Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid ...compounds such as fatty acids and their derivatives, release lipolysis products that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake, whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of thioredoxin-interacting protein (TXNIP) degradation. This, in turn, selectively induces glucose transporter 1 surface localization and glucose uptake in 3T3-L1 adipocytes and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL) and not hormone-sensitive lipase or monoacylglycerol lipase. Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion, and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.
Influenza kills 30,000 to 40,000 people each year in the United States and causes 10 times as many hospitalizations. A common complication of influenza is bacterial superinfection, which exacerbates ...morbidity and mortality from the viral illness. Recently, methicillin-resistant
(MRSA) has emerged as the dominant pathogen found in bacterial superinfection, with
a close second. However, clinicians have few tools to treat bacterial superinfection. Current therapy for influenza/bacterial superinfection consists of treating the underlying influenza infection and adding various antibiotics, which are increasingly rendered ineffective by rising bacterial multidrug resistance. Several groups have recently proposed the use of the antiviral cytokine interferon lambda (IFN-λ) as a therapeutic for influenza, as administration of pegylated IFN-λ improves lung function and survival during influenza by reducing the overabundance of neutrophils in the lung. However, our data suggest that therapeutic IFN-λ impairs bacterial clearance during influenza superinfection. Specifically, mice treated with an adenoviral vector to overexpress IFN-λ during influenza infection exhibited increased bacterial burdens upon superinfection with either MRSA or
Surprisingly, adhesion molecule expression, antimicrobial peptide production, and reactive oxygen species activity were not altered by IFN-λ treatment. However, neutrophil uptake of MRSA and
was significantly reduced upon IFN-λ treatment during influenza superinfection
Together, these data support the theory that IFN-λ decreases neutrophil motility and function in the influenza-infected lung, which increases the bacterial burden during superinfection. Thus, we believe that caution should be exercised in the possible future use of IFN-λ as therapy for influenza.
Induction of labour (IOL) is one of the most commonly performed interventions in maternity care, with outpatient cervical ripening increasingly offered as an option for women undergoing IOL. The ...COVID-19 pandemic has changed the context of practice and the option of returning home for cervical ripening may now assume greater significance. This work aimed to examine whether and how the COVID-19 pandemic has changed practice around IOL in the UK.
We used an online questionnaire to survey senior obstetricians and midwives at all 156 UK NHS Trusts and Boards that currently offer maternity services. Responses were analysed to produce descriptive statistics, with free text responses analysed using a conventional content analysis approach.
Responses were received from 92 of 156 UK Trusts and Boards, a 59% response rate. Many Trusts and Boards reported no change to their IOL practice, however 23% reported change in methods used for cervical ripening; 28% a change in criteria for home cervical ripening; 28% stated that more women were returning home during cervical ripening; and 24% noted changes to women's response to recommendations for IOL. Much of the change was reported as happening in response to attempts to minimise hospital attendance and restrictions on birth partners accompanying women.
The pandemic has changed practice around induction of labour, although this varied significantly between NHS Trusts and Boards. There is a lack of formal evidence to support decision-making around outpatient cervical ripening: the basis on which changes were implemented and what evidence was used to inform decisions is not clear.
Type III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that ...IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown.
Using an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection.
Surprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not.
These data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Huntington's disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, characterised not only by progressive cognitive, motor and psychiatric impairments, but also of ...peripheral pathology. In both human HD and in mouse models of HD there is evidence of increased energy expenditure and weight loss, alongside altered body composition. Unlike white adipose tissue (WAT), brown adipose tissue (BAT), as well as brown-like cells within WAT, expresses the mitochondrial protein, uncoupling protein 1 (UCP1). UCP1 enables dissociation of cellular respiration from ATP utilization, resulting in the release of stored energy as heat. Hyperplasia of brown/beige cells in WAT has been suggested to enhance energy expenditure. In this study, we therefore investigated the gene expression profile, histological appearance, response to cold challenge and functional aspects of WAT in the R6/2 HD mouse model and selected WAT gene expression in the full-length Q175 mouse model of HD. WAT from R6/2 mice contained significantly more brown-like adipocyte regions and had a gene profile suggestive of the presence of brown-like adipocytes, such as higher Ucp1 expression. Cold exposure induced Ucp1 expression in R6/2 inguinal WAT to a markedly higher degree as compared to the thermogenic response in WT WAT. Alongside this, gene expression of transcription factors (Zfp516 and Pparα), important inducers of WAT browning, were increased in R6/2 inguinal WAT, and Creb1 was highlighted as a key transcription factor in HD. In addition to increased WAT Ucp1 expression, a trend towards increased mitochondrial oxygen consumption due to enhanced uncoupling activity was found in inguinal R6/2 WAT. Key gene expressional changes (increased expression of (Zfp516 and Pparα)) were replicated in inguinal WAT obtained from Q175 mice. In summary, for the first time, we here show that HD mouse WAT undergoes a process of browning, resulting in molecular and functional alterations that may contribute to the weight loss and altered metabolism observed with disease progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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