AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.

Gut Microbiota Targeted Approach by Natural Products in Diabetes Management: An Overview.

PURPOSE OF REVIEW: This review delves into the complex interplay between obesity-induced gut microbiota dysbiosis and the progression of type 2 diabetes mellitus (T2DM), highlighting the potential of natural products in mitigating these effects. By integrating recent epidemiological data, we aim to provide a nuanced understanding of how obesity exacerbates T2DM through gut flora alterations. RECENT FINDINGS: Advances in research have underscored the significance of bioactive ingredients in natural foods, capable of restoring gut microbiota balance, thus offering a promising approach to manage diabetes in the context of obesity. These findings build upon the traditional use of medicinal plants in diabetes treatment, suggesting a deeper exploration of their mechanisms of action. This comprehensive manuscript underscores the critical role of targeting gut microbiota dysbiosis in obesity-related T2DM management and by bridging traditional knowledge with current scientific evidence; we highlighted the need for continued research into natural products as a complementary strategy for comprehensive diabetes care.

Paclitaxel and its semi-synthetic derivatives: comprehensive insights into chemical structure, mechanisms of action, and anticancer properties.

Cancer is a disease that can cause abnormal cell growth and can spread throughout the body. It is among the most significant causes of death worldwide, resulting in approx. 10 million deaths annually. Many synthetic anticancer drugs are available, but they often come with side effects and can interact negatively with other medications. Additionally, many chemotherapy drugs used for cancer treatment can develop resistance and harm normal cells, leading to dose-limiting side effects. As a result, finding effective cancer treatments and developing new drugs remains a significant challenge. However, plants are a potent source of natural products with the potential for cancer treatment. These biologically active compounds may be the basis for enhanced or less toxic derivatives. Herbal medicines/phytomedicines, or plant-based drugs, are becoming more popular in treating complicated diseases like cancer due to their effectiveness and are a particularly attractive option due to their affordability, availability, and lack of serious side effects. They have broad applicability and therapeutic efficacy, which has spurred scientific research into their potential as anticancer agents. This review focuses on Paclitaxel (PTX), a plant-based drug derived from Taxus sp., and its ability to treat specific tumors. PTX and its derivatives are effective against various cancer cell lines. Researchers can use this detailed information to develop effective and affordable treatments for cancer.

Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions.

BACKGROUND: High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes. METHODS: We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan-Meier methods to characterize 3-year breast cancer risk in patients without upgrade. RESULTS: Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5-23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8-22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3-26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%). CONCLUSIONS: Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

Unveiling the Mpox menace: exploring the intricacies of a zoonotic virus and clinical implications.

Mpox (formerly known as monkeypox) is an orthopoxvirus based zoonotic infection that induces a smallpox-like human illness. Since the Democratic Republic of the Congo reported the first human case of mpox in 1970, the disease has proliferated to other areas of Africa, predominantly the West, and Central, with instances recently confirmed outside of Africa. Reports of cases of mpox in 2022 have brought into light its re-emergence. Even though the smallpox vaccine protects against the mpox virus, new nonimmune generations contribute to the rising prevalence of the cases. People are coming into contact with potential hosts as a result of environmental factors, raising the probability of animal-to-human transmission. Mpox poses a more serious threat to previously unaffected nations as it is showing up in data provided by governmental bodies due to increased transmission risk brought on by globalization, armed conflict, and environmental factors. In this article, we have extensively covered the virology, etiology, and epidemiology of the disease. Various gene studies, recent drugs studied, and clinical trials pertaining to mpox have been incorporated in this review. Additionally, we have compiled a comprehensive analysis of various systematic reviews and meta-analyses concerning pregnancies complicated by mpox, retrospective studies examining mpox and HIV-coinfection, mpox in conjuction with SARS-CoV-2, and HIV coinfection, as well as case studies exploring the implications of mpox manifestations in conjunction with syphilis, gonorrhoea, myocarditis, and neuroinflammatory implications.

Non-dairy prebiotics: Conceptual relevance with nutrigenomics and mechanistic understanding of the effects on human health.

The increasing health awareness of consumers has made a shift towards vegan and non-dairy prebiotics counterparts. Non-dairy prebiotics when fortified with vegan products have interesting properties and widely found its applications in food industry. The chief vegan products that have prebiotics added include water-soluble plant-based extracts (fermented beverages, frozen desserts), cereals (bread, cookies), and fruits (juices & jelly, ready to eat fruits). The main prebiotic components utilized are inulin, oligofructose, polydextrose, fructooligosaccharides, and xylooligosaccharides. Prebiotics' formulations, type and food matrix affect food products, host health, and technological attributes. Prebiotics from non-dairy sources have a variety of physiological effects that help to prevent and treat chronic metabolic diseases. This review focuses on mechanistic insight on non-dairy prebiotics affecting human health, how nutrigenomics is related to prebiotics development, and role of gene-microbes' interactions. The review will provide industries and researchers with important information about prebiotics, mechanism of non-dairy prebiotics and microbe interaction as well as prebiotic based vegan products.

Biochemical Characterization of γ-Glutamyl Transpeptidase from Bacillus altitudinis IHB B1644 and Its Application in the Synthesis of l-Theanine.

An extracellular γ-glutamyl transpeptidase (GGT) produced from Bacillus altitudinis IHB B1644 was purified to homogeneity employing ion-exchange chromatography. GGT comprised two subunits of 40 and 22 kDa determined by SDS-PAGE. The maximum enzyme activity was optimal at pH 9 and 37 °C. The purified enzyme was stable from pH 5-10 and <50 °C. Steady-state kinetic studies revealed a Km value of 0.538 mM against γ-GpNA. For substrate specificity, GGT showed highest affinity for l-methionine. The inhibitors' effect demonstrated that serine or threonine and tryptophan residues are essential for enzyme activity. l-Theanine production was optimized by employing a one-variable-at-a-time approach with 60-65% conversion rate. The final reaction consisted of 20 mM l-glutamine, 200 mM ethylamine hydrochloride, and 10 U mL-1 enzyme concentration at 37 °C in Tris-Cl (50 mM, pH 9) for 5 h. l-Theanine was purified using a Dowex 50W X 8 hydrogen form resin and confirmed by HPLC and 1H NMR spectroscopies.

Genomic regulation of Krüppel-like-factor family members by corticosteroid receptors in the rat brain.

Hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) mediate glucocorticoid hormone (GC) action in the hippocampus. These receptors bind to glucocorticoid responsive elements (GREs) within target genes, eliciting transcriptional effects in response to stress and circadian variation. Until recently, little was known about the genome-wide targets of hippocampal MRs and GRs under physiological conditions. Following on from our genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus, we investigated the Krüppel-like factors (KLFs) as targets of MRs and GRs throughout the brain under circadian variation and after acute stress. In particular, Klf2, Klf9 and Klf15 are known to be stress and/or GC responsive and play a role in neurobiological processes including synaptic plasticity and neuronal differentiation. We found increased binding of MR and GR to GREs within Klf2, Klf9 and Klf15 in the hippocampus, amygdala, prefrontal cortex, and neocortex after acute stress and resulting from circadian variation, which was accompanied by upregulation of corresponding hnRNA and mRNA levels. Adrenalectomy abolished transcriptional upregulation of specific Klf genes. These results show that MRs and GRs regulate Klf gene expression throughout the brain following exposure to acute stress or in response to circadian variation, likely alongside other transcription factors.

Targeted UHPLC-QTOF-IMS based metabolite profiling for bioactive compounds in Rosa webbiana wallich ex royle: An unexploited native from western himalayas.

The current study focused on the tissues of wild Rosa webbiana from different altitudes of Indian Western Himalayas for vitamin C content, total phenolics, flavonoids, total sugars, and antioxidant potential. To date, there are very few studies on underutilized tissues viz. fruits, leaves and stem of Rosa webbiana growing in the higher altitudes. The targeted UHPLC-QTOF-IMS illustrated the phenolics fingerprinting of tissue extracts. Twelve bioactive compounds were detected with quercetin, kaempferol, and their derivatives dominantly in stem and leaves. The results have revealed that fruits possessed the highest vitamin C, and sugar contents (960, and 191.6 mg/100 g, respectively). Compared to other tissues, leaves showed the highest total phenolics as well as best results in vitro assays employed to assess antioxidant potential. The antioxidant activity showed a positive correlation with total phenolics. A significant variation in total phenolics, total flavonoids, and antioxidant potential was mainly attributed to oxidative stress on plants due to altitude difference, and secondary metabolite production. Taken together, the underutilized tissues of Rosa webbiana could be exploited as a promising, low-cost resource of phenolic compounds in food, cosmetic, and pharmaceutical industries. Our study will pave the way to developing food products from Rosa webbiana, a natural source for health-conscious people.

Nutrient-Mediated Perception and Signalling in Human Metabolism: A Perspective of Nutrigenomics.

The interaction between selective nutrients and linked genes involving a specific organ reveals the genetic make-up of an individual in response to a particular nutrient. The interaction of genes with food opens opportunities for the addition of bioactive compounds for specific populations comprising identical genotypes. The slight difference in the genetic blueprints of humans is advantageous in determining the effect of nutrients and their metabolism in the body. The basic knowledge of emerging nutrigenomics and nutrigenetics can be applied to optimize health, prevention, and treatment of diseases. In addition, nutrient-mediated pathways detecting the cellular concentration of nutrients such as sugars, amino acids, lipids, and metabolites are integrated and coordinated at the organismal level via hormone signals. This review deals with the interaction of nutrients with various aspects of nutrigenetics and nutrigenomics along with pathways involved in nutrient sensing and regulation, which can provide a detailed understanding of this new leading edge in nutrition research and its potential application to dietetic practice.

Sesquiterpenoid lactones as potential anti-cancer agents: an update on molecular mechanisms and recent studies.

Plants-based natural compounds are well-identified and recognized chemoprotective agents that can be used for primary and secondary cancer prevention, as they have proven efficacy and fewer side effects. In today's scenario, when cancer cases rapidly increase in developed and developing countries, the anti-cancerous plant-based compounds become highly imperative. Among others, the Asteraceae (Compositae) family's plants are rich in sesquiterpenoid lactones, a subclass of terpenoids with wide structural diversity, and offer unique anti-cancerous effects. These plants are utilized in folk medicine against numerous diseases worldwide. However, these plants are now a part of the modern medical system, with their sesquiterpenoid lactones researched extensively to find more effective and efficient cancer drug regimens. Given the evolving importance of sesquiterpenoid lactones for cancer research, this review comprehensively covers different domains in a spectrum of sesquiterpenoid lactones viz (i) Guaianolides (ii) Pseudoguaianolide (iii) Eudesmanolide (iv) Melampodinin A and (v) Germacrene, from important plants such as Cynara scolymus (globe artichoke), Arnica montana (wolf weeds), Spilanthes acmella, Taraxacum officinale, Melampodium, Solidago spp. The review, therefore, envisages being a helpful resource for the growth of plant-based anti-cancerous drug development.

Recent updates on anticancer mechanisms of polyphenols.

In today's scenario, when cancer cases are increasing rapidly, anticancer herbal compounds become imperative. Studies on the molecular mechanisms of action of polyphenols published in specialized databases such as Web of Science, Pubmed/Medline, Google Scholar, and Science Direct were used as sources of information for this review. Natural polyphenols provide established efficacy against chemically induced tumor growth with fewer side effects. They can sensitize cells to various therapies and increase the effectiveness of biotherapy. Further pharmacological translational research and clinical trials are needed to evaluate theirs in vivo efficacy, possible side effects and toxicity. Polyphenols can be used to design a potential treatment in conjunction with existing cancer drug regimens such as chemotherapy and radiotherapy.

Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine.

Cancer, one of the leading illnesses, accounts for about 10 million deaths worldwide. The treatment of cancer includes surgery, chemotherapy, radiation therapy, and drug therapy, along with others, which not only put a tremendous economic effect on patients but also develop drug resistance in patients with time. A significant number of cancer cases can be prevented/treated by implementing evidence-based preventive strategies. Plant-based drugs have evolved as promising preventive chemo options both in developing and developed nations. The secondary plant metabolites such as alkaloids have proven efficacy and acceptability for cancer treatment. Apropos, this review deals with a spectrum of promising alkaloids such as colchicine, vinblastine, vincristine, vindesine, vinorelbine, and vincamine within different domains of comprehensive information on these molecules such as their medical applications (contemporary/traditional), mechanism of antitumor action, and potential scale-up biotechnological studies on an in-vitro scale. The comprehensive information provided in the review will be a valuable resource to develop an effective, affordable, and cost effective cancer management program using these alkaloids.

From source to sink: mechanistic insight of photoassimilates synthesis and partitioning under high temperature and elevated [CO2].

Photosynthesis is the vital metabolism of the plant affected by abiotic stress such as high temperature and elevated [CO2] levels, which ultimately affect the source-sink relationship. Triose phosphate, the primary precursor of carbohydrate (starch and sucrose) synthesis in the plant, depends on environmental cues. The synthesis of starch in the chloroplasts of leaves (during the day), the transport of photoassimilates (sucrose) from source to sink, the loading and unloading of photoassimilates, and the accumulation of starch in the sink tissue all require a highly regulated network and communication system within the plant. These processes might be affected by high-temperature stress and elevated [CO2] conditions. Generally, elevated [CO2] levels enhance plant growth, photosynthetic rate, starch synthesis, and accumulation, ultimately diluting the nutrient of sink tissues. On the contrary, high-temperature stress is detrimental to plant development affecting photosynthesis, starch synthesis, sucrose synthesis and transport, and photoassimilate accumulation in sink tissues. Moreover, these environmental conditions also negatively impact the quality attributes such as grain/tuber quality, cooking quality, nutritional status in the edible parts and organoleptic traits. In this review, we have attempted to provide an insight into the source-sink relationship and the sugar metabolites synthesized and utilized by the plant under elevated [CO2] and high-temperature stress. This review will help future researchers comprehend the source-sink process for crop growth under changing climate scenarios.

Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors.

Glucocorticoid hormones (GCs) - acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) - are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.

Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma.

Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

Unfolding Nrf2 in diabetes mellitus.

In spite of much awareness, diabetes mellitus continues to remain one of major reasons for mortality and morbidity rate all over the globe. Free radicals cause oxidative stress which is responsible for causing diabetes. The recent advancements in elucidation of ARE/keap1/Nrf2 pathway can help in better understanding of diabetes mellitus. Various clinical trials and animal studies have shown the promising effect of Nrf2 pathway in reversing diabetes by counteracting with the oxidative stress produced. The gene is known to dissociate from Keap1 on coming in contact with such stresses to show preventive and prognosis effect. The Nrf2 gene has been marked as a molecular player in dealing with wide intracellular as well as extracellular cellular interactions in different diseases. The regulation of this gene gives some transcription factor that contain antioxidant response elements (ARE) in their promoter region and thus are responsible for encoding certain proteins involved in regulation of metabolic and detoxifying enzymes.

Expatiating the molecular approaches of HMGB1 in diabetes mellitus: Highlighting signalling pathways via RAGE and TLRs.

Diabetes mellitus (DM) has become one of the major healthcare challenges worldwide in the recent times and inflammation being one of its key pathogenic process/mechanism affect several body parts including the peripheral and central nervous system. High-mobility group box 1 (HMGB1) is one of the major non-histone proteins that plays a key role in triggering the inflammatory response. Upon its release into the extracellular milieu, HMGB1 acts as an "alarmin" for the immune system to initiate tissue repair as a component of the host defense system. Furthermore, HMGB1 along with its downstream receptors like Toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE) serve as the suitable target for DM. The forthcoming research in the field of diabetes would potentially focus on the development of alternative approaches to target the centre of inflammation that is primarily mediated by HMGB1 to improve diabetic-related complications. This review covers the therapeutic actions of HMGB1 protein, which acts by activating the RAGE and TLR molecules to constitute a functional tripod system, in turn activating NF-κB pathway that contributes to the production of mediators for pro-inflammatory cytokines associated with DM. The interaction between TLR2 and TLR4 with ligands present in the host and the activation of RAGE stimulates various immune and metabolic responses that contribute to diabetes. This review emphasizes to elucidate the role of HMGB1 in the initiation and progression of DM and control over the inflammatory tripod as a promising therapeutic approach in the management of DM.

Exploring the Various Aspects of Brain-Derived Neurotropic Factor (BDNF) in Diabetes Mellitus.

Brain-Derived Neurotrophic Factor (BDNF) serves as a modulator for neurotransmitters by participating in neuronal plasticity, essential for their growth and neuronal survival. It also shows a wide range of expression patterns in the systemic and peripheral tissues; thereby, its biological actions are not just limited to the CNS but may a vital role in peripheral disorders, such as Diabetes Mellitus (DM). Platelets serve as one of the major sources of BDNF, which regulates energy homeostasis and glucose metabolism by participating in the expression of specific pro-survival genes. It also prevents ß cell exhaustion, thus may prove to be a key factor for the management of DM. The current article reviews the intricate role of BDNF in Type 2 DM (T2DM) by involving platelet reactivity and its association with these selected inflammatory platelet activator mediators. Besides, certain adipocytokines, such as adiponectin and leptin, are also involved in the metabolism of glucose during diabetes, which has been clearly proven by recent experimental studies and thus relating BDNF with adipocytokines. It is also involved in the modulation of secretion of various neurotransmitters, peptides and hormones like gherin, leptin and insulin, suggesting its association with T2DM. Thus, based on various evidence, BDNF can be categorised as a potential biomarker in predicting the development of T2DM and may have a distinctive role in the management of this disorder.

Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI.

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.