hypothetical proteins”. The hypothetical protein pecanex-like protein 2 Homo sapiens (PCNXL2) is found to be mutated in colorectal carcinoma with microsatellite instability; therefore, annotation of the function of PCNXL2 in tumorigenesis is very important. In the present study, bioinformatics analysis of PCNXL2 was performed at the molecular level to assess its role in the progression of cancer for designing new anti-cancer drugs. The retrieved sequence of PCNXL2 was functionally and structurally characterized through the web tools Pfam, Batch CD (conserved domain) search, ExPASy, COACH and I-TASSER directed for pathway analysis and design to explore the intercellular interactions of PCNXL2 involved in cancer development. The present study has shown that PCNXL2 encodes multi-pass transmembrane proteins whose tumor suppressor function may involve regulating Notch signaling by transporting protons across the membrane to provide suitable membrane potential for γ secretase function, which may liberate the Notch intracellular domain NICD from the receptor to inside the cell. Furthermore, domain A of PCNXL2 may exhibit nuclear transport activity of NICD from the cytoplasm to the nucleus through interaction with a nuclear localization signal that may act as an activator for Notch signaling in the nucleus. Conclusively, the tumor suppressor role of PCNXL2 by regulation of the Notch signaling pathway and its functional and structural characteristics are important findings. However, further studies are required to validate the putative role of PCNXL2 as a cancer biomarker in cancer development.

Since the last decade, various genome sequencing projects have led to the accumulation of an enormous set of genomic data; however, numerous protein-coding genes still need to be functionally characterized.     

Treatment Outcomes and Health Care Resource Utilization in Patients With Newly Diagnosed Multiple Myeloma Receiving Lenalidomide-only Maintenance,Any Maintenance,or No Maintenance: Results from the Connect MM Registry

Purpose

Maintenance therapy after autologous stem cell transplantation (ASCT) improves clinical outcomes in multiple myeloma (MM), but the effect of continued treatment with lenalidomide-only maintenance, or any maintenance, on health care resource utilization (HCRU) is largely unknown.

Arylnaphthalene lactone analogues: synthesis and development as excellent biological candidates for future drug discovery

Arylnaphthalene lactones are natural products extracted from a wide range of different parts of plants. The progressing interest in the synthesis of these compounds is due to their significant biological activities, which have made them potential candidates in drug discovery and development. This review mainly covers recent developments in the synthesis and biological applications of arylnaphthalene lactone analogs.

A review of recent developments in the synthesis and biological applications of arylnaphthalene lactones analogs.     

Protective effect of dapsone against renal ischemia-reperfusion injury in rat

Abstract

Background: Ischemia/reperfusion can cause injury to tissues and compromise functionality of organs due to inflammatory processes. Significantly, development of these effects in kidney tissue has been a challenging issue that leads to acute renal injury. In this study, anti-inflammatory, anti-oxidative, and protective features of dapsone on kidney ischemia/reperfusion injury were investigated.

Material and methods: Renal ischemia was induced in rats by bilateral renal arteries clamping for 45?min followed by 24?h reperfusion phase. The effects of different doses of dapsone (1, 3, 10?mg/kg) on ischemia/reperfusion injury in kidney tissue were investigated by targeting BUN, Creatinine, LDH, MDA, MPO, IL-1β, TNF-α, and NFκB. In addition histopathological examination was performed by H&E staining method.

Results and discussion: Comparing the findings of this study showed significant reduction in BUN and LDH in 10?mg/kg dapsone received groups, and Cr, MDA, and MPO in 3?mg/kg dapsone received groups. The serum level of TNF-α was significantly decreased with both doses of 3 and 10?mg/kg dapsone. The same results were observed in the serum level of IL-1β and NFκB. Besides, remarkable improvement in histological damages was also observed with dapsone treatment.

Conclusion: These results support the hypothesis that the positive effects of dapsone on the renal ischemia/reperfusion injury are mediated by modulating inflammatory cascades.     

Virulent and multidrug‐resistant Klebsiella pneumoniae from clinical samples in Balochistan

Klebsiella pneumoniae is an important pathogen causing hospital‐acquired infections in human beings. Samples from suspected patients of K pneumoniae associated with respiratory and urinary tract infections were collected at Bolan Medical Complex, Quetta, Balochistan. Clinical samples (n = 107) of urine and sputum were collected and processed for K pneumoniae isolation using selective culture media. Initially, 30 of 107 isolates resembling Klebsiella spp. were processed for biochemical profiling and molecular detection using gyrase A (gyrA) gene for conformation. The K pneumoniae isolates were analysed for the presence of drug resistance and virulence genes in their genomes. The 21 of 107 (19.6%) isolates were finally confirmed as K pneumoniae pathogens. An antibiogram study conducted against 17 different antibiotics showed that a majority of the isolates are multidrug resistant. All the isolates (100%) were resistant to amoxicillin, cefixime, amoxicillin‐clavulanic acid, cefotaxime, and ceftriaxone followed by tetracycline (95.2%), ciprofloxacin and gentamicin (76.2%), sulphamethoxazol (66.7%), nalidixic acid (61.9%), norfloxacine (42.9%), piperacillin‐tazobactam (23.8%), cefoperazone‐sulbactam (19%), and cefotaxime‐clavulanic acid (33.3%), whereas all the isolates showed sensitivity to amikacin, chloramphenicol, and imipenem. The presence of tetracycline, sulphamethoxazol‐resistant genes, and extended‐spectrum beta‐lactamase was reconfirmed using different specific genes. The presence of virulence genes fimH1 and EntB responsible for adherence and enterobactin production was confirmed in the isolates. The high virulence and drug resistance potential of these Klebsiella isolates are of high public health concern. Multidrug resistance and virulence potential in K. pneumoniae are converting these nosocomial pathogens into superbugs and making its management harder.     

Regulation of immune responses to Mycobacterium tuberculosis secretory antigens by dendritic cells

Towards elucidating the immune responses induced by antigens from the Mycobacterium tuberculosis (M. tb) RD-1 region, we have been characterizing their interactions with dendritic cells (DCs) and their precursors. We have shown that incubation of bone marrow DC precursors with M. tb antigens induces the differentiation of DC precursors and also the maturation of various DC subsets. While MTSA differentiated DCs were immature, MTSA matured DCs were terminally mature. However, regardless of their maturation status M. tb secretory antigen-activated DCs down-regulated pro-inflammatory T helper cell responses to a subsequent challenge with M. tb cell extract (CE) while increasing regulatory responses. Investigations into the underlying mechanisms showed that stimulation with M. tb CE changed the polarization of antigen-activated DCs from DC1 to DC2. This resulted in secretion of high levels of IL-10 and TGF-beta together with increased surface expression of CD86. Blocking either IL-10 or TGF-beta or CD86 restored Th1 responses to CE antigens. Conversely, treatment of antigen-activated DCs with IL-12 and/or IFN-gamma fully restored Th1 responses of CE antigens. These results indicate that M. tb strategically secretes antigens from infected macrophages to down-regulate pro-inflammatory immune responses at sites of infection.     

Selection for a CEACAM Receptor-Specific Binding Phenotype during Neisseria gonorrhoeae Infection of the Human Genital Tract

Infections by Neisseria gonorrhoeae are increasingly common, are often caused by antibiotic-resistant strains, and can result in serious and lasting sequelae, prompting the reemergence of gonococcal disease as a leading global health concern. N. gonorrhoeae is a human-restricted pathogen that primarily colonizes urogenital mucosal surfaces. Disease progression varies greatly between the sexes: men usually present with symptomatic infection characterized by a painful purulent urethral discharge, while in women, the infection is often asymptomatic, with the most severe pathology occurring when the bacteria ascend from the lower genital tract into the uterus and fallopian tubes. Classical clinical studies demonstrated that clinically infectious strains uniformly express Opa adhesins; however, their specificities were unknown at the time. While in vitro studies have since identified CEACAM proteins as the primary target of Opa proteins, the gonococcal specificity for this human family of receptors has not been addressed in the context of natural infection. In this study, we characterize a collection of low-passage-number clinical-specimen-derived N. gonorrhoeae isolates for Opa expression and assess their CEACAM-binding profiles. We report marked in vivo selection for expression of phase-variable Opa proteins that bind CEACAM1 and CEACAM5 but selection against expression of Opa variants that bind to the neutrophil-restricted decoy receptor CEACAM3. This is the first study showing phenotypic selection for distinct CEACAM-binding phenotypes in vivo, and it supports the opposing functions of CEACAMs that facilitate infection versus driving inflammation within the genital tract.     

The assessment of placental volume and mean gray value in preeclamptic placentas by using three-dimensional ultrasonography

Objectives: We aimed to evaluate the placental volume and placental mean gray value in preeclampsia and healthy placentas by using three-dimensional (3D) ultrasonography and Virtual Organ Computer-aided AnaLysis (VOCAL).

Methods: This case–control prospective study consisted of 27 singleton pregnancies complicated by preeclampsia and 54 healthy singleton pregnancies matched for gestational age, maternal age and parity. Placental volume and placental volumetric mean gray values were evaluated. The placental volume (cm³) was analyzed using the VOCAL imaging program, and 3D histogram was used to calculate the volumetric mean gray value (%).

Results: Preeclamptic and control group consisted of 27 (mean age: 28.90?±?5.95 years, mean gestation: 32.0?±?4.55 weeks) and 54 (mean age: 29.48?±?5.78 years, mean gestation: 32.61?±?4.23 weeks) singleton pregnancies, respectively. Placental volume was significantly smaller in preeclampsia (250.62?±?91.69 versus 370.98?±?167.82?cm³; p?=?0.001). Volumetric mean gray value of the placenta was significantly higher in preeclampsia (38.24?±?8.41 versus 33.50?±?8.90%; p?=?0.043). Placental volume was significantly correlated with the estimated fetal weight (r?=?0.319; p?=?0.003). There was negative significant relation between placental volume and umbilical artery pulsatility index, resistance index and systolic/diastolic ratio (r?=?–0.244, p?=?0.024; r?=?–0.283, p?=?0.005; r?=?–0.241, p?=?0.024, respectively).

Conclusions: Placental volume diminishes significantly in preeclampsia, whereas volumetric mean gray values increases. This may reflect the early alterations in preeclamptic placentas, which may help to understand the pathophysiology better.