Computational Bioprospecting Guggulsterone against ADP Ribose Phosphatase of SARS-CoV-2.

Coronavirus Disease-2019 (COVID-19) is a highly contagious disease caused by Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) classified the disease a as global public health hazard on 11 March 2020. Currently, there are no adequate measures to combat viral infections, including COVID-19, and the medication guidelines for the management of COVID-19 are dependent on previous findings from SARS-CoV and MERS-CoV research. Natural products have achieved widespread acceptance around the world as a means of enhancing healthcare and disease prevention. Plants are a potential source of antiviral factors such as flavonoids, phenolic acids, terpenoids, and others. Some of these agents exhibit a broad spectrum of antiviral activity. This study aimed to screen herbal leads for possible inhibitors of the SARS-CoV-2 ADP Ribose Phosphatase enzyme (ARP). Guggulsterone was found to be highly stabilized within the active site of the viral ARP enzyme by molecular dynamic simulation with very little fluctuation throughout the simulation timeframe of 100 ns. Thus, guggulsterone can be further used to develop a safe and competent medication for evolving therapy against SARS-CoV-2 in post-preclinical and clinical trials.

Epidermal growth factor receptor pathway mutation and expression profiles in cervical squamous cell carcinoma: therapeutic implications.

BACKGROUND: Cervical squamous cell carcinoma (CSCC) is a major cause of female mortality worldwide. This study has examined epidermal growth factor receptor (EGFR) pathway markers that represent actionable pharmacological targets. METHODS: HPV16 positive CSCCs (n = 105 patients) from Madhya Pradesh, India were screened for KRAS and PIK3CA mutations by PNA-clamp real-time PCR. Immunohistochemistry (IHC) was performed for EGFR, PIK3CA, PTEN, phospho-AKT, phospho-mTOR and phospho-44/42 MAPK (ERK1/2). RESULTS: KRAS mutations were detected in 0/91 (0%) and PIK3CA mutations in 19/95 (20.0%) informative specimens: exon 9, E542 (n = 3) and E545 (n = 15); exon 20, H1047R (n = 1). PIK3CA mutation detection was associated with older mean patient age [48.2 vs. 56.6 years (P = 0.007)] and with post-menopausal age: 5/45 (11.1%) patients <50 years vs. 14/50 (28.0%) patients ≥50 years (P = 0.045; OR = 3.11). EGFR expression was present in 60/101 (59.4%) CSCCs and was associated with PIK3CA mutation detection (P < 0.05) but not age (P > 0.05). EGFR and phospho-AKT staining showed associations with tumor grade and/or lymph node status (P < 0.05). Significant associations were not found for the other study markers (P > 0.05). CONCLUSION: These data show that PIK3CA mutation acquisition is related to patient age and EGFR expression. The absence of KRAS mutations supports the potential of anti-EGFR therapies for CSCC treatment. The relatively high PIK3CA mutation rates indicate that PI3K may be a therapeutic target for a significant subset of CSCC patients. Qualitatively distinct IHC staining profiles for the marker panel were noted patient to patient; however, across patients, consistent linear relationships between up- and downstream pathway markers were not observed. Evaluation of the expression status of potential cancer pathway targets may be of value in addition to molecular profiling for choosing among therapeutic options.

Human papillomavirus type distribution in invasive cervical cancers from Madhya Pradesh: implications for vaccination programs in central India.

Invasive cervical carcinoma (ICC) remains a leading cause of female mortality in India. There is a paucity of data about human papillomavirus (HPV) type distribution among ICCs from Central India. Formalin-fixed, paraffin-embedded ICC specimens (n=270 patients) from Madhya Pradesh state were screened for HPV by GP5/6 primer-based polymerase chain reaction followed by cycle sequencing and NCBI BLAST search. HPV was detected in 93.3% of the tumors. Thirteen types were detected: HPV16 (73.7%), HPV18 (11.9%), HPV45 (2.2%), HPV66 (1.5%), HPV35 (1.1%), and HPV56 (0.7%). HPV31, 51, 58, 59, 67, 82 and JEB2 were each seen in 1 case (0.4%). HPV16 was more common among women less than 40 yr than 40 yr or older (P=0.006), and HPV18 was more common in women aged 40 yr or older (P=0.013). Squamous cell carcinomas were more frequently HPV-positive than adenocarcinomas (P=0.01). HPV18 was more common in adenocarcinoma than in squamous cell carcinoma (P=0.02). These data contribute to the pan-India profile of HPV-type relationship to ICC and show the potential of current vaccines to greatly relieve (by up to 85.6%) the ICC burden in Central India. The findings are also suggestive that next-generation HPV vaccines might be designed on a regional basis rather than from compounded global data.

Molecular targets and therapeutic potential of baicalein: a review.

Aim: Researchers using herbs and natural products to find new drugs often prefer flavonoids because of their potential as antioxidants and anti-inflammatories. The planned review addressed baicalein research findings in detail. This manuscript provides a complete review of baicalein's potential pharmacological effects along with several molecular targets for better understanding of its therapeutic activities. Materials and methods: We targeted the review on in vitro and in vivo studies reported on baicalein. For this, the literature is gathered from the database available on search engines like PubMed, ScienceDirect, Scopus, and Google Scholar up to 21 December 2023. The keywords "Scutellaria baicalensis", "Oroxylum indicum", "Neuroprotective", "Cardioprotective", "Toxicity studies", and "Baicalein" were used to fetch the content. Results: Baicalein's molecular receptor binding approach has shown anticancer, antidiabetic, antimicrobial, antiaging, neuroprotective, cardioprotective, respiratory protective, gastroprotective, hepatic protective, and renal protective effects. The synergistic effects of this drug with other selective herbs are also contributed towards significant therapeutic potential. Conclusion: This systematic review article from a contemporary and scientific perspective offers fresh insight into S. baicalensis, O. indicum, and its bioactive component baicalein as a potential complementary medicine. Baicalein may be transformed into more efficacious and acceptable evidence-based medicine. However, we recommend more clinical and mechanistic approaches to confirm safety and efficacy of baicalein.

A Mechanistic Review on Therapeutic Potential of Medicinal Plants and their Pharmacologically Active Molecules for Targeting Metabolic Syndrome.

Metabolic syndrome (MetS) therapy with phytochemicals is an emerging field of study with therapeutic potential. Obesity, insulin resistance, high blood pressure, and abnormal lipid profiles are all components of metabolic syndrome, which is a major public health concern across the world. New research highlights the promise of phytochemicals found in foods, including fruits, vegetables, herbs, and spices, as a sustainable and innovative method of treating this illness. Anti-inflammatory, antioxidant, and insulin-sensitizing qualities are just a few of the many positive impacts shown by bioactive substances. Collectively, they alleviate the hallmark symptoms of metabolic syndrome by modulating critical metabolic pathways, boosting insulin sensitivity, decreasing oxidative stress, and calming chronic low-grade inflammation. In addition, phytochemicals provide a multimodal strategy by targeting not only adipose tissue but also the liver, skeletal muscle, and vascular endothelium, all of which have a role in the pathogenesis of MetS. Increasing evidence suggests that these natural chemicals may be useful in controlling metabolic syndrome as a complementary treatment to standard medication or lifestyle changes. This review article emphasizes the therapeutic potential of phytochemicals, illuminating their varied modes of action and their ability to alleviate the interconnected causes of metabolic syndrome. Phytochemical-based interventions show promise as a novel and sustainable approach to combating the rising global burden of metabolic syndrome, with the ultimate goal of bettering public health and quality of life.

Nanoparticle Polymers Influence on Cardiac Health: Good or Bad for Cardiac Physiology?

Cardiovascular diseases (CVD) are one of the leading causes of death and morbidity worldwide. Lifestyle modifications, medications, and addressing epidemiological factors have long been at the forefront of targeting therapeutics for CVD. Treatments can be further complicated given the intersection of gender, age, unique comorbidities, and healthcare access, among many other factors. Therefore, expanding treatment and diagnostic modalities for CVD is absolutely necessary. Nanoparticles and nanomaterials are increasingly being used as therapeutic and diagnostic modalities in various disciplines of biomedicine. Nanoparticles have multiple ways of interacting with the cardiovascular system. Some of them alter cardiac physiology by impacting ion channels, whereas others influence ions directly or indirectly, improving cellular death via decreasing oxidative stress.  While embedding nanoparticles into therapeutics can help enhance healthy cardiovascular function in other scenarios, they can also impair physiology by increasing reactive oxidative species and leading to cardiotoxicity. This review explores different types of nanoparticles, their effects, and the applicable dosages to create a better foundation for understanding the current research findings.

Revolutionizing clinical trials: the role of AI in accelerating medical breakthroughs.

Clinical trials are the essential assessment for safe, reliable, and effective drug development. Data-related limitations, extensive manual efforts, remote patient monitoring, and the complexity of traditional clinical trials on patients drive the application of Artificial Intelligence (AI) in medical and healthcare organisations. For expeditious and streamlined clinical trials, a personalised AI solution is the best utilisation. AI provides broad utility options through structured, standardised, and digitally driven elements in medical research. The clinical trials are a time-consuming process with patient recruitment, enrolment, frequent monitoring, and medical adherence and retention. With an AI-powered tool, the automated data can be generated and managed for the trial lifecycle with all the records of the medical history of the patient as patient-centric AI. AI can intelligently interpret the data, feed downstream systems, and automatically fill out the required analysis report. This article explains how AI has revolutionised innovative ways of collecting data, biosimulation, and early disease diagnosis for clinical trials and overcomes the challenges more precisely through cost and time reduction, improved efficiency, and improved drug development research with less need for rework. The future implications of AI to accelerate clinical trials are important in medical research because of its fast output and overall utility.

Pharmacokinetics and tissue distribution of hydrazinocurcumin in rats.

BACKGROUND: Curcumin, a natural polyphenol from Curcuma longa, is known to possess diversified pharmacological roles including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic properties; however, its bioavailability is severely limited due to its poor solubility, poor absorption, rapid metabolism, and significant elimination. Hydrazinocurcumin (HZC), a novel analogue of curcumin has been reported to overcome the limitations of curcumin and also possesses multiple pharmacological activities. The present study aimed to evaluate the unexplored pharmacokinetic profile of this agent in experimental rats. METHODS: Drug formulations were administered to the experimental animals via oral, intravenous and intraperitoneal routes. Blood samples were collected at different pre-determined time intervals to determine the pharmacokinetic parameters. To understand the biodistribution profile of HCZ, tissue samples were isolated from different groups of Sprague-Dawley rats at different time points. The pharmacokinetic parameters of HZC were evaluated after administration through oral (100 mg/kg), intraperitoneal (100 mg/kg) and intravenous (10 mg/kg) routes. RESULTS: Significantly (p < 0.05) higher total AUC along with maximum concentration were evident with intraperitoneal administration when compared to the results of oral administration at a similar dose. In addition, shorter time to peak was observed with intraperitoneal administration. These results revealed a faster rate and longer duration of absorption with intraperitoneal administration, which further resulted in enhanced absolute bioavailability of HZC (29.17%) when compared to 5.1% upon oral dosing. The obtained data from the pharmacokinetic study indicated that HZC was instantaneously distributed and moderately eliminated from body fluids. CONCLUSION: Based on the findings, it could be concluded that absorption of HZC is much higher via intraperitoneal route of administration compared to the oral administration.

Fine needle aspiration cytology in mediastinal myxoid liposarcoma: a case report.

BACKGROUND: The mediastinum is an uncommon site for liposarcoma, with <1 % of all tumors occurring in this site. CASE: A 40-year-old woman presented with superior vena caval syndrome. Radiologic investigations revealed the presence of a large soft tissue mass occupying the anterior and middle mediastinum. A computed tomography (CT)-guided fine needle aspiration cytology (FNAC) sample showed the presence of fibrillary myxoid material with arborizing blood vessels and atypical lipoblasts. A diagnosis of myxold liposarcoma was made, which was later confirmed on bistopathology. CONCLUSION: The mediastinum is a challenging area for FNAC, which is a useful tool for accurate diagnosis. Awareness of the presence of liposarcoma is important for its recognition.

Preoperative diagnosis of renal angiomyolipoma with fine needle aspiration cytology: a report of 3 cases.

BACKGROUND: Angiomyolipoma is a rare benign neoplasm, commonly involving the kidney. Preoperative diagnosis on fine needle aspiration cytology can confirm the diagnosis, reducing the chances of unnecessary surgery. CASES: We studied cases of renal angiomyolipoma (AML) presenting within 1 year with palpable renal masses confirmed on ultrasound to be of renal origin. Fine needle aspiration cytology (FNAC) smears showed a few cohesive syncytial fragments with adipocytes, spindle cells and isolated single cells with foamy cytoplasm; a diagnosis of AML was made. The diagnosis was confirmed on histopathology, which showed mature adipose tissue, tortuous and thick-walled blood vessels lacking elastic tissue lamina and bundles of smooth muscles that seemed to emanate from the blood vessels. CONCLUSION: A preoperative diagnosis of renal AML is of great importance for correct management. In fact, when the lesion is small and asymptomatic, a conservative approach may be considered. Partial nephrectomy is possible with masses < 5 cm. Preoperative FNAC along with computed tomographic findings and immunocytochemical analysis of FNAC smears with HNB-45 can confirm the diagnosis of AML, thus preventing unindicated nephrectomy.

Application of bleach method in diagnosis of extra-pulmonary tuberculosis.

Extra pulmonary tuberculosis (TB) comprises 15% of the total tuberculosis cases. Bleach concentration method for demonstration of Acid fast bacilli (AFB) has been recently described for sputum. The aim of this study is to apply this method for demonstration of AFB in material obtained from extra-pulmonary sites and to correlate with cytology and conventional Ziehl Neelsen (Z N) staining. A total of 55 samples were studied from clinically suspected cases of extrapulmonary TB which included, FNA lymph nodes (17), abscesses drained from various body parts (18), body fluids (18) and skin scrapping (2). All the samples were processed for routine cytology, conventional ZN staining and bleach method followed by ZN staining. Out of 55 samples, 24(43.40%) were indicative of tuberculosis on cytology, 12(21.8%) were positive for AFB on conventional ZN staining, while the positivity increased to 39(70.90%) by Bleach method. Bleach solution is inexpensive and readily available in hospitals and its application has been proved in pulmonary tuberculosis. However to the best of our knowledge this is a pioneer study applied to the extra-pulmonary samples and the results of the present study shows improved detection of AFB.

Attenuating effect of standardized lyophilized Cinnamomum zeylanicum bark extract against streptozotocin-induced experimental dementia of Alzheimer's type.

BACKGROUND: The Cinnamomum zeylanicum (CZ; family Lauraceae) bark, an important spice, has also been used traditionally for nervous stress, as a nervine tonic, and as a stimulant. Therefore, the present study was designed to evaluate the effect of the standardized lyophilized aqueous extract of CZ bark (LCZE) on learning and memory in rodents at 50, 100, and 200 mg/kg, p.o. dose levels against streptozotocin (STZ)-induced memory impairment. METHODS: LCZE was standardized based on the cinnamaldehyde content using high-performance thin-layer chromatography (HPTLC). The effect on learning and memory was evaluated using two widely used behavioral models, the Morris water maze (MWM) test and the object recognition test (ORT). The effect of LCZE on the acetylcholinesterase (AChE) activity and oxidative stress parameters in the cerebral cortex and hippocampus of rat brain was also evaluated. RESULTS: LCZE significantly (p<0.05) and dose-dependently attenuated STZ-induced cognitive deficit in both models in comparison to only STZ-treated animals. In the MWM test, LCZE (100 and 200 mg/kg) significantly decreased the transfer latency and increased the time spent by the animals in target quadrant. Similarly in the ORT, the LCZE-treated animals exhibited an improved discrimination between a familiar object and a novel object, indicating the reversal of STZ-induced memory impairment. LCZE also restored STZ-induced alteration in AChE activity and oxidative stress parameters in both brain parts. CONCLUSIONS: The results clearly indicate toward the memory-enhancing effect of LCZE, which could be due to the synergistic effect of anti-AChE and antioxidant activities.

Histomorphological Patterns of Endometrium in Infertility.

BACKGROUND: Endometrium is the most sensitive indicator of ovarian function and endometrial biopsy is one of the most important investigations in infertility. The current study was carried out to investigate the histomorphological patterns of endometrium in infertile women and to compare the results with other similar studies. MATERIALS AND METHODS: A cross-sectional study on 2,080 infertile women was carried out to find the incidence of various histomorphological patterns in hematoxylin-eosin stained sections of endometrium and compare them with other Indian studies. RESULTS: In the current study majority of cases (88.50 %) were of primary infertility; the highest number of cases was in the age group of 21-30 years and the oldest patient was of 50 years age. The various abnormalities observed were anovulatory endometrium (15.75 %), inadequate proliferative (1.90 %), inadequate secretory (9.52 %), glandulo-stromal disparity (GSD) (4.21 %), hyperplasia (1.10 %), and endometritis (1.63 %). In 3.0 % cases menstrual cycle history was not available and curettage was done at inappropriate period of the cycle in 11.63 %. Comparison with other studies revealed the results matching with some and differing with others. CONCLUSION: In the current study, anovulatory endometrium and luteal phase defect are the major causes of infertility, and tuberculous endometritis, non-specific endometritis and GSD are minor contributing factors. These are treatable causes. Premenstrual endometrial biopsy, if accompanied by information of menstrual cycle and date of biopsy, can be a very reliable diagnostic tool for hormonal dysfunction and intrinsic endometrial factors in infertility.

Intratumoral DNA content heterogeneity in breast carcinomas demonstrated by core punch tissue sampling and flow cytometry.

Further to advancements in instrumentation and fluorescent dye technologies, there has been a resurgence of interest in the flow cytometric assay of formalin-fixed, paraffin-embedded specimens. Here we present a novel, simple and effective alternative to whole block sectioning that allows selective multisampling of tissues within a specimen block and the investigation of intratumoral heterogeneity. Formalin-fixed, paraffin-embedded breast carcinoma specimens were core-punched using 1.0 mm diameter needles and assayed by flow cytometry using a modified Hedley method. Intratumoral heterogeneity for DNA index and per cent S-phase fraction was detected in 10 of 23 (44%) and 11 of 23 (47%) specimens respectively. Macro-level genomic heterogeneity is common in breast cancer even within a single surgical specimen block. Studies investigating the relationship of DNA content heterogeneity to other markers of genomic instability such as mutations, deletions, insertions and translocations are warranted.

Co-existing tubercular axillary lymphadenitis with carcinoma breast can falsely over-stage the disease--case series.

The synchronous occurrence of tuberculosis and carcinoma in breast is unusual. The simultaneous occurrence of both the diseases can complicate the neoplastic disease. The diagnosis and treatment of tuberculosis in a patient with cancer assumes importance as it can prevent high mortality in patients with co-existent disease and thereby create problems in treatment decision. Axillary lymph node enlargement in breast cancer patient is not always caused by metastatic tumour of the breast even in the ipsilateral axillary nodes. We present here six case reports as an example of tuberculous axillary lymphadenitis co-existing with invasive ductal carcinoma of the breast. Accurate diagnosis has helped in down-staging carcinoma of the breast and also in identifying curable disease.

Primary right atrial sarcoma.

Primary malignant tumors of heart are rare with unfavorable prognosis and are mostly diagnosed on autopsy. They have varied presentation and are difficult to diagnose. Most of the cases are benign and others are sarcomas. Here we present a case of primary cardiac sarcoma which had varied presentation and was undiagnosed due to non specific symptoms. Diagnosis of atrial tumor was confirmed on histopathological examination of tissue obtained after thoracotomy. Being inoperable, the patient was given palliative chemotherapy with which we could provide her a better quality of life.

Basal cell carcinoma over chest wall (sternum) treated with dufourmentel flap: report of a case with review of literature.

Basal cell carcinoma (BCC) is the most common malignancy of the skin, accounting for approximately 70-80% of all cutaneous cancers. The commonest site of basal cell carcinoma is the face; 80% arise above a line from the corner of the mouth to the ear lobe. The lifetime ultraviolet radiation damage is the most important factor in its pathogenesis, and the vast majority is observed on sun-exposed skin. BCCs can develop in sun-protected areas, but its occurrence is rare. Here we are reporting a case of rare site of BCC with review of literature in a 65-year-old male who presented with a lesion over anterior chest wall. A clinical diagnosis of BCC was made and patient was subjected to excision biopsy. Biopsy revealed it to be a BCC and it was treated with a Dufourmentel flap.

Immunohistochemical analysis of ER, PR, Her2 and CK5/6 in infiltrative breast carcinomas in Indian patients.

AIM: Breast cancer is biologically a heterogeneous disease. Patients with the same diagnostic profile have markedly different clinical outcomes. Gene expression studies identified distinct breast cancer subtypes that differ in prognosis. Aim is to identify the immunohistochemical subtypes of breast carcinoma and correlate the results with pathological features associated with adverse prognosis in our study population. METHOD: We included 107 consecutive cases of invasive breast carcinoma and sub classified using immunohistochemical staining for ER, PR, Her2, and CK5/6 into the following subtypes: luminal A, luminal B, basal-like, Her2(+) and unclassified. Associations between tumor subtypes and tumor characteristics were examined. RESULTS: The proportion of each subtype in our patient population was: luminal A 37.4%, luminal B 11.1%, Her2(+) 29% and basal-like 7.5%. The following variables were significantly associated with IHC breast cancer subtypes: patient age (p<0.05), overall histopathology grade (p<0.001), nuclear grade (p<0.005) and mitotic index (p<0.001). Her2(+) and basal like subtypes were associated with poor differentiation (p<0.01), higher nuclear grade (p<0.05) and high mitotic index (p<0.05). CONCLUSIONS: Our data show a higher proportion of patients in the study population undergo total mastectomy and harbor poorly differentiated, node positive tumors than reported. There was also a relatively high percentage of the Her2(+) subtype (29%).