Effect of human umbilical cord blood-mesenchymal stem cells on cisplatin-induced nephrotoxicity in rats.

BACKGROUND: Cisplatin-containing regimen is an effective treatment for several malignancies. However, cisplatin is an important cause of nephrotoxicity. So, many trials were performed to transplant stem cells systemically or locally to control cisplatin-induced nephrotoxicity. Stem cell therapeutic effect may be dependent on the regulation of inflammation and oxidant stress. AIM: To investigate the effect of human umbilical cord blood-mesenchymal stem cells (hUCB-MSCs) on the histological structure, the oxidant stress, and the inflammatory gene expression in an experimental model of cisplatin-induced nephrotoxicity in rats. METHOD: The rats were divided into 6 equal groups (each of 10 rats): Group I included normal rats that received no treatment. Group II included healthy rats that received IV hUCB-MSCs. Group III included untreated cisplatin-induced nephrotoxic rats. Group IV included cisplatin-induced nephrotoxic rats that received magnesium (Mg) injections after injury. Group V was injected with hUCB-MSCs after injury. Group VI received both Mg and hUCB-MSCs after injury. In tissue homogenates, reduced glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA) activities were measured. Quantitative real-time-polymerase chain reaction (qRT-PCR) was performed to assess iNOS, TLR4, and NF-kB gene expression. Hematoxylin and eosin (H&E) staining was performed to study the histological structure of the kidney. Immunohistochemical staining of iNOS and NF-κB was performed, as well. RESULTS: Disturbed kidney functions, oxidative status, and histological structure were seen in the rats that received cisplatin. Treated groups showed improvements in kidney functions, oxidative status, and histological structure, particularly in the combined treatment group. CONCLUSION: In the cisplatin-induced nephrotoxicity model, hUCB-MSCs could improve the functional and morphological kidney structure by modulation of oxidative and inflammatory status.

Health information and health-seeking behaviour in Yemen: perspectives of health leaders, midwives and mothers in two rural areas of Yemen.

BACKGROUND: Humanitarian crises can lead to the rapid change in the health needs of women and newborns, which may give rise to a complex situation that would require various interventions as solutions. This study aimed to examine the health education and promotion patterns, health-seeking behaviour of mothers, and barriers to the use of maternal health services from public health facilities in two rural areas of Yemen. METHODS: We used a qualitative approach. We conducted in-depth interviews and focus group discussions with frontline health professionals and mothers respectively. Nine in-depth interviews were conducted with the health professionals, including 4 health leaders and 5 midwives, and 2 focus group discussions with mothers aged 18-45 years in Abyan and Lahj. Thematic analysis approach was used to analyze the data in Atlas.ti (version 8) Software. RESULTS: Our data showed that health education and promotion activities on maternal health were ad hoc and coverage was poor. Maternal health services were underutilized by women. According to the data from the focus group discussions, the poor quality of services, as indicated by inadequate numbers of female doctors, lack of medical equipment and medicines, and costs of services were barriers to use maternal health services. Moreover, the use of prenatal and postnatal care services was associated with women's' perceived need. However, according to the health professionals, the inadequate human resource, workload, and inadequate funding from government have contributed significantly to the perceived quality of maternal health services provided by public health facilities. Despite the identified barriers, we found that a safe motherhood voucher scheme was instituted in Lahj which facilitated the use of maternal health services by disadvantaged women by removing financial barriers associated with the use of maternal health services. CONCLUSION: This study identified several obstacles, which worked independently or jointly to minimize the delivery and use of health services by rural women. These included, inadequate funding, inadequate human resources, poor quality of health services, and high cost of services. These barriers need to be addressed to improve the use of reproductive health services in Yemen.

Ameliorative effect of combined low dose of Pioglitazone and omega-3 on spermatogenesis and steroidogenesis in diabetic rats.

BACKGROUND: Chronic hyperglycemia is linked to either subfertility or infertility among diabetic males. Pioglitazone is one of the thiazolidinediones (TZDs) drugs that are selective peroxisome proliferator-activated receptor (PPAR-γ agonists used for treating type 2 diabetes mellitus (T2DM). AIM: This study aims to explore the possible effect of low Pioglitazone dose and omega (ω-3) on rat male reproductive function. Furthermore, we evaluated the add-on effect of combined use of low Pioglitazone dose of and ω-3 on reproductive functions in adult male T2DM rats. METHODS: Fifty adult male rats were included and subdivided into control and four test subgroups. T2DM was induced in test groups and subdivided into non-treated T2DM, ω-3 treated, 0.6 mg/kg Pioglitazone treated, and combined treated group (orally by gavage). Following 16 weeks, final body weight, testicular weight, fasting plasma glucose, and serum testosterone levels were measured. Semen analysis, testicular testosterone, malondialdehyde (MDA) concentrations, superoxide dismutase (SOD) activity, immunohistochemistry staining for apoptosis marker B-cell lymphoma protein 2 (Bcl-2), proliferation marker as proliferating cell nuclear antigen (PCNA), estrogen receptor α (ERα), androgen receptor (AR) were determined. Caspase-3, nuclear factor-kappa B (NF-kB), glucose transporter 3 (GLUT3), 17ß-hydroxysteroid dehydrogenases (17ß-HSD) PPARγ, and PPARα genes expression were analyzed by real-time polymerase chain reaction (RT-PCR). RESULTS: Our findings revealed that treatment with low dose of Pioglitazone or ω-3 significantly lowered fasting plasma glucose and MDA levels, ameliorated diabetes effects on histological damage, improved antioxidant activity (SOD), significantly improved anti-apoptosis BCL-2 and proliferation (PCNA), remarkably elevated ERα, AR, 17ß-HSD PPARγ, and PPARα expression with significant reduction in caspase-3, NF-kB genes expression and improved semen quality as well. Combined use of low dose of and ω-3 has better effects on all measured parameters. CONCLUSION: Small Pioglitazone dose and ω-3 possess beneficial effects on spermatogenic and steroidogenic functions in adult diabetic rat; while combined use of both has an add-on effect.

Limited changes in spinal lamina I dorsal horn neurons following the cytotoxic ablation of non-peptidergic C-fibers.

BACKGROUND: Non-peptidergic nociceptive neurons are a sub-population of small diameter primary sensory neurons that comprise approximately 50 % of the C fiber population. Together with the peptidergic sub-population, they transmit nociceptive information from the periphery to the superficial dorsal horn of the spinal cord. Despite the numerous studies investigating the role of the non-peptidergic primary afferents, their role in normal nociception and in pain remains poorly understood. Our lab has previously demonstrated that, in rat models of neuropathic and inflammatory pain, there is a de novo expression of substance P receptors (NK-1r) by lamina I pyramidal projection neurons, a neuronal population that normally does not express these receptors. RESULTS: In this study, we used a ribosomal toxin, saporin, conjugated to the lectin IB4 to selectively ablate the non-peptidergic nociceptive C fibers, to investigate if the loss of these fibers was enough to induce a change in NK-1r expression by lamina I projection neurons. IB4-saporin treatment led to the permanent ablation of the IB4-positive afferents but also to a small non-significant reduction in CGRP-positive afferents. An overall increase in immunoreactivity for the NK-1r was observed in lamina I projection neurons, however, the lack of non-peptidergic afferents did not increase the number of lamina I pyramidal projection neurons immunoreactive for the receptor. CONCLUSIONS: Our results demonstrate that the deletion of the non-peptidergic afferents, at the L4-L5 spinal levels, is not sufficient to trigger the de novo expression of NK-1r by projection pyramidal neurons but increases the expression of NK-1r in fusiform and multipolar projection neurons. Furthermore, our data suggest that a neuropathic component is essential to trigger the expression of NK-1r by pyramidal neurons.

De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion.

Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons that express the SP receptor, also known as the neurokinin-1 receptor (NK-1r). Three types of lamina I projection neurons have been described: multipolar, fusiform, and pyramidal. Most neurons of the first two types are thought to be nociceptive and express the NK-1r, whereas most pyramidal neurons are nonnociceptive and do not express the NK-1r. In this immunocytochemical and behavioral study, we induced a neuropathic pain-like condition in the rat by means of a polyethylene cuff placed around in the sciatic nerve. We document that this lesion led to a de novo expression of NK-1r on pyramidal neurons as well as a significant increase in SP-immunoreactive innervation onto these neurons. These phenotypic changes were evident at the time of onset of neuropathic pain-related behavior. Additionally, we show that, after a noxious stimulus (intradermal capsaicin injection), these NK-1r on pyramidal neurons were internalized, providing evidence that these neurons become responsive to peripheral noxious stimulation. We suggest that the changes following nerve lesion in the phenotype and innervation pattern of pyramidal neurons are of significance for neuropathic pain and/or limb temperature regulation.

Non-peptidergic primary afferents are presynaptic to neurokinin-1 receptor immunoreactive lamina I projection neurons in rat spinal cord.

BACKGROUND: Pain-related (nociceptive) information is carried from the periphery to the dorsal horn of the spinal cord mostly by two populations of small diameter primary afferents, the peptidergic and the non-peptidergic. The peptidergic population expresses neuropeptides, such as substance P and calcitonin gene-related peptide, while the non-peptidergic fibers are devoid of neuropeptides, express the purinergic receptor P2X3, and bind the isolectin B4 (IB4). Although it has been known for some time that in rat the peptidergic afferents terminate mostly in lamina I and outer lamina II and non-peptidergic afferents in inner lamina II, the extent of the termination of the latter population in lamina I was never investigated as it was considered as very minor. Because our preliminary evidence suggested otherwise, we decided to re-examine the termination of non-peptidergic afferents in lamina I, in particular with regards to their innervation of projection neurons expressing substance P receptors (NK-1r). We used retrograde labeling of neurons from the parabrachial nucleus combined with lectin IB4 binding and immunocytochemistry. Samples were examined by confocal and electron microscopy. RESULTS: By confocal microscopy, we studied the termination of non-peptidergic afferents in lamina I using IB4 binding and P2X3 immunoreactivity as markers, in relation to CGRP immunoreactivy, a marker of peptidergic afferents. The number of IB4 or P2X3-labeled fibers in lamina I was higher than previously thought, although they were less abundant than CGRP-labeled afferents. There were very few fibers double-labeled for CGRP and either P2X3 or IB4. We found a considerable number of IB4-positive fiber varicosities in close apposition to NK-1r-positive lamina I projection neurons, which were distinct from peptidergic varicosities. Furthermore, we confirmed at the ultrastructural level that there were bona fide synapses between P2X3-immunoreactive non-peptidergic boutons and neurokinin-1 receptor-positive lamina I dendrites. CONCLUSIONS: These results indicate the presence of direct innervation by non-peptidergic nociceptive afferents of lamina I projection neurons expressing NK-1r. Further investigations are needed to better understand the role of these connections in physiological conditions and chronic pain states.