Innovative approaches to Alzheimer's therapy: Harnessing the power of heterocycles, oxidative stress management, and nanomaterial drug delivery system.

Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aß). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.

Targeted Cancer Stem Cell Therapeutics: An Update.

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.

Targeting Various Pathogenic Pathways for the Development of Antialzheimer's Drugs: An Update.

Alzheimer's disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid ß (Aß) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-ß, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters' balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases.

Bioelectricity production and xylene biodegradation through double chamber benthic microbial fuel cells fed with sugarcane waste as a substrate.

Xylene, a recalcitrant compound present in wastewater from activities of petrochemical and chemical industries causes chronic problems for living organisms and the environment. Xylene contaminated wastewater may be biodegraded through a benthic microbial fuel cell (BMFC) as seen in this study. Xylene was oxidized into intermediate 3-methyl benzoic acid and entirely converted into non-toxic carbon dioxide. The highest voltage of the BMFC reactor was generated at 410 mV between 23 and 90 days when cell potential was 1 kΩ. The reactor achieved a maximum power density of about 63 mW/m2, and a current of 0.4 mA which was optimized from variable resistance (20 Ω - 1 kΩ). However, the maximum biodegradation efficiency of the BMFC was at 87.8%. The cyclic voltammetry curve helped to determine that the specific capacitance was 0.124 F/g after 30 days of the BMFC operation. Furthermore, the fitting equivalent circuit was observed with the help of Nyquist plot for calculating overall internal resistance of 65.82 Ω on 30th day and 124.5 Ω on 80th day. Staphylococcus edaphicus and Staphylococcus sparophiticus were identified by 16S rRNA sequencing as the dominant species in the control and BMFC electrode, presumably associated with xylene biodegradation.

Electrodeposited Hybrid Biocathode-Based CO2 Reduction via Microbial Electro-Catalysis to Biofuels.

Microbial electrosynthesis is a new approach to converting C1 carbon (CO2) to more complex carbon-based products. In the present study, CO2, a potential greenhouse gas, was used as a sole carbon source and reduced to value-added chemicals (acetate, ethanol) with the help of bioelectrochemical reduction in microbial electrosynthesis systems (MES). The performance of MES was studied with varying electrode materials (carbon felt, stainless steel, and cobalt electrodeposited carbon felt). The MES performance was assessed in terms of acetic acid and ethanol production with the help of gas chromatography (GC). The electrochemical characterization of the system was analyzed with chronoamperometry and cyclic voltammetry. The study revealed that the MES operated with hybrid cobalt electrodeposited carbon felt electrode yielded the highest acetic acid (4.4 g/L) concentration followed by carbon felt/stainless steel (3.7 g/L), plain carbon felt (2.2 g/L), and stainless steel (1.87 g/L). The alcohol concentration was also observed to be highest for the hybrid electrode (carbon felt/stainless steel/cobalt oxide is 0.352 g/L) as compared to the bare electrodes (carbon felt is 0.22 g/L) tested, which was found to be in correspondence with the pH changes in the system. Electrochemical analysis revealed improved electrotrophy in the hybrid electrode, as confirmed by the increased redox current for the hybrid electrode as compared to plain electrodes. Cyclic voltammetry analysis also confirmed the role of the biocatalyst developed on the electrode in CO2 sequestration.

Advancement in Benthic Microbial Fuel Cells toward Sustainable Bioremediation and Renewable Energy Production.

Anthropogenic activities are largely responsible for the vast amounts of pollutants such as polycyclic aromatic hydrocarbons, cyanides, phenols, metal derivatives, sulphides, and other chemicals in wastewater. The excess benzene, toluene and xylene (BTX) can cause severe toxicity to living organisms in wastewater. A novel approach to mitigate this problem is the benthic microbial fuel cell (BMFC) setup to produce renewable energy and bio-remediate wastewater aromatic hydrocarbons. Several mechanisms of electrogens have been utilized for the bioremediation of BTX through BMFCs. In the future, BMFCs may be significant for chemical and petrochemical industry wastewater treatment. The distinct factors are considered to evaluate the performance of BMFCs, such as pollutant removal efficiency, power density, and current density, which are discussed by using operating parameters such as, pH, temperature and internal resistance. To further upgrade the BMFC technology, this review summarizes prototype electrode materials, the bioremediation of BTX, and their applications.

Insights into Advancements and Electrons Transfer Mechanisms of Electrogens in Benthic Microbial Fuel Cells.

Benthic microbial fuel cells (BMFCs) are a kind of microbial fuel cell (MFC), distinguished by the absence of a membrane. BMFCs are an ecofriendly technology with a prominent role in renewable energy harvesting and the bioremediation of organic pollutants through electrogens. Electrogens act as catalysts to increase the rate of reaction in the anodic chamber, acting in electrons transfer to the cathode. This electron transfer towards the anode can either be direct or indirect using exoelectrogens by oxidizing organic matter. The performance of a BMFC also varies with the types of substrates used, which may be sugar molasses, sucrose, rice paddy, etc. This review presents insights into the use of BMFCs for the bioremediation of pollutants and for renewable energy production via different electron pathways.

Bio-Mediated Synthesis of Reduced Graphene Oxide Nanoparticles from Chenopodium album: Their Antimicrobial and Anticancer Activities.

A novel method of preparing reduced graphene oxide (RGOX) from graphene oxide (GOX) was developed employing vegetable extract, Chenopodium album, as a reducing and stabilizing agent. Chenopodium album is a green leafy vegetable with a low shelf life, fresh leaves of this vegetable are encouraged to be used due to high water content. The previously modified 'Hummers method' has been in practice for the preparation of GOX by using precursor graphite powder. In this study, green synthesis of RGOX was functionally verified by employing FTIR and UV-visible spectroscopy, along with SEM and TEM. Our results demonstrated typical morphology of RGOX stacked in layers that appeared as silky, transparent, and rippled. The antibacterial activity was shown by analyzing minimal inhibitory concentration values, agar diffusion assay, fluorescence techniques. It showed enhanced antibacterial activity against Gram-positive and Gram-negative bacteria in comparison to GOX. It has also been shown that the synthesized compound exhibited enhanced antibiofilm activity as compared to its parent compound. The efficacy of RGOX and GOX has been demonstrated on a human breast cancer cell line, which suggested RGOX as a potential anticancer agent.

Tumor aggression among hepatitis-C related hepatocellular carcinoma patients: an observational study regarding the impact of anti-HCV therapy.

BACKGROUND: Hepatitis C virus (HCV) represents a major risk factor for hepatocellular carcinoma (HCC) development and anti-HCV therapy is a significant measure to reduce the incidence of HCC, however development of HCC in HCV treated patients is an emerging clinical problem which needs to be investigated. In this study we aim to analyze association between anti-HCV therapy and tumor pattern of HCV related HCC patients. METHODS: Hepatocellular Carcinoma (HCC) patients with seropositivity for hepatitis C virus (HCV) antibodies, registered at three tertiary care hospitals of Rawalpindi and Islamabad, Pakistan during August 2017 to July 2018 were enrolled. Selected patients were then segregated in two groups on the basis of their HCV treatment history i.e., "TN" (HCV Treatment Naïve i.e. having no history/medical record for treatment prior to HCC diagnosis) and "TH" (Treated for HCV infection). Aggressiveness index (AgI) scoring system was applied to determine the tumor pattern. Univariate and multivariate analysis was carried out to analyze the independent effect of anti-HCV therapy on tumor pattern. RESULTS: Out of 234 consecutive HCC patients, 171 HCV-related HCC patients were enrolled in final analysis and labeled as "TN" (n = 120) and "TH" (n = 51). Tumor pattern was found to be significantly aggressive (P = 0.02) in the treated cohort with an adjusted odds of 2.47 for aggressive and 6.92 for highly aggressive tumor. Neutrophil to lymphocyte ratio (NLR) was strongly associated with highly aggressive tumor pattern (P = 0.012). Patients in TN group were found to be marginally older than those in the TH group (59.5 vs. 55 years) where mean age of the patients treated with direct acting anti-viral agents was found to be visibly lower than mean age of patients who received interferon based treatment (53.5 vs. 57 years) with significant masculine predominance (62.1 vs. 37.9%, P = 0.049). CONCLUSION: We observed raised neutrophil to lymphocyte ratio and prominence of younger age with aggressive tumor biology in HCV treated HCC patients. These observations highlight the need for a longitudinal prospective study on HCV positive subjects treated with antivirals, irrespective of treatment response.

Nrf2 protein as a therapeutic target during diethylnitrosamine-induced liver injury ameliorated by ß-carotene-reduced graphene oxide (ßC-rGO) nanocomposite.

Oxidative stress plays a central role in the incidence of liver injury. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a key protein regulator of antioxidant response elements (ARE)-mediated gene expression. Thus, Nrf2 can be regarded as a plausible therapeutic target during liver injury. ß-Carotene is implicated as one of the important antioxidant with diverse health benefits. The delivery of ß-carotene to the target tissue has been debatable due to its low bioavailability, poor water solubility and instability. Here, a nanocomposite of ß-carotene with reduced graphene oxide (ßC-rGO) has been developed to demonstrate its pronounced effect in regulating Nrf2 to trigger protection against diethylnitrosamine (DEN)-induced hepatic fibrosis in rats. The rGO and ßC-rGO samples were characterised by scanning electron microscopy (SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy. Progress of disease was monitored through ultrasonography, in vitro liver and serum biochemistry (alanine transaminase, aspartate transaminase, alkaline phosphatase, bilirubin, lipid peroxidation, protein carbonyls, superoxide dismutase, catalase, glutathione-S-transferase, Nrf2, vitamin-A, retinol dehydrogenase), histopathology, confocal and ultrastructural studies. In fibrotic animals liver biochemistry was significantly altered along with massive changes in liver anatomy. ßC-rGO ameliorates experimental fibrogenesis and restores liver functioning due to increased availability of ß-carotene in the liver. It is suggested that ßC-rGO nanocomposite promotes cellular antioxidant status via upregulation of Nrf2 protein factor and invigorate hepatic stellate cells (HSCs) through restoring vitamin-A.

Electrochemical paper based cancer biosensor using iron oxide nanoparticles decorated PEDOT:PSS.

We report results of the studies relating to the fabrication of a label-free, flexible, light weight and disposable conducting paper based immunosensing platform comprising of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) and nanostructured iron oxide (nFe2O3@PEDOT:PSS) nanocomposite for detection of carcinoembryonic antigen (CEA), a cancer biomarker. The effect of various solvents such as sorbitol, ethanol, propanol, n-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO) on the electrical conductivity of Whatman filter paper (WP) modified with nFe2O3@PEDOT:PSS/WP was investigated. The electrical conductivity of the PEDOT:PSS/WP electrode was found to be enhanced by two orders of magnitude (from 6.8× 10-4 to 1.92 × 10-2 Scm-1) after its treatment with DMSO. Further, nFe2O3 doped PEDOT:PSS/WP electrode exhibited the electrical conductivity as 2.4 × 10-2 Scm-1. Besides this, the incorporation of iron oxide nanoparticles (nFe2O3) into PEDOT:PSS/WP resulted in improved electrochemical performance and signal stability. This nFe2O3@PEDOT:PSS/WP based platform was used for immobilization of the anti-carcinoembronic antigen (anti-CEA) protein for quantitative estimation of cancer biomarker (CEA). The results of electrochemical response studies revealed that this conducting paper based immunoelectrode had a sensitivity of 10.2 µAng-1mLcm-2 in the physiological range (4-25 ngmL-1) and shelf life of 34 days. Further, the proposed immunoelectrode was validated with conventional ELISA for the detection of CEA in serum samples of cancer patients.

Synthesis, acute toxicity, analgesic activity and cytotoxicity of Some bisthiourea derivatives.

Bisthiourea derivatives were synthesized by the reaction of benzoylisothiocyanate and diamines to give 1,2-Bis(N'-benzoylthioureidobenzene (1), 1,3-di(benzoylthioureido)benzene (2) and 1,4-di(benzoylthioureido)benzene (3) in acetone. Acute toxicity study revealed that LD50 of compound (1) and (3) is 120 mg/kg body weight. Visceral pain induced by injecting i.p acetic acid in mice were strongly inhibited by all the compounds. 94.65, 95.25 and 85.54% analgesic activity were observed in compounds (1), (2) and (3) at 15 mg/kg and (2) and (3) shows 97.63 and 96.42% at 30 mg/kg body weight respectively while (1) gives 100% analgesic activity. 100% cytotoxicity was observed in compounds (2) and (3) and 96% in compound (1) at 750 ppm. The results suggest that these compounds may have potential values for treatment of cancer and painful disorders.

Ultrasonographic pattern of plasma leak in dengue haemorrhagic fever.

OBJECTIVE: To note ultrasonographic findings used for diagnosing plasma leakage in dengue haemorrhagic fever patients. METHODS: The observational retrospective study was conducted at the Holy Family Hospital, Rawalpindi and comprised records of patients with confirmed dengue infection who were screened for dengue haemorrhagic fever according to Dengue Expert Advisory Group criteria from July 1 to December 31, 2013. Each patient underwent ultrasonography for the detection of ascites, gall bladder wall thickness, pleural and/or pericardial effusion along with their quantification and localisation. RESULTS: Of the 240 patients, 166(69.2%) were men. The overall mean age was 28.9±12.4 years. Of the total, 215(89.5%) had ultrasonographic abnormalities, suggestive of plasma leakage. Quantification and localisation wise, mild abdominal ascites 68(47.2%), right pleural effusion 82(74.5%) and mild pleural effusion 98(89%) were commonly noted. None had pericardial effusion. CONCLUSIONS: Mild ascites and mild right pleural effusion were the commonest pattern of ultrasonographic leak in dengue haemorrhagic fever patients.

Early predictability of virological response in patients of chronic hepatitis-C with genotype-3, treated with pegylated interferon and ribavirin.

BACKGROUND: This study was conducted to assess the early predictability of virological response in chronic hepatitis-C patients (Genotype-3), treated with pegylated interferon alpha-2a and ribavirin with an objective of determining predictive values of Rapid Virological Response (RVR) and Early Virological Response (ETR) on Sustained Virological Response (SVR). METHOD: This cross sectional study was conducted in January 2014, at Holy Family Hospital, Rawalpindi by inclusion of 582 patients of chronic hepatitis being treated with Pegylated Interferon a 2b and ribavirin. Based on Polymerase Chain Reaction (PCR) for HCV RNA Qualitative on 4th, 12h and 24th week of treatment regimen, RVR, EVR and End treatment Response (ETR) was assessed respectively whereas 24th week post treatment PCR concluded as SVR. Effect of treatment was determined as proportions for responses in total and then compared for treatment naive, responders and relapsers to previous conventional therapy using Chi square test. Positive and Negative Predictive Values were also calculated. RESULTS: Qualitative PCR for HCV revealed that 281 (69.2%) achieved RVR where 60.3% attained SVR. PPV and NPV of RVR in study population were 67.41% and 44.45% respectively and 66.29% and 57.14% respectively for EVR..Statistically significant differences in RVR, EVR and ETR were observed in patients based on conventional treatment response. CONCLUSION: Attainment of RVR is a prospect to categorize patients appropriate for abridged treatment and this study supported the evidence that failure to achieve EVR was congruent with failure to achieve SVR.

Prophylaxis of DVT with enoxaparin in patients undergoing total knee replacement.

OBJECTIVE: To evaluate the efficacy and safety of the low molecular weight heparin as prophylaxis against thromboembolism following total knee replacement surgery. METHODS: Post-operative bilateral lower extremity colour duplex scan was performed on 55 patients subjected to total knew arthroplasty. The scan was performed 7 days after surgery for detection of DVT. All patients were given Enoxaparin 40mg subcutaneous daily for 2 weeks as prophylaxis against DVT. RESULTS: Two patients were diagnosed as DVT by color duplex scanning and both were distal but only one was asymptomatic. Another patient developed pulmonary embolism and died subsequently. The major and minor wound problems were seen in two and six patients respectively; nearly all complications were seen in obese patients. CONCLUSION: DVT is not a nonexistent entity in our population. Low molecular weight heparins are safe drugs but apparently the bleeding complications are more as compared to Western literature. Larger case control studies are required to determine the true efficacy and safety of LMWH.

Autoclaved tumor bone for reconstruction: an alternative in developing countries.

The options for reconstruction after excision of skeletal tumors include reimplanting the autoclaved tumor-bearing bone. We asked whether such bone will survive and unite with normal bone and whether the local tumor recurrence rate increases after its use. We ascertained the functional outcome (Musculoskeletal Tumor Society score) and complications in 19 patients. After wide excision, the bony segment was autoclaved at 120 degrees for 10 minutes and reimplanted at the original defect with intramedullary nails and compression plates. Twelve of our 19 patients were available for followup. The autoclaved segment united with the normal bone in 11 of the 12 patients. No patients had fracture or resorption of the autoclaved segment. Two patients had local tumor recurrence in nearby soft tissues, apparently unrelated to the autoclaved bone. The mean functional score was 70%. Complications included fatigue failure of the nail in one patient, superficial infection in three patients, and deep infection in two patients. Reconstruction with autoclaved tumor-bearing bone is a simple and effective tool in limb salvage. This technique is a cost-effective alternative for developing countries circumventing complications of prosthetic and allograft reconstruction.

A 12 years audit of upper gastrointestinal endoscopic procedures.

OBJECTIVE: Evaluation of upper gastrointestinal (GI) endoscopy in terms of indications, diagnostic efficacy, and diseases diagnosed. DESIGN: Retrospective, observational case series. PLACE AND DURATION OF STUDY: DHQ Teaching Hospital, Rawalpindi, from March 1990 to December 2001. SUBJECTS AND METHODS: Patients who underwent upper GI endoscopy in 12 years were included. Upper GI endoscopies were performed according to standard protocol. Endoscopic diagnoses were based on widely accepted criteria. RESULTS: Of the 8481 patients, 4935 (58.2%) were female and 3546 (41.8%) male. Mean patient age was 40.5 years. Dyspepsia (42.6%), upper GI bleed (32.8%), and evaluation of chronic liver disease (10.2%) were common indications of the procedure. An endoscopic diagnosis was possible in 82.6% patients. Varices, gastritis, duodenitis, and combined lesions were common endoscopic diagnosis. Gastritis and duodenitis were most frequent causes of upper GI bleed. We noted more gastric ulcers compared to duodenal ulcers. Females had significantly more normal endoscopies, p-value=0.02. CONCLUSION: Upper GI endoscopy is an effective procedure. Dyspepsia evaluation is commonest indication for upper GI endoscopy in our patients. Etiology of upper GI bleed, and incidence of duodenal ulcer compared to gastric ulcer in our patients are different than described in literature. Females have significantly more normal endoscopies.