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b-type procyanidin-rich foods consumed in right amounts have multiple health benefits

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B-type procyanidins, made of catechin oligomers, are a class of polyphenols found abundantly in foods like cocoa, apples, grape seeds, and red wine. Several studies have established the benefits of these micronutrients in reducing the risk of cardiovascular diseases and strokes. B-type procyanidins are also successful in controlling hypertension, dyslipidemia, and glucose intolerance. Studies attest to the physiological benefits of their intake on the central nervous system (CNS), namely an improvement in cognitive functions. These physiological changes follow a pattern of hormesis—a phenomenon in which peak benefits of a substance are achieved at mid-range doses, becoming progressively lesser at lower and higher doses.

The dose-response relationship of most bioactive compounds follows a monotonic pattern, in which a higher dose shows a greater response. However, in some exceptional cases, a U-shaped dose-response curve is seen. This U-shaped curve signifies hormesis—an adaptive response, in which a low dose of usually a harmful compound induces resistance in the body to its higher doses. This means that exposure to low levels of a harmful trigger can induce the activation of stress-resistant pathways, leading to greater repair and regeneration capabilities. In case of B-type procyanidins, several in vitro studies support their hormetic effects, but these results have not been demonstrated in vivo.

To address this knowledge gap, researchers from Shibaura Institute of Technology (SIT), Japan, led by Professor Naomi Osakabe from the Department of Bioscience and Engineering, reviewed the data from intervention trials supporting hormetic responses of B-type procyanidin ingestion. The team, comprising Taiki Fushimi and Yasuyuki Fujii from the Graduate School of Engineering and Science (SIT), also conducted in vivo experiments to understand possible connections between B-type procyanidin hormetic responses and CNS neurotransmitter receptor activation. Their article was made available online on June 15, 2022 and has been published in volume 9 of Frontiers of Nutrition on September 7, 2022.

B-type procyanidins

Researchers from SIT, Japan investigated the dose-response effects of B-type procyanidins on the hormetic response system./CREDIT:Reprinted with permission from, Osakabe N, Fushimi T and Fujii Y (2022) Hormetic response to B-type procyanidin ingestion involves stress-related neuromodulation via the gut-brain axis: Preclinical and clinical observations. Front. Nutr. 9:969823. doi: 10.3389/fnut.2022.969823. Copyright © 2022 Osakabe, Fushimi and Fujii.

The researchers noted that a single oral administration of an optimal dose of cocoa flavanol temporarily increased the blood pressure and heart rate in rats. But the hemodynamics did not change when the dose was increased or decreased. Administration of B-type procyanidin monomer and various oligomers produced similar results. According to Professor Osakabe, “These results are consistent with those of intervention studies following a single intake of food rich in B-type procyanidin, and support the U-shaped dose-response theory, or hormesis, of polyphenols.”

To observe whether the sympathetic nervous system (SNS) is involved in the hemodynamic changes induced by B-type procyanidins, the team administered adrenaline blockers in test rats. This successfully decreased the temporary increase in heart rate induced by the optimal dose of cocoa flavanol. A different kind of blocker—a1 blocker—inhibited the transient rise in blood pressure. This suggested that the SNS, which controls the action of adrenaline blockers, is responsible for the hemodynamic and metabolic changes induced by a single oral dose of B-type procyanidin.

The researchers next ascertained why optimal doses, and not high doses, are responsible for the thermogenic and metabolic responses. They co-administered a high dose of cocoa flavanol and yohimbine (an α2 blocker) and noted a temporary but distinct increase in blood pressure in test animals. Similar observations were made with the use of B-type procyanidin oligomer and yohimbine. Professor Osakabe surmises, “Since α2 blockers are associated with the down-regulation of the SNS, the reduced metabolic and thermogenic outputs at a high dose of B-type procyanidins seen in our study may have induced α2 auto-receptor activation. Thus, SNS deactivation may be induced by a high dose of B-type procyanidins.”

Previous studies have proven the role of the gut-brain axis in controlling hormetic stress-related responses. The activation of the hypothalamus-pituitary-adrenal (HPA) axis by optimal stress has a strong influence on memory, cognition, and stress tolerance. This article highlights how HPA activation occurs after a single dose of B-type procyanidin, suggesting that stimulation with an oral dose of B-type procyanidin might be a stressor for mammals and cause SNS activation.

Hormesis and its triggering biochemical pathways deliver protection against various pathological and aging processes, enhancing our general health and making us resilient to future stress. Though the exact relation between B-type procyanidins and the CNS needs more research, the health benefits of B-type procyanidin-rich foods remains undisputed.

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Scientists sequence world’s largest pangenome to help unlock genetic mysteries behind finer silk

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BGI Genomics, in collaboration with Southwest University, the State Key Laboratory of Silkworm Genome Biology, and other partners, has constructed a high-resolution pangenome dataset representing almost the entire genomic content in a silkworm.

Previously, due to the scarcity of wild silkworms and technical limitations of former studies, many trait-associated sites were missing. This is the first research ever to digitize silkworm gene pool and create a “digital silkworm”, greatly facilitating functional genomic research, promoting precise breeding, and thus enabling additional silk use cases.

The team deeply re-sequence 1,078 silkworms (B. mori, including 205 local strains, 194 improved varieties, and 632 genetic stocks and 47 wild silkworms, B. mandarina) and assemble long-read genomes on 545 of these samples, generating 55.57 T of genomic data.

This pangenome dataset contains the most comprehensive information on the genomes of domestic and wild silkworm, and is the largest long-read pangenome in the world for plants and animals to date. At the same time, in-depth studies on various genetic variation, population structure, artificial selection and ecological adaptations and economic traits of silkworm have been carried out, yielding fruitful results.

Phenotypic diversity in silkworms/CREDIT:BGI Genomics

The origins of the domestic silkworm:

The domestic silkworm, B. mori, domesticated from the wild mulberry silkworm, B. mandarina. It has an history of over 5,000 years, but its domestication origin location has long been an open question, due to a lack of strong biological evidence.

The study found out that endemic species from China’s lower and middle Yellow River region are distributed at the base of the domestic silkworm branch on the evolutionary tree, thus suggesting that the domestic silkworm originated in this region. The available archaeological evidence, including a half cocoon excavated in 1926 at Xiyin Village, Xia County, Shanxi Province, and a stone-carved silkworm pupa excavated in 2019 at Shicun in the same county, provide important support to this conclusion.

Breaking the bottleneck in silkworm breeding:

The traditional breeding of silkworms has a long and unique history, but since the 1990s remained stuck in a bottleneck. Systematic analysis of the genetic basis of domestication and improvement selection is essential to solve the unresolved issues in silkworm breeding. The team has identified 468 domestication-associated genes and 198 improvement-associated genes, of which respectively 264 and 185 are newly identified. These genes will be important candidate targets for molecular improvement of silkworm.

At the same time, it was found out that the Chinese and Japanese utility species share less than 3% of the improvement loci. This not only reveals the relatively independent breeding histories of Chinese and Japanese silkworm, but also explains why this shared genetic basis provides such hybrid advantages for both species. This result sheds new insights for future breeding of the silkworm.

Economic traits of silkworm breeding:

Yield and quality of silk have long been targeted as the main economic criteria for artificial selection of silkworm. However, up to this date, little is known about how genes and loci control these quantitative traits. The pangenome is arguably the ‘nearest bridge’ between phenotypes, especially complex traits.

A case in point is the regulation of silk production by the cell cycle-related transcription factor BmE2F1, which was revealed through selection signalling and structural variation. CRISPR-cas9 mediated knockout of BmE2F1 reduces the number of silk gland cells by 7.68% and silk yield by 22%. Conversely, the transgenic overexpression of BmE2F1 increases the number of silk gland cells by 23% and silk yield by 16%.

Fine silk has unique applications and higher economic value, but the genetic basis of fiber fineness remained previously unknown. Analysis of rare variants in the genomes of slender varieties led to the identification of BmChit β-GlcNAcase, a gene controlling silk fineness that can significantly be detected in fine varieties, and CRISPR-cas9 mediated knockout, resulting in coarser silk fineness produced by domestic silkworms. This suggests this gene plays a key role in determining silk fineness.

Adaptive traits of silkworm breeding:

Diapause is a common ecological adaptive trait in insects that ensures that insects can survive despite unfavorable environmental conditions. Although the diapause hormone was first identified in the silkworm in 1957, little information is available on the embryonic dipause gene. In this study, based on the analysis of the pnd strain and genomic structural variation in the silkworm, and functional validation by gene editing, the BmTret1-like gene revealed itself to be an important determinant of post-embryonic stalling. This is the first time that a post-embryonic determinant gene has been identified in an insect.

This study reveals the complete pan-genome of the silkworm to unlock artificial selection and ecological adaptation insights. Shuaishuai Tai, co-author and BGI Genomics senior researcher commented, “With comprehensive sampling and dataset combined with a variety of experiments to identify genes for future potential study, we hope to accelerate the process of silkworm molecular design breeding.”

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Some cancer immunotherapy treatments may damage fertility, women’s hormonal health

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Researchers have discovered that some immunotherapy treatments used to treat cancer can cause fertility damage.

It means these treatments could affect the future fertility and hormonal health of female cancer survivors, prompting experts to call for more research and preventative measures, such as freezing eggs.

Led by the Biomedicine Discovery Institute at Monash University and the Peter MacCallum Cancer Centre, the pre-clinical trial showed that immune checkpoint inhibitors, a common type of immunotherapy drug, resulted in permanent damage to mouse ovaries and the eggs stored inside.

cancer/photo:en.wikipedia.org

Traditional cancer therapies, such as chemotherapy and radiotherapy, are already linked to permanent, negative side effects on the ovaries. This can lead to infertility and premature menopause in young girls and women.

Researchers found that checkpoint inhibitor immunotherapy reduced the number and quality of their eggs, interfered with ovulation, and disrupted the fertility cycle.

Until now the potential fertility side effects of immunotherapy, an emerging and increasingly common cancer treatment that stimulates the immune system, have been unknown.

The study found that a type of immunotherapy called immune checkpoint inhibitors, which ‘release the brakes’ on the immune system to enhance a patient’s ability to fight cancer, could impair immediate and future fertility.

Its authors said studies in female patients were now needed to investigate the findings. In the meantime, fertility preservation through egg or embryo freezing should be considered for women using these immunotherapies.

“Initially these treatments were thought to be less damaging (than chemo and radiotherapy) in the context of off-target effects to the body in general,” Ms Alesi said. “However, it is now clear that inflammatory side effects in other organ systems are quite common with these drugs.

“Our study highlights that caution should be exercised by clinicians and their patients, for whom fertility may be a concern. Studies in women receiving these drugs must now be prioritised.”

Peter MacCallum Cancer Centre Specialist Medical Oncologist Professor in breast cancer and a senior author on the study Sherene Loi said further research into how these drugs impact the ovarian function and fertility of women receiving these drugs must be prioritised and should be included in future clinical trials involving women of reproductive age.

“Our study further highlights that fertility discussions are critical for all age appropriate women who are recommended to receive chemotherapy as well as immunotherapy,” Professor Loi said.

“Appropriate interventions that can preserve fertility and ovarian function can be implemented to facilitate pregnancies in the future, post completion of treatment. These interventions need to be implemented in a timely manner, so as not to delay anti-cancer treatment.

“Immunotherapy is now becoming a standard of care for many women with curable early stage breast cancer, due to impressive results in reducing breast cancer recurrences, but further research into the long-term effects of immunotherapy is needed.”

Apart from drugs that block ovaries from producing hormones during chemotherapy, and strategies to prevent premature menopause in younger women, Ms Alesi said egg and embryo freezing was the only fertility preservation measure available.

She said it was important to remember that embryo freezing was expensive, invasive and did not prevent ovarian damage. This meant that premature menopause could still be a risk for these women.

“Therefore, we are now prioritising investigation of targeted ovarian preservation strategies that aim to prevent the damage to the ovary from occurring in the first place, without interfering with the drugs’ ability to fight the cancer” she said.