Daidzein attenuated paclitaxel-induced neuropathic pain via the down-regulation of TRPV1/P2Y and up-regulation of Nrf2/HO-1 signaling.

Paclitaxel (PTX) is an anti-microtubule agent, used for the treatment of various types of cancers; however, it produces painful neuropathy which limits its use. Many neuroprotective agents have been introduced to mitigate PTX-induced neuropathic pain (PINP), but they pose many adverse effects. The purpose of this study was to evaluate the pharmacological characteristics of soy isoflavone, and daidzein (DZ) in attenuating PINP. At the beginning of the investigation, the effect of DZ was confirmed through behavioral analysis, as it reduced pain hypersensitivity. Moreover, changes in the histological parameters were reversed by DZ administration along with vascular permeability. PTX administration upregulated transient receptor potential vanilloid 1 (TRPV1) channels and purinergic receptors (P2Y), contributing to hyperalgesia; but administration of DZ downregulated the TRPV1 and P2Y, thus reducing hyperalgesia. DZ increased nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), playing a pivotal role in the activation of the antioxidant pathway. DZ also decreased neuronal apoptosis by decreasing caspase-3 and Bcl2-associated X-protein (Bax), while simultaneously, increasing Bcl-2. PTX administration produced severe DNA damage, which was mitigated by DZ. Similarly, DZ administration resulted in inhibition of neuroinflammation by increasing antioxidant enzymes and reducing oxidative stress markers. PTX caused increased in production of pro-inflammatory mediators such as the cytokines production, while DZ inhibited the pro-inflammatory mediators. Additionally, in silico pharmacokinetic and toxicodynamic study of DZ was also conducted. In summary, DZ demonstrated significant neuroprotective activity against PTX induced neuropathic pain.

Second-Line Antiretroviral Treatment Outcome in HIV-Infected Patients Coinfected with Tuberculosis in Pakistan.

Background: Tuberculosis (TB) coinfection in human immunodeficiency virus- (HIV-) infected patients is considered a risk of antiretroviral therapy (ART) failure. Coadministration of antitubercular therapy (ATT) with ART is another challenge for TB management. Objective: The study was aimed at investigating contributing factors affecting treatment outcomes in HIV-/TB-coinfected patients. Design: Cross-sectional. Setting. Samples were collected from the Pakistan Institute of Medical Sciences Hospital Islamabad. Subject and Methods. Clinicodemographic and immunovirological factors between the two groups were compared. The Student t-test and chi-square test were applied to compare outcome variables, and logistic regression was applied to determine the effect of TB on virological failure (VF). Main Outcome Measures. TB coinfection did not increase VF even in univariate (p = 0.974) and multivariate analysis at 6 and 12 months of 2nd-line ART start. ARV switching was significant (p = 0.033) in TB-coinfected patients. VF was significantly high in ATT-coadministered patients along with a viral load of ≥1000 (p = 0.000). Sample Size and Characteristics. We recruited seventy-four HIV patients on 2nd-line ART; 33 coinfected with TB were followed for at least 12 months. Conclusion: In HIV-/TB-coinfected patients, CD4 count, CD4 gain, and VF remained comparable to HIV patients with no TB infection. ATT significantly affects the treatment outcome, suggesting drug-to-drug interactions. These factors are important to revisit the therapeutic guidelines to maximize the benefit of dual therapy in resource-limited settings.

Anti-nociceptive effects of magnolol via inhibition of TRPV1/P2Y and TLR4/NF-κB signaling in a postoperative pain model.

AIMS: The current study explored the anti-nociceptive activity of magnolol in post-incisional inflammatory nociceptive pain. MAIN METHODS: Preliminary, the anti-inflammatory, antioxidant, and cytoprotective potential of magnolol were confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. Next, an in-vivo model of planter incision surgery was established in BALB/c mice. Tramadol 50 mg/kg intraperitoneal (i.p.) and magnolol (0.1, 1, 10 mg/kg i.p. + 10 mg/kg intra planter) were administered after plantar incision surgery and behavior parameters were measured. KEY FINDINGS: The results indicate that magnolol significantly suppressed post-incision-induced mechanical allodynia, thermal hyperalgesia, and paw edema. Magnolol promisingly inhibited post-incision induces nitric oxide (NO), malondialdehyde (MDA), eosinophil peroxidase (EPO), and neutrophil infiltration. Magnolol strongly attenuated post-incision inducing the release of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and inhibited deoxyribonucleic acid (DNA) fragmentation. Magnolol markedly reverses post-incisional histopathological changes and biochemical composition of the incised paw. Magnolol markedly down-regulated post-incisional increase expression of transient receptor potential vanilloid 1 (TRPV1), purinergic (P2Y) nociceptors as well as toll-like receptor 4 (TLR4), nuclear factor kappa light chain enhancer of activated B cell (NF-κB), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) while upregulating the expression of inhibitor of nuclear kappa B alpha (IκB-α). SIGNIFICANCE: The present study strongly suggests that magnolol significantly suppressed post-incisional inflammatory nociceptive pain by targeting TRPV1/P2Y and TLR4/NF-κB signaling.

Association Between Helicobacter pylori Infection and the Risk of Pancreatic Cancer: A Systematic Review Based on Observational Studies.

Helicobacter pylori (H. pylori) bacterial infection has long been scrutinized as one of the potential risk factors for the development of pancreatic cancer with quite inconsistent and unequivocal data. Little is known about the risk factors involved with this malignancy. In this systematic review, we aimed to examine the relationship between H. pylori infection and pancreatic cancer based on the evidence from the existing observational studies across the world. We searched major electronic databases such as PubMed, MEDLINE, Science Direct, and Cochrane Library. After a careful and thorough screening process, we selected 15 observation studies for this systematic review. Six of 15 studies found a significant association between H. pylori infection and pancreatic cancer. Additionally, four of these studies found a significant relationship between the cytotoxin-associated gene A strain of H. pylori and pancreatic cancer. Based on the evidence from the selected studies, a weak association was observed between H. pylori infection and cancer of the pancreas, especially in European and Asian populations compared to the North American population. The cross-sectional evidence from the case-control studies only suggests the existence of an association but does not provide substantial evidence of the causative relationship. Further large-scale, prospective cohort studies are warranted in the future to understand this contradictory relationship better.

A Systematic Review on Whether an Association Exists Between Adolescent Obesity and Idiopathic Intracranial Hypertension.

Pseudotumor cerebri syndrome (PTCS)/idiopathic intracranial hypertension (IIH) is a clinical presentation appertaining to signs/symptoms of raised intracranial pressure, like headache and papilledema. It is an uncommon but clinically significant cause of morbidity such as permanent vision loss. It is crucial to understand if idiopathic intracranial hypertension (IIH) is on the rise in adolescents, it is probably due to the rising prevalence of obesity worldwide. Our study aimed to find an association between obesity and IIH in adolescents. We utilized Preferred Reporting Items for Systematic Review and Meta-Analysis 2020 (PRISMA) guidelines to run this systematic review. Many publications related to the topic in the discussion were scrutinized through a comprehensive database search. We filtered them down to a final count of 10 articles after utilizing our inclusion/exclusion criteria and assessing the quality of work. In these final papers, we identified several possibilities to explain the link between obesity and IIH in adolescents. Overweight and obese adolescents were found to have a significantly increased risk of IIH development, with a more severe clinical picture seen in morbidly obese female patients.

Determining the Frequency of Acquired Cystic Kidney Disease in End Stage Renal Disease Patients on Hemodialysis at Dialysis Centre of Tertiary Care Hospital.

Objectives To determine the frequency of acquired cystic kidney disease (ACKD) among patients of end-stage renal disease. Methods This cross-sectional study was conducted at the University of Lahore Teaching Hospital after approval from the ethical review committee. About 150 patients with end-stage renal disease fulfilling the inclusion criteria and undergoing three hemodialysis sessions per week for six months were approached. The patients underwent ultrasonography by the same consultant radiologist and the presence of acquired polycystic kidney disease was noted in the proforma. Data was stratified for age, gender and duration of hemodialysis and the chi-square test was applied. Results The mean age of the study participants was 47.31±9.44 years and males were majority in number with 92 (61.3%). The acquired cystic kidney disease was noted in 20 (13%) participants. There was significant difference noted in different age groups as six (6.5%) patients in the 18-40 age group and 14 (24%) patients in the 40-80 age group have acquired kidney disease (p-value=0.002). No important association between ACKD, age, and gender were found. None of these patients had evidence of renal cell carcinoma, extrarenal cysts, retroperitoneal or intrarenal hemorrhage. Conclusion There was a significant correlation between acquired cystic kidney disease and the duration of hemodialysis, and the chances of the development of acquired cystic kidney disease rise progressively with increasing time on hemodialysis.