The fork remodeler helicase-like transcription factor in cancer development: all at once.

The Helicase-like Transcription Factor (HLTF) is a member of the SNF2-family of fork remodelers, primarily studied for its capacity to provide DNA Damage Tolerance (DDT) and to induce replication fork reversal (RFR). HLTF is recruited at stalled forks where both its ATPase motor and HIP116 Rad5p N-terminal (HIRAN) domains are necessary for regulating its interaction with DNA. HIRAN bestows specificity to ssDNA 3'-end and imparts branch migration as well as DNA remodeling capabilities facilitating damage repair. Both expression regulation and mutation rate affect HLTF activity. Gene hypermethylation induces loss of HLTF function, in particular in colorectal cancer (CRC), implying a tumour suppressor role. Surprisingly, a correlation between hypermethylation and HLTF mRNA upregulation has also been observed, even within the same cancer type. In many cancers, both complex mutation patterns and the presence of gene Copy Number Variations (CNVs) have been reported. These conditions affect the amount of functional HLTF and question the physiological role of this fork remodeler. This review offers a systematic collection of the presently strewed information regarding HLTF, its structural and functional characteristics, the multiple roles in DDT and the regulation in cancer progression highlighting new research perspectives.

Incidence of surgical site infection following open hernioplasty and comparison of infection rate among ventral and groin hernia repairs at a THQ hospital Lahore: a single surgeon experience.

OBJECTIVE: To determine the incidence of surgical site infection following open hernioplasty, and to compare the infection rate among ventral and groin hernia repairs. Method: The retrospective study was conducted from April 2 to November 30, 2021, at the Government Tehsil Headquarter Hospital Sabzazar, Lahore, Pakistan, and comprised data form June 2018 to December 2020 of patients with ventral abdominal and groin hernia. All patients underwent hernioplasty by a single consultant surgeon and were discharged within 2 days of surgery. Surgical-site infections were recorded on follow-up visits up to 30 days of operation, and were compared between ventral and groin hernia cases. Data was analysed using SPSS 22. RESULTS: Of the 218 patients with mean age 37.07±4.94 years, 117(53.67%) were males, 108(49.54%) smokers and 127(58.25%) hypertensive, while 110(50.45%) had ventral abdominal hernia and 108(49.54%) had groin hernias. Mean operative time and mean hospital stay were 56.53±6.20 minutes and 3.06±1.31days, respectively. Mean wound drainage in abdominal hernia cases was 8.99±2.02 days. Surgical site infection incidence following open hernioplasty was 2(0.91%). Infection rate among ventral abdominal and groin hernioplasty were 1(0.90%) and 1(0.92%) (p=0.50). CONCLUSIONS: Incidence of surgical site infection following open hernioplasty showed no significant difference between ventral abdominal and groin hernia repairs.

Inhibition of poly (ADP-ribose) Polymerase-1 (PARP-1) improves endothelial function in pulmonary hypertension.

Endothelial dysfunction is critical in the pulmonary vasculature during pulmonary hypertension (PH). Moreover, in PH, increased inflammation and oxidative/nitrosative stress cause DNA damage, activating poly (ADP-ribose) polymerase-1 (PARP-1). Meloche et al. (2014) and our previous research have shown that inhibiting PARP-1 is protective in PH and associated RV hypertrophy. However, the role of PARP-1 in pulmonary arterial endothelial dysfunction has not been explored completely. Therefore, the current study aims to investigate the involvement of PARP-1 in endothelial dysfunction associated with PH. Hypoxia (1% O2) was used to induce a PH-like phenotype in human pulmonary artery endothelial cells (HPAECs), and PARP-1 inhibition was achieved via siRNA (60 nM). For the in vivo study, male Sprague Dawley rats were administered monocrotaline (MCT; 60 mg/kg, SC, once) to induce PH, and 1, 5-isoquinolinediol (ISO; 3 mg/kg) was administered daily intraperitoneally to inhibit PARP-1. PARP-1 inhibition decreased proliferation and inflammation, as well as improved mitochondrial dysfunction in hypoxic HPAECs. Furthermore, PARP-1 inhibition also promoted apoptosis by increasing DNA damage in hypoxic HPAECs. In addition, inhibition of PARP-1 reduced cell migration, VEGF expression, and tubule formation in hypoxic HPAECs. In in vivo studies, PARP-1 inhibition by ISO significantly decreased the RVP and RVH as well as improved endothelial function by increasing the pulmonary vascular reactivity and expression of p-eNOS in MCT-treated rats.

Pyrroloquinoline quinone (PQQ) improves pulmonary hypertension by regulating mitochondrial and metabolic functions.

Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs), inflammation, as well as mitochondrial and metabolic dysregulation, contributes to the development of pulmonary hypertension (PH). Pyrroloquinoline quinone (PQQ), a potent natural antioxidant with anti-diabetic, neuroprotective, and cardioprotective properties, is known to promote mitochondrial biogenesis. However, its effect on cellular proliferation, apoptosis resistance, mitochondrial and metabolic alterations associated with PH remains unexplored. The current study was designed to investigate the effect of PQQ in the treatment of PH. Human pulmonary artery smooth muscle cells (HPASMCs), endothelial cells (PAECs), and primary cultured cardiomyocytes were subjected to hypoxia to induce PH-like phenotype. Furthermore, Sprague Dawley (SD) rats injected with monocrotaline (MCT) (60 mg/kg, SC, once) progressively developed pulmonary hypertension. PQQ treatment (2 mg/kg, PO, for 35 days) attenuated cellular proliferation and promoted apoptosis via a mitochondrial-dependent pathway. Furthermore, PQQ treatment in HPASMCs prevented mitochondrial and metabolic dysfunctions, improved mitochondrial bioenergetics while preserving respiratory complexes, and reduced insulin resistance. In addition, PQQ treatment (preventive and curative) significantly attenuated the increase in right ventricle pressure and hypertrophy as well as reduced endothelial dysfunction and pulmonary artery remodeling in MCT-treated rats. PQQ also prevented cardiac fibrosis and improved cardiac functions as well as reduced inflammation in MCT-treated rats. Altogether, the above findings demonstrate that PQQ can attenuate mitochondrial as well as metabolic abnormalities in PASMCs and also prevent the development of PH in MCT treated rats; hence PQQ may act as a potential therapeutic agent for the treatment of PH.

Cissus quadrangularis extract mitigates diabetic cardiomyopathy by inhibiting RAAS activation, inflammation and oxidative stress.

BACKGROUND: Diabetic cardiomyopathy (DCM) is an age-related disease, and its progression is accompanied by hyperglycaemia, cardiac dysfunction, and myocardial structural and functional abnormalities. Cissus quadrangularis, a traditional medicinal plant, contains polyphenols, flavonoids, phytosterols, carbohydrates and ascorbic acid. It is used to treat osteoporosis, asthma, haemorrhoids and menstrual disorders.Objective: In the current research, we have investigated the effect of ethanolic extract of C. quadrangularis (EECQ) against a high-fat diet (HFD)/streptozotocin-induced DCM by estimating cardiac biomarkers, inflammatory markers and Reactive oxygen species (ROS) production. MATERIAL AND METHODS: Rats were fed with an HFD for 12 weeks, followed by single-shot low-dose streptozotocin (35 mg/kg; i.p.). The treatment was performed by EECQ (200 mg/kg/day, orally) for six weeks. RESULTS: The extract EECQ improves glucose, insulin tolerance tests and hypercholesteremia. DCM is characterized by cardiac dysfunction, cardiac biomarkers CKMB and LDH, which were attenuated by the EECQ treatment. The hypertrophic biomarker ANP, BNP expression and cardiomyocyte surface area were decreased by EECQ. Moreover, EECQ also alleviated the biomarkers Angiotensin II and renin level. EECQ also reduced oxidative stress, ROS production and cardiac inflammation. CONCLUSIONS: Thus, these findings suggested that EECQ could be used as a possible therapeutic regiment to treat DCM.

Cissus quadrangularis ameliorates hyperglycaemia, hyperinsulinemia and hyperlipidaemia.Cissus quadrangularis mitigates cardiac dysfunction.Cissus quadrangularis decreases RAAS activation, thereby down-regulates ANP, BNP expression.Cissus quadrangularis alleviates ROS propagated oxidative stress and apoptosis.

Modeling mortality rates and environmental degradation in Asia and the Pacific: does income group matter?

This two-dimensional study makes significant incursions into the health-environment literature by interrogating whether non-renewable energy moderates the impact of environmental degradation on mortality rates. It further aligns with the 2030 United Nations Sustainable Development Goals and 11, which aim to ensure healthy lives and promote well-being for all at all ages and make cities and human settlements inclusive, safe, resilient and sustainable. It contributes to the health-environment literature by investigating the intrinsic relationships among mortality rates, carbon emissions (environmental degradation), and non-renewable energy consumption. The study uses an unbalanced sample of 42 Asia and Pacific countries to determine (1) whether carbon emissions exaggerate the incidence of mortality rates and (2) if the interaction of non-renewable energy with carbon emissions enhances or alters the impact of carbon emissions on mortality rates. Consistent findings from the panel spatial correlation consistent least-squares dummy variables (PSCC-LSDV) and two-step system generalized method of moments (GMM) techniques reveal that (i) carbon emissions exacerbate mortality rates; (ii) non-renewable energy consumption exhibit mortality-reducing properties; (iii) non-renewable energy attenuates the impact of carbon emissions on mortality rates, (iv) persistency in mortalities occurs; and (v) the health-environment-energy dynamics differ across income groups. The paper's conjecture is expected to channel a new line of discourse on how non-renewable energy influences the environment and health outcomes.

Involvement of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2) in endothelial dysfunction associated with pulmonary hypertension.

AIMS: Increased proliferation, inflammation, and endothelial microparticle (EMP) generation in the pulmonary vasculature lead to endothelial dysfunction in pulmonary hypertension (PH). Interestingly, MK2, a downstream of p38MAPK, is a central regulator of inflammation, proliferation, and EMP generation in cardiovascular diseases. However, the role of MK2 in pulmonary endothelial dysfunction remains unexplored. MAIN METHODS: The Human Pulmonary Artery Endothelial cells (HPAECs) were exposed to hypoxia (1% O2) for 72 h, and MK2 inhibition was achieved by siRNA treatment. Western blotting, qualitative RT-PCR, immunocytochemistry, flow cytometry and enzyme-linked immunoassays were conducted to study pathological alterations and molecular mechanisms. Neoangiogenesis was studied using cell migration and tubule formation assays. For in vivo study, Male Sprague Dawley rats and MK2 knock-out mice with littermate control were treated with monocrotaline (MCT) 60 mg/kg and 600 mg/kg, respectively (s.c. once in rat and weekly in mice) to induce PH. MMI-0100 (40 µg/kg, i.p. daily for 35 days), was administered in rats to inhibit MK2. KEY FINDINGS: MK2 inhibition significantly decreased inflammation, cell proliferation, apoptosis resistance, and improved mitochondrial functions in hypoxic HPAECs. Hypoxia promoted cell migration, VEGF expression, and angiogenesis in HPAECs, which were also reversed by MK2 siRNA. MK2 inhibition decreased EMP generation and increased the expression of p-eNOS in hypoxic HPAECs, a marker of endothelial function. Furthermore, MK2 deficiency and inhibition both reduced the EMP generation in mice and rats, respectively. SIGNIFICANCE: These findings proved that MK2 is involved in endothelial dysfunction, and its inhibition may be beneficial for endothelial function in PH.

Deep Learning Approach for Discovery of In Silico Drugs for Combating COVID-19.

Early diagnosis of pandemic diseases such as COVID-19 can prove beneficial in dealing with difficult situations and helping radiologists and other experts manage staffing more effectively. The application of deep learning techniques for genetics, microscopy, and drug discovery has created a global impact. It can enhance and speed up the process of medical research and development of vaccines, which is required for pandemics such as COVID-19. However, current drugs such as remdesivir and clinical trials of other chemical compounds have not shown many impressive results. Therefore, it can take more time to provide effective treatment or drugs. In this paper, a deep learning approach based on logistic regression, SVM, Random Forest, and QSAR modeling is suggested. QSAR modeling is done to find the drug targets with protein interaction along with the calculation of binding affinities. Then deep learning models were used for training the molecular descriptor dataset for the robust discovery of drugs and feature extraction for combating COVID-19. Results have shown more significant binding affinities (greater than -18) for many molecules that can be used to block the multiplication of SARS-CoV-2, responsible for COVID-19.

Antihypertensive Effect of a Novel Angiotensin II Receptor Blocker Fluorophenyl Benzimidazole: Contribution of cGMP, Voltage-dependent Calcium Channels, and BKCa Channels to Vasorelaxant Mechanisms.

Background: The current study presents the novel angiotensin II receptor blocker fluorophenyl benzimidazole (FPD) as an antihypertensive agent in the SHR model of hypertension. We investigated the role of cGMP, voltage-dependent L-type calcium channels, and BKCa channels in the vasorelaxant mechanisms of FPD in the rat superior mesenteric artery. Methods: The antihypertensive effect of FPD was examined using an invasive technique measuring blood pressure in SHR animals. Using a myograph, tension measurement was completed in the superior mesenteric artery to elucidate the mechanisms of vasorelaxation involving AT1 receptors, the NO/cGMP pathway, L-type calcium channels, and BKCa channels. Ion flux (Ca2+, K+) studies were conducted in aortic smooth muscle cells. Putative targets proteins were determined by in silico docking studies. A safety evaluation of FPD was carried out using Swiss albino mice. Results: FPD significantly decreased blood pressure in SHR. It relaxed superior mesenteric arteries in a concentration-dependent manner and significantly inhibited angiotensin II-induced contraction. The relaxation response was also mediated by an increase in tissue cGMP levels, inhibition of L-type calcium channels, and the opening of BKCa channels. FPD further enhanced efflux of K+ and inhibited Bay K8644-stimulated Ca2+ influx in aortic smooth muscle cells and docked well in an in silico study with the targets. It was well tolerated in the toxicity study. Conclusion: The present study reports the antihypertensive activity of novel AT-1 receptor blocker FPD at 50 and 100 mg kg-1 with cGMP, L-type calcium channels, and BKCa channels as putative targets of vasorelaxation, and was found safe in oral toxicity.

Inhibition of Mitogen-Activated Protein Kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension.

[Figure: see text].

Percutaneous trans-ulnar versus trans-radial arterial approach for coronary angiography and angioplasty, a preliminary experience at an Egyptian cardiology center.

BACKGROUND: Trans-ulnar approach was proposed primarily for elective procedures in patients not suitable for trans-radial approach that was introduced two decades ago. The trans-ulnar approach is as safe and effective as the trans-radial approach for coronary angiography and intervention. AIM: This study's aim was to assess the feasibility and safety of the trans-ulnar approach in coronary procedures as a preliminary experience for operators experienced in trans-radial approach with no/minimal trans-ulnar approach experience at an Egyptian center. RESULTS: Vascular access in 120 patients was selected randomly for coronary angiography and angioplasty-80 through radial and 40 through ulnar approach. Patients were examined for local complications and Doppler evaluation to both radial and ulnar arteries a day after the procedure was done. Ulnar approach success was 82.5% versus 93.7% in the radial group; failure of ulnar artery puncture was the only cause of crossover in the ulnar group, while occurrence of persistent spasm was the leading cause of crossover in the radial group followed by radial artery tortuosity. The procedure time of coronary angiography and percutaneous coronary intervention of the ulnar group was significantly higher than that of the radial group (P value = 0.011 and 0.034, respectively). The mean caliber of the right ulnar artery was 2.45 ± 0.38, slightly larger than that of the radial artery 2.33 ± 0.38 at the level of the wrist, but this difference was statistically non-significant. CONCLUSION: Our study demonstrated that ulnar access with experienced radial operators and in our patients is a safe and practical approach for coronary angiography or angioplasty, without any major complications. Bearing in mind its high success rate, it can be used when a radial artery is not useful for the catheterization or as a default approach on the expense of slightly longer procedural time.

Organic Polymer and Metal Nano-particle Based Composites for Improvement of the Analytical Performance of Electrochemical Biosensors.

Metal nanoparticles (NPs) are described in the nanoscale and made from either pure metals or their compounds such as oxides. Metallic NPs have certain indistinct functional groups due to which these can bind with any type of ligand, antibody and drugs. Organic polymers, which conduct electricity, are called conducting polymers (intrinsically conducting polymers). They behave like semiconductors by exhibiting metallic conductivity. Process-ability is the major advantage of conducting polymers. Nanocomposite is a novel material having nano-fillers scattered in a matrix with morphology and interfacial characteristics of nano-composites including their individual property that influence their characteristics. Conducting polymers and NP composites can enhance the rate of electron transport between the current collector material (electrode) and the electrolyte; therefore they have been employed in the construction of improved electrochemical sensors such as amperometric, catalytic and potentiodynamic affinity sensors.

Involvement of fatty acid synthase in right ventricle dysfunction in pulmonary hypertension.

Apart from pulmonary vascular resistance and right ventricle (RV) hypertrophy, metabolic dysfunction also plays a major role in pathophysiology of pulmonary hypertension (PH). Recently, we have shown that fatty acid synthase (FAS), an enzyme involved in de novo fatty acid synthesis, plays a pivotal role in PH as its inhibition was protective and decreased pulmonary vascular remodelling, RV pressure and hypertrophy and improved endothelial functions. However, the precise mechanism behind protective effect of FAS inhibition on right ventricle dysfunction associated with PH is not completely understood. Therefore, the present study delineated the mechanism of protective effect of FAS inhibition on RV dysfunction associated with PH. siRNA mediated inhibition of FAS reduced FAS expression, hypertrophy, inflammation, apoptosis, autophagy and improved the glucose oxidation, mitochondrial membrane potential and ATP level in hypoxic cardiomyocytes. In monocrotaline (MCT) treated rats, FAS inhibition by C75 (2 mg/kg, i.p., once a week from 21 to 35 days) decreased the expression and activity of FAS and palmitate level. C75 also improved cardiac functions and mitochondrial membrane potential leading to decreased apoptosis in RV of MCT treated rats. In conclusion, our study reveals that inhibition of FAS decreases RV hypertrophy and improves cardiac function associated with PH by perking up metabolic functions.

Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate exhibits antihypertensive activity in rats through increase in intracellular cGMP level and blockade of calcium channels.

We report here the antihypertensive and vasorelaxant potential of some steroidal and non-steroidal compounds identified through a library of compounds. All the novel analogues showed vasorelaxant potential in isolated rat aorta. The most potent lead neolignan1 (Diethyl-4,4'-dihydroxy-8,3'-neolign-7,7'-dien-9,9'-dionate) produced concentration dependent relaxation with [pD2 5.16±0.05; n=16 and Emax 96.97%±1.12%; n=16]. The neolignan1 relaxation is independent of endothelium and is sensitive to ODQ (1H-[1, 2, 4] oxadiazolo [4, 3-a] quinoxalin-1-one; a blocker of soluble guanylyl cyclase (sGC) which synthesizes cGMP (cyclic guanosine monophosphate)). ELISA analysis of treated arterial tissues showed concentration-dependent increase in cGMP level in treated tissues compared to control (2.03 and 7.16 fold of control at 10 and 30µM of neolignan1, respectively) and a synergistic increase in cGMP level by 26.66 fold compared to control when used in combination with sildenafil (10µM; a known inducer of cGMP level by selectively blocking cGMP specific phosphodiesterase 5). Our present study reports for the first time that neolignans produce relaxation in isolated rat aorta through increase in intracellular cGMP level. The ODQ resistant relaxation of neolignan1 is mediated by blockade of voltage dependent L-type calcium channel (VDCC) as observed in the experiment with CaCl2. Neolignan1 upon intravenous administration via tail vein in Spontaneously Hypertensive Rats (SHR) produced significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP). The present study concludes that neolignan1 exhibited antihypertensive potential in rats through rise in intracellular cGMP and blockade of VDCC.