N/OFQ-NOP System in Peripheral and Central Immunomodulation.

Classical opioids (µ: mu, MOP; δ: delta, DOP and κ: kappa, KOP) variably affect immune function; they are immune depressants and there is good clinical evidence in the periphery. In addition, there is evidence for a central role in the control of a number of neuropathologies, e.g., neuropathic pain. Nociceptin/Orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor, NOP; peripheral and central activation can modulate immune function. In the periphery, NOP activation generally depresses immune function, but unlike classical opioids this is in part driven by NOP located on circulating immune cells. Peripheral activation has important implications in pathologies like asthma and sepsis. NOP is expressed on central neurones and glia where activation can modulate glial function. Microglia, as resident central 'macrophages', increase/infiltrate in pain and following trauma; these changes can be reduced by N/OFQ. Moreover, the interaction with other glial cell types such as the ubiquitous astrocytes and their known cross talk with microglia open a wealth of possibilities for central immunomodulation. At the whole animal level, clinical ligands with wide central and peripheral distribution have the potential to modulate immune function, and defining the precise nature of that interaction is important in mitigating or even harnessing the adverse effect profile of these important drugs.

Opioids, gliosis and central immunomodulation.

Neuropathic pain is a common health problem that affects millions of people worldwide. Despite being studied extensively, the cellular and molecular events underlying the central immunomodulation and the pathophysiology of neuropathic pain is still controversial. The idea that 'glial cells are merely housekeepers' is incorrect and with respect to initiation and maintenance of neuropathic pain, microglia and astrocytes have important roles to play. Glial cells differentially express opioid receptors and are thought to be functionally modulated by the activation of these receptors. In this review, we discuss evidence for glia-opioid modulation of pain by focusing on the pattern of astrocyte and microglial activation throughout the progress of nerve injury/neuropathic pain. Activation of astrocytes and microglia is a key step in central immunomodulation in terms of releasing pro-inflammatory markers and propagation of a 'central immune response'. Inhibition of astrocytes before and after induction of neuropathic pain has been found to prevent and reverse neuropathic pain, respectively. Moreover, microglial inhibitors have been found to prevent (but not to reverse) neuropathic pain. As they are expressed by glia, opioid receptors are expected to have a role to play in neuropathic pain.

Stress as a possible cause of a high incidence of hypertension and diabetes and a low incidence of asthma in the Iraqi population.

Hypertension and diabetes represent a significant public health burden worldwide and are significant risk factors for heart disease and stroke. Nevertheless, Iraqi people, in particular, experience higher levels of stress due to political instability and economic issues. The study aimed to investigate the prevalence of common morbidities among Iraqi patients and the possible relationship with exposure to stress. The data was collected from patients (n=500) who attended the health center in Najaf, Iraq, between 25 August 2021 and 30 September 2021. The prevalence of hypertension, diabetes, and asthma among Iraqi people was determined along with patients' awareness and control of these conditions. In addition, patients were asked about their experiences with stress, including the type of stress they encountered. Our findings revealed that nearly 47% of patients involved in this study had hypertension, with the highest percentage in patients over 40. Moreover, the incidence of diabetes was 12%, with the highest incidence in the age group of 40-59. The incidence of asthma was lower in all groups. Data analysis concerning exposure to stress demonstrated that about 60% of patients suffer from a stressful life. We found that the incidence of hypertension and diabetes was high while the incidence of asthma was low. This study also reveals that a considerable number of people were unaware of their hypertension and diabetes. Exposure to daily life stress among Iraqi people may play a role in the observed incidence of these morbidities.

Potential nephroprotective effects of angiotensin II type 2 receptor agonist Compound 21 in renal ischemia-reperfusion injury.

This study examined the reno-protective potential of Compound 21 during renal ischemia-reperfusion injury by regulating the PI3K expression. 20 adult male Swiss-albino mice, aged 8-12 weeks and weighing 20-30g, were randomly assigned to four equal groups: sham, control, vehicle, and Compound 21. Serum urea, creatinine, inflammatory mediators, tissue 8-isoprostane, and myeloperoxidase were quantified using ELISA. Compared to the sham group, blood levels of urea, creatinine, TNF-α, IL-6, and IL-10 were significantly higher in the ischemia-reperfusion group than in the sham group (p<0.05). However, these indicators were significantly lower in the Compound 21 group (p<0.05). Histological analysis revealed significant renal tissue damage in the ischemia-reperfusion group (p<0.05), which was significantly reduced in the Compound 21 group (p<0.05). PCR results showed that PI3K expression was significantly lower (p<0.05) in the control group compared to the sham group but significantly higher in the Compound 21 group (p<0.05). Furthermore, P-AKT expression levels in the control group were considerably lower than in the sham group (p<0.05). On the other hand, the level of P-AKT expression in the Compound 21 group was significantly upregulated compared to the control group (p<0.05). The findings revealed that Compound 21 could mitigate renal dysfunction induced by ischemia-reperfusion injury in male mice through modulation of the PI3K/AKT signaling pathway, resulting in decreased levels of pro-inflammatory cytokines and renal oxidative stress markers.

Computational Investigations of Traditional Chinese Medicinal Compounds against the Omicron Variant of SARS-CoV-2 to Rescue the Host Immune System.

Macrodomain-I of the NSP3 (non-structural protein 3) is responsible for immune response hijacking in the SARS-CoV-2 infection known as COVID-19. In the omicron variant (B.1.1.529), this domain harbors a new mutation, V1069I, which may increase the binding of ADPr and consequently the infection severity. This macrodomain-I, due to its significant role in infection, is deemed to be an important drug target. Hence, using structural bioinformatics and molecular simulation approaches, we performed a virtual screening of the traditional Chinese medicines (TCM) database for potential anti-viral drugs. The screening of 57,000 compounds yielded the 10 best compounds with docking scores better than the control ADPr. Among the top ten, the best three hits-TCM42798, with a docking score of -13.70 kcal/mol, TCM47007 of -13.25 kcal/mol, and TCM30675 of -12.49 kcal/mol-were chosen as the best hits. Structural dynamic features were explored including stability, compactness, flexibility, and hydrogen bonding, further demonstrating the anti-viral potential of these hits. Using the MM/GBSA approach, the total binding free energy for each complex was reported to be -69.78 kcal/mol, -50.11 kcal/mol, and -47.64 kcal/mol, respectively, which consequently reflect the stronger binding and inhibitory potential of these compounds. These agents might suppress NSP3 directly, allowing the host immune system to recuperate. The current study lays the groundwork for the development of new drugs to combat SARS-CoV-2 and its variants.

Chromogenic in Situ-Hybridization of HPV16/18 DNA in Relation to the Over-Expressed Protein of P73-Gene in Tissues from a Group of Thyroid Carcinoma.

Thyroid cancer has been related to many environmental, genetic, and viral factors. Human Papilloma Viruses (HPV) are epitheliotropic viruses infecting cutaneous and mucosal tissues, leading to a variety of benign and malignant tumors. The p73-gene expresses two important isoforms from the N-terminal end with two opposite activities in the regulation of cell fate. The present study aimed to assess the histopathological expression of tissues from thyroid cancers in relation to the over-expression of the p73 gene with HPV 16/18 infection. A total of 116 thyroid tissues were examined for HPV 16/18-DNA and P73-gene protein expression. The samples belonged to 36 patients diagnosed with thyroid carcinoma, 40 thyroid adenoma tissues blocks, and 40 apparently normal thyroid tissues. The detection of HPV 16/18-DNA was performed by in situ hybridization (ISH), whereas P73 gene expression was carried out by immunohistochemistry (IHC). The HPV16/18 DNA-ISH reactions in thyroid cancers were found in 72.2% tissues, 35% HPV16/18- positivity was detected in the thyroid adenoma tissues group, and 27.5% of healthy thyroid tissues revealed ISH reactions. Statistically, the difference of the HPV16/18 in thyroid cancers and control was highly significant. The p73 was detected in 66.7% and 57.5% of thyroid cancer and adenoma thyroid tissues, respectively, while 45% of the examined healthy thyroid tissues revealed IHC-reactions. The difference between the p73-protein expression percentages detected in tissues of thyroid tumors and the control group was non statistically significant. The presence of HPV16/18, as well as an over-expressed p73-gene, in thyroid cancer patients, suggests that the virus, as well as this protein, may play an etiologic role in thyroid carcinogenesis.

Insights into the Binding of Receptor-Binding Domain (RBD) of SARS-CoV-2 Wild Type and B.1.620 Variant with hACE2 Using Molecular Docking and Simulation Approaches.

Recently, a new variant, B.1620, with mutations (S477N-E484K) in the spike protein's receptor-binding domain (RBD) has been reported in Europe. In order to design therapeutic strategies suitable for B.1.620, further studies are required. A detailed investigation of the structural features and variations caused by these substitutions, that is, a molecular level investigation, is essential to uncover the role of these changes. To determine whether and how the binding affinity of ACE2-RBD is affected, we used protein-protein docking and all-atom simulation approaches. Our analysis revealed that B.1.620 binds more strongly than the wild type and alters the hydrogen bonding network. The docking score for the wild type was reported to be -122.6 +/- 0.7 kcal/mol, while for B.1.620, the docking score was -124.9 +/- 3.8 kcal/mol. A comparative binding investigation showed that the wild-type complex has 11 hydrogen bonds and one salt bridge, while the B.1.620 complex has 14 hydrogen bonds and one salt bridge, among which most of the interactions are preserved between the wild type and B.1.620. A dynamic analysis of the two complexes revealed stable dynamics, which corroborated the global stability trend, compactness, and flexibility of the three essential loops, providing a better conformational optimization opportunity and binding. Furthermore, binding free energy revealed that the wild type had a total binding energy of -51.14 kcal/mol, while for B.1.628, the total binding energy was -68.25 kcal/mol. The current findings based on protein complex modeling and bio-simulation methods revealed the atomic features of the B.1.620 variant harboring S477N and E484K mutations in the RBD and the basis for infectivity. In conclusion, the current study presents distinguishing features of B.1.620, which can be used to design structure-based drugs against the B.1.620 variant.